HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Matthias Siepe Torsten Doenst Friedhelm Beyersdorf Christian Schlensak Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siepe, M. Articles by Schlensak, C. Search for Related Content PubMed PubMed Citation Articles by Siepe, M. Articles by Schlensak, C. Related Collections Extracorporeal circulation

---

Original Articles: Adult Cardiac

Pulsatile Pulmonary Perfusion During Cardiopulmonary Bypass Reduces the Pulmonary Inflammatory Response

^a Department of Cardiovascular Surgery, University Medical Center, Freiburg, Germany
^b Department of Anesthesiology and Critical Care Medicine, University Medical Center, Freiburg, Germany

Accepted for publication March 25, 2008.

^_* Address correspondence to Dr Schlensak, Department of Cardiovascular Surgery, University Medical Center Freiburg, Hugstetter Str 55, Freiburg, 79106, Germany (Email: christian.schlensak{at}uniklinik-freiburg.de).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
Background: Pulmonary dysfunction presumably linked to an inflammatory response is frequent after cardiac operations using cardiopulmonary bypass (CPB) and pulmonary hypoperfusion. We previously demonstrated that active perfusion of the lungs during CPB reduces ischemic lung injury. We now hypothesized that avoiding ischemia of the lungs during CPB by active pulmonary perfusion would decrease pulmonary inflammatory response.

Methods: Pigs were randomized to a control group with CPB for 120 minutes, followed by 120 minutes of postbypass reperfusion, or to the study groups where animals underwent active pulmonary perfusion with pulsatile or nonpulsatile perfusion during CPB (n = 7 in each group). Activation of transcription factor activity (nuclear factor [NF]-B and activating protein [AP]-1) was determined by electrophoretic mobility shift assay. Levels of proinflammatory protein expression (interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-) were quantified by enzyme-linked immunoabsorbent assay. Caspase-3 activity was measured using a fluorogenic assay.

Results: The activation of transcription factor AP-1 and NF-B was reduced in the pulsatile pulmonary perfusion group. The caspase-3 activity and the expression of IL-1, IL-6, and TNF- revealed a significant decrease in the pulsatile and nonpulsatile pulmonary perfusion groups. Animals of the pulsatile pulmonary perfusion group showed significantly reduced IL-6 expression and caspase-3 activity compared with the nonpulsatile pulmonary perfusion group.

Conclusions: Active pulmonary perfusion reduces the inflammatory response and apoptosis in the lungs observed during conventional CPB. This effect is greatest when pulmonary perfusion is performed with pulsatility. The reduction in cytokine expression by pulsatile pulmonary perfusion might be mediated by AP-1 and NF-B.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
Postoperative pulmonary dysfunction in patients undergoing cardiopulmonary bypass (CPB) is a substantial clinical problem. The disturbance may present as conditions varying from subclinical functional changes in most patients to full-scale acute respiratory distress syndrome in less than 2% of cardiac surgical patients with the use of the CPB [1]. The contact of blood with the artificial surface is believed to be the main reason for this complication [2]. We have previously demonstrated that bronchial arterial blood flow is significantly reduced during CPB and that the reduction of bronchial arterial blood flow leads to a low-flow ischemia in the lung with significant accumulations relative to control of albumin, lactate dehydrogenase, neutrophils, and elastase in the bronchoalveolar lavage fluid [3]. We therefore speculated that the mechanism for the pulmonary inflammatory response is associated with pulmonary ischemia during CPB.

In the present study we hypothesized that (1) the ischemia of the lung during CPB leads to an inflammatory response in lung tissue, (2) active pulmonary perfusion of the lung during CPB would reduce the pulmonary inflammatory response, and that (3) pulsatility of the active pulmonary blood flow during CPB would reduce the pulmonary inflammatory response even more than nonpulsatile flow characteristics.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
Animals
The study used German Landrace hybrid pigs, which received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Institute of Health Publication No. 86–23, revised 1985). All procedures were performed in accordance with the German Animal Protection Law after permission was obtained from the local veterinary office.

Anesthesia and Monitoring
Healthy pigs, weighing 28 to 32 kg, were premedicated with intramuscular ketamine (20 mg/kg body weight [BW]) and midazolam (0.5 mg/kg BW). The animals were endotracheally intubated. Anesthesia was maintained by intravenous infusion of fentanyl (10 µg/kg BW/h), propofol (4 to 6 mg/kg BW/h), and cis-atracurium (0.7 to 1 mg/kg BW/h) with basal volume administration. The lungs received volume-controlled ventilation at a frequency of 14 min, a tidal volume of 6 to 8 mL/kg BW, and a positive end-expiratory pressure of 5 mbar. Inspired oxygen fraction was constantly 0.5.

