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Ann Thorac Surg 2001;72:1465-1472
© 2001 The Society of Thoracic Surgeons
a Division of Cardiovascular Surgery, The Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada
b Division of Plastic Surgery, Montreal General Hospital, McGill University Health Center, Montreal, Quebec, Canada
c Division of Cardiology, Montreal General Hospital, McGill University Health Center, Montreal, Quebec, Canada
d Division of Anesthesia, Montreal General Hospital, McGill University Health Center, Montreal, Quebec, Canada
* Address reprint requests to Dr Shum-Tim, Cardiovascular Surgery, Montreal Children’s Hospital, 2300 Tupper St, Room C-829, Montreal, Quebec, Canada H3H 1P3
e-mail: dominique.shum-tim{at}muhc.mcgill.ca
Presented at the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.
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Abstract |
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Methods. Four-week-old piglets randomly placed into two groups (n = 5 per group) were given methylprednisolone (30 mg/kg) into the pump prime (group PP), or pretreated intravenously 4 hours before CPB (group PT). All animals underwent 100 minutes of DHCA (15°C), were weaned off CPB, and were sacrificed 6 hours later. Postoperative changes in body weight, bioimpedance, and colloid oncotic pressure (COP) were measured. Cerebral trypan blue content, immunohistochemical evaluation of transforming growth factor-ß1 (TGF-ß1) expression, and caspase-3 activity were performed.
Results. Percentage weight gain (group PP 25.0% ± 10.4% versus group PT 12.5% ± 4.0%; p = 0.036), and percentage decrease in bioimpedance (PP 37.2% ± 14.5% versus PT 15.6% ± 7.9%; p = 0.019) were significantly lower, whereas postoperative COP was significantly higher in group PT versus group PP (PT 15.3 ± 1.8 mm Hg versus PP 11.6 ± 0.8 mm Hg; p = 0.003). Cerebral trypan blue (ng/g dry tissue) was significantly lower in group PT (PT 5.6 x 10-3 ± 1.1 x 10-3 versus PP 9.1 x 10-3 ± 5.7 x 10-4; p = 0.001). Increased TGF-ß1 expression and decreased caspase-3 activity were shown in group PT.
Conclusions. Systemic steroid pretreatment significantly reduced total body edema and cerebral vascular leak and was associated with better immunohistochemical indices of neuroprotection after DHCA.
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Material and methods |
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All surgical procedures were carried out under sterile conditions. A superficial branch of the left femoral artery was first cannulated with an indwelling catheter for continuous arterial blood pressure monitoring. Central venous pressure (CVP) in the right atrium (RA) was also recorded. After systemic anticoagulation with heparin (300 IU/kg), an 8-Fr arterial cannula (Medtronic; Bio-Medicus, Minneapolis, MN) was inserted into the right femoral artery followed by a 24-Fr venous cannulation (Stöckert Instrumente Gmbh, Lilienthalalle, Germany) of the RA appendage exposed through a right anterolateral thoracotomy. Once CPB was initiated, all animals were cooled to 15°C over 30 minutes, followed by 100 minutes of DHCA, then weaned off CPB after 40 minutes of reperfusion. Intravenous protamine (5 mg/kg) was given to reverse the heparin effect. Decannulation and closure of all incisions completed the operative procedure.
The experimental protocol was approved by McGill Animal Care Committee (No. 4064). All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (National Institutes of Health publication No. 85-23, revised 1985).
Extracorporeal circuit preparation
The CPB circuit consisted of a roller pump (Stöckert Instrumente, Munich, Germany), sterile tubing, and a membrane oxygenator (Lilliput1; Dideco, Mirandola, Italy). Fresh heparinized whole blood obtained from a donor animal harvested on the same day of experiment was used to prepare the pump prime solution. Crystalloid solution was titrated to achieve a priming hematocrit (Hct) of 25% in all groups. Cefazolin sodium (25 mg/kg), furosemide (0.25 mg/kg), and sodium bicarbonate (10 mEq) were standard additions to the prime. After baseline recording was obtained and instrumentation completed, full CPB support was established at a flow rate of 100 mL · kg-1 · min-1 using the pH-stat strategy.