An arterial catheter was inserted in the right carotid artery to monitor blood pressure and blood gases. In addition, a pulmonary thermodilution catheter (Arrow, Reading, PA) was inserted into the pulmonary artery through the right external jugular vein.

Experimental Design
All animals received sternotomy after complete hemodynamic monitoring, and heparin (300 IU/kg BW) was administered. Initiation of CPB was achieved using a 24F venous cannula in the right atrial appendage and a 14F aortic cannula. The CPB circuit (Stöckert, Munich, Germany) was primed with isotonic saline solution (800 mL), 6% hydroxyethyl starch (500 mL), mannitol (250 mL), and heparin (300 IU/kg BW). CPB was maintained for 120 minutes at normothermia with a completely unloaded beating heart (clamped proximal pulmonary artery to exclude antegrade flow). The hemodilution through the large priming volume was counteracted using furosemide. Continuous positive airway pressure to the lungs was kept at 5 mbar during CPB. Starting with CPB weaning, a 30-second recruiting maneuver was performed and standard ventilation was reestablished. CPB was removed, protamine matching the heparin dosage was administered, and another 120 minutes of post-CPB observation followed.

We recorded the following variables and collected samples at six defined time-points (before CPB, 10 minutes after initiation of CPB, at the end of CPB, and additionally at 15, 60, and 120 minutes after CPB): blood gas analysis including hemoglobin concentration and electrolytes, a 300-mg lung tissue biopsy specimen at each time-point, and ethylenediaminetetraacetic acid-blood samples. We also measured heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure (PAPm), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO) by the thermodilution method except during the CPB. Systemic (SVR) and pulmonary vascular resistance (PVR) were calculated as: SVR = (MAP-CVP)/CO and PVR = (PAPm-PCWP)/CO, respectively.

The lung biopsy specimen was minced and stored at –80°C for protein analysis.

The animals were randomized into four groups. The sham group (n = 3) served as a negative control and underwent sternotomy alone. In the CPB group (n = 7), which served as a positive control, the CPB was initiated and maintained for 120 minutes, followed by a 120-minute observation period. In the study groups with CPB and pulmonary perfusion, the pulmonary artery was cannulated using a 12F aortic cannula. During pulmonary perfusion, 20% of the systemic flow was administered to the pulmonary artery using either a roller pump with laminar flow and continuous pulmonary perfusion (group CPB+CP, n = 7) or using pulsatile perfusion (group CPB+PP, n = 7). The pulsatility was achieved by using a diagonal pump (DeltaSream DP1, MEDOS Medizintechnik AG, Stolberg Germany). A soft venous bag for neonates (D 901, Sorin S.p.A., Milano, Italy) was connected between the oxygenator and the DeltaStream to prevent negative pressure in the pump inlet. By this strategy, the pressure curve resembled the normal pulsatile profile in the pulmonary artery.

The animals were euthanized 120 minutes after postbypass reperfusion by intracardial potassium injection.

Protein Extraction, Enzyme-Linked Immunoabsorbent Assay
Protein was extracted and enzyme-linked immunoabsorbent assay was performed following the manufacturer's instruction (Quantikine, R&D, Minneapolis, MN). Protein concentration was determined using the Bradford Assay (Bio-Rad Laboratories, Munich, Germany).

Electrophoretic Mobility Shift Assay and Supershift Analysis
Double stranded oligonucleotides containing the consensus sequences for the transcription factor binding sites for activating protein-1 (AP-1) and nuclear factor-B (NF-B) were purchased from Promega (Madison, WI). The electrophoretic mobility shift assays were performed as previously described [4].

Caspase Activity Assay
Caspase activity was analyzed using a fluorogenic Ac-DEVD-AMC (N-acetyl)-(Asp-Glu-Val-Asp)-(7-amino-4-methylcoumarin) substrate for caspase-3, –6, and –7 (ALEXIS Biochemicals, Grünberg, Germany). Briefly, protein solubilized in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/potassium hydroxide buffer was exposed to the substrate and the photosensitive reaction was measure at wavelength of = 405 nm for 30 minutes.