Before reperfusion, furosemide (0.2 mg/kg), mannitol (0.5 mg/kg), and sodium bicarbonate (10 mEq) were added to the pump. Each animal was rewarmed at similar flow rates for more than 40 minutes to achieve a rectal temperature of 35°C before weaning off CPB. The heart was defibrillated as necessary at 25°C. The Hct was maintained between 27% and 28% by blood transfusion or crystalloid infusion upon weaning off CPB. Mechanical ventilation with FiO2 of 1.0 was reestablished 10 minutes before CPB was discontinued. When hemodynamic stability was achieved, protamine was given, followed by decannulation and skin closure.
Experimental groups
Ten piglets (n = 5 per group) were randomly assigned to two groups. In group PP, methylprednisolone sodium succinate (30 mg/kg; Upjohn Company of Canada, Don Mills, Ontario) was administered into the CPB prime. In group PT, a similar dose of intravenous steroid (30 mg/kg) was given 4 hours before CPB. No additional steroid was given in the prime otherwise.
Postoperative management
All animals were monitored hemodynamically with an arterial line and CVP, with the core temperature maintained at normothermia using a warming blanket and a heating lamp, while they remained fully sedated, paralyzed, and mechanically ventilated. Crystalloid infusion was administrated to maintain CVP and Hct at about preoperative levels. Dopamine was titrated between 5 to 10 µg · kg-1 · min-1 as required. Periodic blood gas and Hct levels were evaluated hourly for the first 3 hours and at 6 hours and corrected accordingly. Postoperative Hct was kept between 27% and 28% by crystalloid infusion or blood transfusion as indicated. Random blood sugar levels were assessed before and after surgery. Continuous monitoring and data collection were carried out until elective termination of the experiment at 6 hours after weaning off CPB.
Data collection
Baseline body weight (BW) was recorded immediately after the induction of anesthesia and endotracheal intubation. Subsequent weight measurement was repeated at 6 hours postoperatively before termination of the experiment. Postoperative weight was expressed as percent increase from baseline and was calculated as follows: 
To obtain the bioelectrical impedance index (BEI), the baseline resistance and reactance were measured by a bioimpedance analyzer (BIA-101Q; RJL Systems, Inc, Clinton Township, MI) using two pairs of signal and detecting electrodes attached to the upper and lower extremities after intubation. Measurements were repeated upon weaning off CPB and at 6 hours postoperatively. The BEI was then derived from the following equation: 
. The total body water content (TBWC) has a reciprocal relationship with the BEI (TBWC 
height2/BEI). Higher TBWC is associated with lower BEI because of the higher conductivity of water in the biologic system [4]. BEI expressed as percent decrease from baseline was calculated as follows: 
.
To measure colloid oncotic pressure (COP), blood samples were obtained at baseline, immediately after weaning off CPB, and at 6 hours postoperatively. The blood COP was measured by a membrane colloid osmometer (Wescor 4420, Wescor, Utah) calibrated with 5% albumin (19.3 ± 1.4 mm Hg) with a molecular weight cut off of 30,000.
Trypan blue analysis was performed to assess the cerebrovascular integrity and the extent of leakage at the blood brain barrier (BBB) after each experiment. Immediately upon elective termination of the experiment, all animals were euthanized. Each brain was perfused with 1 L saline, followed by 2% trypan blue infusion (approximately l mL/g of brain tissue). In situ brain fixation with 4 L of 4% paraformaldehyde was then carried out. After decapitation, the head was submerged in 10% formaldehyde solution for 7 days before the brain was removed from the skull and further preserved in formaldehyde. Three consistent areas of the frontal, temporal, and occipital cortices were sampled and submitted for spectrophotometric analysis [5]. The specimens were weighed and dried at 105°C for 24 hours, then reweighed and placed in Krebs-Ringer solution for another 24 hours. The samples were then homogenized in the Krebs-Ringer solution and mixed with 0.5 mL of 60% trichloro-acetic acid to precipitate protein. The samples were then cooled for 30 minutes, centrifuged, and the supernatants measured at 610 nm for absorbance of trypan blue using a spectrophotometer (BIO-RAD Microplate Reader model 3550, Baltimore, MD). Cerebral trypan blue content is expressed as ng/g of dry weight calculated against a standard curve. The evaluation was performed in a blinded fashion. The mean values of the examined areas were used for statistical analysis.