Statistics
Data were analyzed using SigmaStat statistical software (Systat Software, Inc, San Jose, CA). Values are given as mean ± standard deviation. Two-way analysis of variance for repeated measurements was used to compare variables within and between groups. A value of p < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
All animals survived the procedure and the observation time. No sign of disease or harm was recognized in any of the operated on animals.

Blood Gas Analysis and Hemodynamic Variables
The arterial oxygen partial pressure was comparable between the study and control groups (Table 1). Hemoglobin concentration in all CPB groups dropped significantly with the initiation of CPB (data not shown) and remained stable until the end. All animals of the CPB groups had significantly lower hemoglobin concentrations at 120 minutes' postbypass reperfusion time compared with sham pigs, without differences between the groups (Table 1). Animals in the CPB+PP group had a significantly lower hemoglobin concentration than the conventional CPB group at 15 minutes'postbypass reperfusion time. Lactate, pH, standard base excess, and the partial pressure of O₂ and CO₂ did not differ significantly among the three CPB groups. We detected no significant group differences in the lactate and acid-base balance throughout the study.

View this table: [in this window] [in a new window]   Table 3 Protein Data for Tumor Necrosis Factor-, Interleukin-1, and Interleukin-6, and Statistical Evaluation a

View larger version (25K): [in this window] [in a new window]   Fig 1. (A) Protein expression of interleukin (IL)-1 and (B) IL-6 in the lung tissue is visualized by enzyme-linked immunoabsorbent assay. The left side shows the baseline values of the groups with CPB (black bar), CPB+CP (light gray bar), and CPB+PP (dark gray), and the respective values at the end of the investigation are highlighted on the ride hand side. Values are shown with the standard deviation. (CPB = cardiopulmonary bypass; CP = continuous perfusion; PP = pulsatile perfusion; $p < 0.001 CPB vs CPB+CP and CPB+PP; *p < 0.05 CPB+CP vs CPB+PP.)

Caspase-3 activity was measured to analyze apoptosis in addition to the proinflammatory markers. Caspase-3 activity showed no differences in the perfusion groups during bypass time compared with sham or conventional CPB (Fig 2). At 15 minutes' postbypass reperfusion time, caspase-3 activity in the CPB+CP and CPB+PP groups was significantly lower compared with the CPB group. At 60 minutes' postbypass reperfusion time, caspase-3 activity in the CPB+PP group was significantly lower compared with the CPB group. However, at 120 minutes' postbypass reperfusion time, caspase-3 activity in the CPB+CP and CPB+PP groups increased and almost reached the level of conventional CPB.

View larger version (16K): [in this window] [in a new window]   Fig 2. Caspase-3 activity in the lung tissue is visualized by fluorogenic assay. In the CPB+CP (red triangles) and CPB+PP (green triangles) groups, especially, caspase-3 activity values are lower than those in the CPB (open circles) group directly after bypass termination. At 60 minutes' postbypass time the caspase activity in the CPB+PP group is significantly lower compared with CPB (sham operation, solid circle). (CPB = cardiopulmonary bypass; CP = continuous perfusion; PP = pulsatile perfusion; #p < 0.05 groups CPB+CP and CPB+PP vs group CPB, *p < 0.05 CPB+PP vs CPB; data are presented with the standard deviation.)

DNA Binding Activity of NF-B and AP-1

View larger version (35K): [in this window] [in a new window]   Fig 3. Electrophoretic mobility shift assays of intracellular transcription factor expression of (A) nuclear factor-B and (B) activating protein in the two groups of cardiopulmonary bypass (CPB) plus continuous pulmonary perfusion (CPB+CP, light gray bars) and pulsatile pulmonary perfusion (CPB+PP, dark gray bars) compared with the conventional CPB group (black bars.) (*p < 0.05 vs CPB and CPB+PP group; data are presented with the standard deviation.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

1 CPB leads to an inflammatory response in the lung.

2 The inflammatory response in the lungs is inhibited by active (pulsatile and nonpulsatile) pulmonary perfusion during CPB as revealed by reduced cytokine expression.

3 Pulmonary perfusion during CPB reduces caspase-3 activity in the early postbypass period.

4 CPB is associated with an activation of the transcription factor AP-1 (but not NF-B) and that this activation is attenuated by pulmonary perfusion.