Immunohistochemical analysis of cerebral transforming growth factor-ß1 (TGF-ß1) was performed to evaluate the expression of this neuroprotective agent after different steroid administration protocol set in this study. Brain specimens were fixed in formaldehyde, serially dehydrated in ethanol, and embedded in paraffin. The samples were sectioned at 6 µm, floated onto slides, deparaffinized, rehydrated and endogenous peroxidase activity blocked by incubating with 3% H2O2 in 99% methanol. The sections were then permeabilized using phosphate-buffered saline (PBS pH 7.5) containing 0.1% Triton X-100. Nonspecific binding was blocked with PBS containing 10% normal goat serum, 0.3% Triton X-100, and 0.5% bovine serum albumin. Anti–TGF-ß1 antibody was then applied to the sections for 1 hour at room temperature. The slides were incubated with biotinylated goat antirabbit secondary antibody and stained with 3-amion-9-ethyl-carbazole. The slides were washed, counterstained with Mayer’s hematoxylin (Sigma, St. Louis, MO), and mounted. The anti–TGF-ß1 antibody has been shown to be specific by complete absorption of its immunoreactivity when incubated with TGF-ß1. Controls for the immunohistochemistry included experiments in which the primary antibody was omitted, and nonimmune IgG was substituted in place of primary antibody.
The apoptotic index of brain injury was assessed by immunohistochemical caspase-3 assay. Brain tissues from groups PP and PT were fixed in formaldehyde. The tissues were embedded in paraffin, cut into 6 µm thick slides, then processed for immunohistochemistry analysis. Caspase-3 fluorescent staining was carried out using a polyclonal antibody recognizing the active 17 kDa caspase-3 fragment (New England BioLabs, cat. #9661S). Digital images of the fluorescent staining were analyzed in a blinded fashion.
Statistical analysis
All results are expressed as absolute mean ± SD with the exception of BW and BEI, which are expressed as percent change from baseline ± SD. Data were analyzed by unpaired t test for continuous data between groups. A p value less than 0.05 is considered statistically significant.
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Changes in body weight
Baseline BW was comparable between the two groups (PP 6.9 ± 0.9 kg versus PT 7.1 ± 0.9 kg; p = not significant). Postoperative changes in body weight were expressed as percent increase from baseline ± SD. At 6 hours after discontinuation of CPB, the percent increase in BW was significantly higher in group PP (25.0% ± 10.4%) versus PT (12.5% ± 4.0%; p = 0.036).
Changes in BEI
There were no differences in BEI between groups before the operation (PP 164.5 ± 17.2 
versus PT 175.6 ± 14.9 ; p = NS). Subsequent changes in postoperative BEI are expressed as percent decrease from baseline ± SD. Immediately after coming off CPB, there was no significant difference in BEI between the two groups. However, at 6 hours postoperatively, the BEI in group PP was significantly decreased compared with group PT (PP 37.2% ± 14.5% versus PT 15.6% ± 7.9%; p = 0.019) suggesting a significant increase in TBWC in animals receiving steroids in pump prime.
Colloid oncotic pressure
The baseline COP values were similar between the two groups. Upon termination of CPB, the mean COP remained relatively unchanged with no significant difference between groups. At 6 hours postoperatively, the COP in group PP was significantly reduced compared with group PT (PP 11.6 ± 0.8 mm Hg versus PT 15.3 ± 1.8 mm Hg; p = 0.003; Fig 1).
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Comment |
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Steroids and cardiopulmonary bypass
The application of steroids in the early days of CPB was directed at reducing the negative hemodynamic effect of the extracorporeal circulation. Significant reduction of the vasoconstriction and low output state with subsequent improvement in peripheral perfusion has been reported using 30 mg/kg of methylprednisolone [7]. Although early studies have shown improvement in survival and outcome associated with the use of steroids, their mechanisms of action and biochemical benefits have only been recently documented [8]. It has been suggested that steroids may reduce the release of lipid mediators and the concentration of proinflammatory cytokines 1, 6, 8 and TNF-
while increasing the antiinflammatory interleukin 10 [8, 9].
This study has documented the beneficial effect of steroid pretreatment with respect to the systemic manifestation of capillary leak syndrome. In the steroid pretreatment group, there was a significantly better preservation of COP associated with less need for crystalloid infusion reflected by the changes in BW and BEI. In contrast, one extreme animal in group PP manifested a classic picture of severe capillary leak syndrome, with ascites, hypotension, increasing Hct, and low CVP despite fluid administration.