5 Pulsatile pulmonary perfusion lowers the inflammatory response during CPB more pronounced than nonpulsatile perfusion.

6 Additional pulmonary perfusion does not impair pulmonary function in the early postbypass period.

A number of important inflammatory markers are activated in the lung after initiation of CPB, as shown by IL-6, IL-8, IL-10, and TNF- levels in pulmonary vein blood [5] and activated neutrophils in the airways [6]. The release of these mediators can lead to an inflammatory response with relevant postoperative complications such as serious respiratory insufficiency as well as renal and hepatic dysfunction. It has been suggested that the CPB-associated inflammation is mainly caused by the contact between blood and artificial surfaces [2]. Other causative factors for the inflammatory response are endotoxemia, surgical trauma, and blood loss [7].

Various pharmacologic interventions, including aprotinin, corticosteroids, heparin-coated circuits, and technical advances such as perfusion technology, roller pump vs centrifugal pump, and anesthetic and surgical techniques failed to sustain or improve the rate of perioperative pulmonary dysfunction after undergoing CPB [8, 9]. In our previous investigations, we found evidence of low-flow ischemia in the lungs during CPB [3]. This ischemia and reperfusion is associated with an increase of albumin, lactate dehydrogenase, neutrophils, and elastase in the bronchoalveolar lavage fluid.

We therefore hypothesized that active pulmonary perfusion would attenuate molecular regulators of inflammation (transcription factors NF-B and AP-1) and result in elevated proinflammatory cytokines in the lung tissue. Other studies found evidence for ischemic lung damage during extracorporal membrane oxygenator therapy in an animal model [10] and in the clinical setting in neonates [11], which might support our hypothesis.

This present study demonstrated that controlled perfusion of the lungs during CPB significantly reduces the inflammatory reaction in the lungs. Taken together, these observations may suggest a paradigm shift. We can speculate that a great deal of the inflammatory response during operations with CPB is not caused by the extracorporeal perfusion itself (ie, artificial surface) but by the changes in regional perfusion patterns during CPB. This speculation is supported by the differences between the pulsatile and nonpulsatile perfusion because the pulsatile perfusion seems to resemble the natural perfusion better than nonpulsatile flow. It is further supported by reports that similar inflammatory reactions can be seen after cardiac operations without CPB (off-pump) [12]. In contrast, other groups found evidence for a diminished inflammatory response after off-pump cardiac procedures compared with operations with the use of CPB [13]. With regards to the present findings, the different degree of pulmonary perfusion during heart dislocation for graft placement in these studies might be a reason for the inconclusive findings.

The caspase enzymes have an essential role in apoptosis (cell death) and inflammation [14]. Caspase-3, an effector caspase in the end of the apoptotic cascade, is a direct hint toward apoptosis whenever an increased activity is noticed. The conventional CPB results in an increased inflammatory response going along with increased apoptosis. The reduction in caspase-3 activity in the pulmonary perfusion groups compared with conventional CPB points towards reduced apoptosis using pulmonary perfusion strategies. The protective effect of pulmonary perfusion is greatest in the early postbypass period of 15 to 60 minutes and is greatest in the pulsatile perfusion groups mimicking the physiologic flow pattern. Other mechanisms, which have not been investigated in detail, seem to be involved in the later postbypass period, at 120 minutes' postbypass reperfusion time, because caspase-3 activity was elevated in all CPB groups. From the present data we can only speculate that a delay for caspase-3 activity might decrease the overall potential maximum of apoptosis, which is probably not reached at 120 minutes' postbypass time.

In the CPB group without pulmonary perfusion, we measured typical features of the inflammatory cascade resulting in high proinflammatory cytokine release. These changes were partly reversed by pulmonary perfusion. Of interest was that the differential results of the transcription factor analysis provide an indirect indication of what the cellular mechanisms are in this intervention. The transcription factors AP-1 and NF-B possess complex regulatory properties in the inflammatory cascade [15, 16]. However, the molecular mechanisms of CPB-induced inflammation are not fully understood. Naidu and colleagues [17] have demonstrated that activation of AP-1 is etiologically involved in the ischemia and reperfusion injury in the lung. In accordance with our data, AP-1 activation might be involved in the signaling pathway of CPB-induced inflammation and is inhibited by both pulmonary perfusion types.

Nuclear factor-B is involved in the context of a large number of cellular processes in the lung. Epithelial cells, macrophages, and neutrophils have been shown to be involved in lung inflammation through signalling mechanisms that are dependent on activation of NF-B [18]. The induction of NF-B may be either protective (eg, reducing apoptosis or suppression of p53) or harmful (eg, inflammation). Which of these biologic functions is exerted seems to depend on the onset of NF-B activation. This temporal regulation is similarly observed in the heat shock paradox [19]. Our results demonstrate NF-B activation during CPB and recovery back to normal levels in the postbypass time (Fig 3A). In contrast, pulmonary perfusion leads to an activation of NF-B even after 120 minutes' postbypass time. Moreover the pulsatile perfusion prevented activation of NF-B during and after extracorporeal circulation. Accordingly, CPB-treated animals showed significantly higher levels of TNF-, IL-1, and IL-6. We therefore we conclude that activation of NF-B during CPB is responsible for the expression of proinflammatory cytokines in the lungs and that pulsatile perfusion attenuates NF-B regarding inflammation.

Because the pulmonary inflammatory reaction during CPB with pulmonary perfusion strategies could not be avoided completely, other mechanisms such as the artificial surface of the extracorporeal circuit might be involved as well.

It is suggested that nonpulsatile flow leads to organ hypoperfusion and that pulsatile perfusion might be beneficial 20, 21. However, there has been no clear evidence that pulsatile blood flood flow is superior to nonpulsatile regarding the inflammatory response in specific organs. Studies on end-organ function in patients with an axial-flow left ventricular assist device have demonstrated a comparable outcome with those patients who have a pulsatile device [22].

We could demonstrate that pulsatile perfusion counteracted the inflammatory response and apoptosis in the lungs significantly better than nonpulsatile pulmonary perfusion did. The differences between the two groups reached statistical significance for IL-1 and IL-6 protein expression as well as for caspase-3 activity in selected observation points. The present analysis supports the use of pulsatile flow in pulmonary perfusion and therefore favors the more physiologic flow pattern.

Surprisingly, pulmonary vascular resistance rose significantly at 120 minutes' postbypass reperfusion time in the pulsatile pulmonary perfusion. The reason for this effect is currently not clear and requires further investigation.

In the present study, we could exclude adverse consequences on blood gas exchange during the postoperative observation time. We also noticed no damaging hemodynamic effects of the pulmonary perfusion strategy. Sievers and colleagues [23] observed a positive effect in oxygen concentration after pulmonary perfusion in patients undergoing CABG. It can be speculated that the possible functional benefits resulting from avoided inflammatory process in the lungs might be observed after longer observation times and, in particular, in sick patients presenting with pulmonary impairment (ie, chronic obstructive pulmonary disease, patients with assist devices).

The present study was performed in a short-term animal model with a short postoperative observation time and limited lung-function measurements. Our results can thus not guarantee a reduction in inflammation-related complications in the lung achieved by pulmonary perfusion during extracorporeal circulation. However, this study was initiated primarily to confirm the effect of pulmonary perfusion on the cellular mechanisms in lung inflammation. A follow-up phase I study in humans must be focused on functional end points.

Our strategy of pulmonary perfusion might not be eligible for all procedures with a short duration of CPB. The additional efforts with cannulation of the pulmonary artery and an extra pump system might be preferable in patients at high risk for pulmonary complications, including type-A dissections, severe chronic obstructive pulmonary disease, and infants with complex congenital defects.

No systemic indicators of the inflammatory response were analyzed. The benefit observed in the lung tissue by pulmonary perfusion therefore cannot be correlated to possible benefits in the systemic inflammatory response. However, the sole aim of this study was to evaluate pulmonary inflammation and subsequent pulmonary dysfunction.

Pulmonary perfusion during CPB reduces the inflammatory response in lung tissue. Pulsatile pulmonary perfusion reduces indicators of inflammation slightly more than nonpulsatile flow characteristics. The pulmonary perfusion strategy may prove to be a valuable tool in preventing pulmonary complications in patients undergoing operations that require long CPB times.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
This study was conducted with the support of the German Research Foundation (SCHL 604/2–1). We thank Dr Katharina Förster for taking care of the animals.

	Footnotes

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 
^_* The first two authors contributed equally to the work.