Steroids and brain injury
Steroid therapy has been applied in the setting of central nervous system injury. Its effectiveness has been a subject of controversy primarily because of undefined dosage, timing of administration, different mode of brain injury, and concern for side effects. However, Jane and coworkers [10] reported a significant improvement in severely injured patients who received an initial 15 to 30 mg/kg dose of methylprednisolone at the scene of the head-related accident. The mortality rate was strikingly reduced compared with that of a comparable group receiving no steroids.
In our setting of ischemia-reperfusion brain injury and inflammatory response to CPB, the trypan blue findings suggested significant disturbances in the neurovascular integrity of the BBB in the pump prime steroid group compared with steroid pretreatment. This increase in permeability of the BBB was translated into a higher index of apoptotic neuronal damage. All apoptotic caspases normally exist in cells as inactive enzymes. When cells undergo apoptosis, these caspases become activated through sequential proteolytic events that cleave the single peptide precursor into the active enzyme. Caspase-3 has been shown to play a central role in the regulation and execution of apoptosis [11]. In addition, there was a significantly better preservation of cerebral TGF-ß1 expression in steroid pretreated animals. Although TGF-ß1 is minimally expressed in intact adult brain, at a young age while organ development is very active, its expression is increased [12]. Increased TGF-ß1 expression has also been demonstrated after ischemic brain injury. This upregulation was thought to be a crucial response to injury since it possesses angiogenic and antiinflammatory properties that affect neurodegeneration, chemotaxis, and extracellular matrix remodeling. It also has a neuroprotective capacity to rescue cultured neurons from excitotoxic and hypoxic cell deaths, to reduce infarct size after cerebral ischemia [13]. The failure to activate otherwise normal amounts of TGF-ß1, on the other hand, is a negative prognostic factor.
Timing of steroid administration
Intuitively, it seems unlikely that a simple variation in the timing of steroids administration during CPB and DHCA can have different physiologic consequences. However, it is interesting to note that in the majority of reports demonstrating the benefit of steroids during extracorporeal circulation, the medication was administered directly into the patients before initiation of CPB [8, 14]. Although this detail has not been emphasized in their conclusions, more recent studies suggested that the timing of steroid administration played an important role. In a piglet model of DHCA, Lodge and associates [15] have shown that methylprednisolone pretreatment before surgery was associated with better pulmonary functions as compared with steroid in pump prime or no steroid groups. Similar findings were confirmed in clinical settings [8]. Our study incidentally revealed a strong tendency toward a decrease in arterial oxygen tension in group PP at 6 hours postoperatively. Steroid pretreatment has also been shown to have superior cerebral oxygen metabolism and recovery of cerebral blood flow after DHCA in a piglet model [16]. Our study results concurred with these previous reports and demonstrated that steroid pretreatment significantly decreased fluid accumulation, loss of COP, and trypan blue leakage across cerebral vasculature, with better indices of cerebral protection.
Several lines of evidence support the pharmacologic basis of these benefits. First, methylprednisolone is usually esterified with succinic acid to produce a water-soluble prodrug salt (methylprednisolone sodium succinate). Upon administration, this prodrug is hydrolyzed to the active moiety methylprednisolone by carboxylesterase enzymes. Among patients undergoing CPB, the peak concentration of methylprednisolone is reached approximately 1 to 2 hours after administration of methylprednisolone sodium succinate [17]. Second, steroids suppress inflammation by exerting their effects at various molecular levels. Through their receptors in the cytoplasm of target cells, they inhibit the adhesion molecule expression in the endothelial cells, which relates to the trafficking of leukocytes into the injured areas [18]. They also affect enzyme induction, protein synthesis, gene transcription, and even chromatin structure [19]. In view of these pharmacokinetics and mechanisms of action of steroids, it is logical that the steroids should be prophylactically present at the target sites when activation of blood elements is triggered by the contact of the synthetic surfaces of the CPB circuits. Although it remains controversial whether blunting the activation and release of various proinflammatory cytokines alone may favorably improve clinical outcome, our study suggests that in the presence of cerebral ischemia-reperfusion injury related to DHCA, the seemingly benign inflammatory reaction might aggravate end-organ damage.
There are several limitations to the current study. This acute experiment reflects early indices of neurologic damage. The implications of these findings with regard to the neurologic outcome therefore remain undefined. Nevertheless, ischemic changes that occurred during the early postoperative period have been correlated with subsequent neurohistologic damage in surviving animals [20]. In addition, although we have not assessed the effect of no steroid treatment in this study, research in our laboratory is ongoing to address this issue. However, the data from Lodge and colleagues [15] suggested that in the presence of DHCA, pulmonary function was significantly worse for the groups not receiving steroids than for the groups receiving steroids either in the pump prime or by systemic pretreatment.
In conclusion, this study demonstrated that under the condition of prolonged DHCA, systemic steroid pretreatment resulted in significant reduced total body edema and cerebral vascular leak and was associated with decreased apoptosis, and therefore better indices of neuroprotection.
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Discussion |
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The second thing I wonder about is why you chose just 4 hours of interval before exposure to bypass, as it may take steroids when used as a pretreatment mode much longer than 4 hours to have some kind of an effect. I think you have shown us in your study a change in the inflammatory response to steroids, but I wonder if you could describe a little bit for us why you chose the methodology that you used.
DR SHUM-TIM: Thank you for your kind comment. We are very aware of the literature originated from your lab and we must say that our current study is based on the previous findings from Lodge and Langley’s studies who documented the beneficial effect of steroid pretreatment in regards of pulmonary function and cerebral oxygen metabolism. First of all, we chose this protocol for the evaluation of cerebral protection following deep hypothermic circulatory arrest because this is an established model that I have been made familiar with at the Boston Children’s Hospital. Secondly, we chose to give the steroids 4 hours prior to surgery based on practicality. Obviously, as your previous papers suggested to give steroids 8 hours prior to surgery meant that if a patient was to have an operation at 8:00 in the morning, one had to start an intravenous and give a large dose of steroids at midnight. We found this was very impractical and inconvenient from a clinical point of view. Thirdly, there are certain pharmacologic studies that actually supported the benefits of using 4 hours pretreatment. There is a study looking at the pharmacokinetics of methylprednisolone in patients undergoing cardiopulmonary bypass, for instance. As you know, the active moiety of this steroid is the methylprednisolone. However, the preparation given clinically is the methylprednisolone sodium succinate. This preparation is to increase the water solubility of the medication so that it can be injected intravenously. This study found that in those patients undergoing cardiopulmonary bypass, the peak concentration of the active medication (ie, methylprednisolone) in the circulation is actually about 1 to 2 hours after the administration. Therefore, we think that the drug should be administered into the patient and allowed the active part of the medication to bind the proper receptors before activation of the blood element is initiated by contact with CPB. To answer your first question, the dose of 30 mg/kg of methylprednisolone is a very large pharmacological bolus given under normal circumstances. We do not think that giving it intravenously or giving it into the pump prime which, in our model, has approximately 300 cc of blood prime would create a difference in terms of the actual dose of steroids given. Therefore, to answer your first question, we do not think that the difference in the outcome measured in the study is based on a dose-related phenomenon. Rather, I think the bottom line is that the medication should be onboard at the time when all the inflammatory reactions are activated. It is also unlikely that the difference observed is due to a variation in the timing when the peak medication is present in the circulation. In other words, if we wait long enough, will the beneficial effects be similar? I don’t have data to back up this statement but our clinical experience in which we give steroids directly to our patients intravenously, I can tell you that the hemodynamic effect and the remarkable difference in the extent of capillary leak syndrome are quite impressive. Therefore, I don’t think that the beneficial effect of steroid pretreatment is solely based on the timing of the peak nor the difference in the concentration. I think the bottom line is the medication should be onboard before the injury is started.
DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): Thank you for that presentation. How did your two interventional groups compare to a control untreated animal undergoing the same process? And secondly, what part of the inflammatory response do you think that the methylprednisolone is acting on? Is it at the endothelial level or at the neutrophil level? Is it inhibiting the generation of superoxide radicals through inhibition of neutrophils? Or at this point do you not know?
DR SHUM-TIM: To answer your last question, I think we all know that steroids have a very broad spectrum of activities and it works at several molecular levels. At this point, we don’t have the data to show exactly at what level it works but I believe it works at the endothelial cells of the vessels as well as the steroid receptors on the plasma membrane of the target cells as suggested by the literature. It has also been shown that steroids affect the transcription of messenger RNAs and the protein synthesis. All in all, the systemic inflammatory reaction caused by cardiopulmonary bypass is so extensive and redundant. I believe that it takes something equally wide spectrum in order to effectively counteract these effects.
With respect to your first question, at the time when we submitted this abstract, we did not have the information regarding another group without steroid treatment at all. As a continuation of this study, which we have recently completed, to our surprise, the group without steroids versus the group with steroids in pump prime does not have significant differences.
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