	References

Top Abstract Introduction Material and Methods Results Comment Footnotes Acknowledgments References

 

1. Ng CS, Wan S, Yim AP, Arifi AA. Pulmonary dysfunction after cardiac surgery Chest 2002;121:1269-1277.[Medline]
2. Fitch JC, Rollins S, Matis L, et al. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass Circulation 1999;100:2499-2506.[Abstract/Free Full Text]
3. Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres Eur J Cardiothorac Surg 2001;19:326-331.[Abstract/Free Full Text]
4. Morse D, Pischke SE, Zhou Z, et al. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1 J Biol Chem 2003;278:36993-36998.[Abstract/Free Full Text]
5. Massoudy P, Zahler S, Becker BF, Braun SL, Barankay A, Meisner H. Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass Chest 2001;119:31-36.[Medline]
6. Kotani T, Kotake Y, Morisaki H, et al. Activation of a neutrophil-derived inflammatory response in the airways during cardiopulmonary bypass Anesth Analg 2006;103:1394-1399.[Abstract/Free Full Text]
7. Schlensak C, Beyersdorf F. Lung injury during CPB: pathomechanisms and clinical relevance Interact Cardiovasc Thorac Surg 2005;4:381-382.[Free Full Text]
8. Ashraf S, Tian Y, Cowan D, Entress A, Martin PG, Watterson KG. Release of proinflammatory cytokines during pediatric cardiopulmonary bypass: heparin-bonded versus nonbonded oxygenators Ann Thorac Surg 1997;64:1790-1794.[Abstract/Free Full Text]
9. Royston D, Levy JH, Fitch J, et al. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes Anesth Analg 2006;103:1082-1088.[Abstract/Free Full Text]
10. Koul B, Willen H, Sjoberg T, Wetterberg T, Kugelberg J, Steen S. Pulmonary sequelae of prolonged total venoarterial bypass: evaluation with a new experimental model Ann Thorac Surg 1991;51:794-799.[Abstract]
11. Jaggers JJ, Forbess JM, Shah AS, et al. Extracorporeal membrane oxygenation for infant postcardiotomy support: significance of shunt management Ann Thorac Surg 2000;69:1476-1483.[Abstract/Free Full Text]
12. Quaniers JM, Leruth J, Albert A, Limet RR, Defraigne JO. Comparison of inflammatory responses after off-pump and on-pump coronary surgery using surface modifying additives circuit Ann Thorac Surg 2006;81:1683-1690.[Abstract/Free Full Text]
13. Staton GW, Williams WH, Mahoney EM, et al. Pulmonary outcomes of off-pump vs on-pump coronary artery bypass surgery in a randomized trial Chest 2005;127:892-901.[Medline]
14. Danial NN, Korsmeyer SJ. Cell death: critical control points Cell 2004;116:205-209.[Medline]
15. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors Oncogene 1999;18:6853-6866.[Medline]
16. Wisdom R. AP-1: one switch for many signals Exp Cell Res 1999;253:180-185.[Medline]
17. Naidu BV, Krishnadasan B, Farivar AS, et al. Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury J Thorac Cardiovasc Surg 2003;126:200-207.[Abstract/Free Full Text]
18. Park GY, Christman JW. Nuclear factor kappa B is a promising therapeutic target in inflammatory lung disease Curr Drug Targets 2006;7:661-668.[Medline]
19. Chen Y, Voegeli TS, Liu PP, Noble EG, Currie RW. Heat shock paradox and a new role of heat shock proteins and their receptors as anti-inflammation targets Inflamm Allergy Drug Targets 2007;6:91-100.[Medline]
20. Alghamdi AA, Latter DA. Pulsatile versus nonpulsatile cardiopulmonary bypass flow: an evidence-based approach J Card Surg 2006;21:347-354.[Medline]
21. Murkin JM, Martzke JS, Buchan AM, Bentley C, Wong CJ. A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. I. Mortality and cardiovascular morbidity. J Thorac Cardiovasc Surg 1995;110:340-348.[Abstract/Free Full Text]
22. Saito S, Nishinaka T. Chronic nonpulsatile blood flow is compatible with normal end-organ function: implications for LVAD development J Artif Organs 2005;8:143-148.[Medline]
23. Sievers HH, Freund-Kaas C, Eleftheriadis S, et al. Lung protection during total cardiopulmonary bypass by isolated lung perfusion: preliminary results of a novel perfusion strategy Ann Thorac Surg 2002;74:1167-1172.[Abstract/Free Full Text]

This article has been cited by other articles:

				B. Ji and Y. Luo Importance of precise quantification of pressure-flow waveforms in comparison between pulsatile versus nonpulsatile perfusion. Ann. Thorac. Surg., March 1, 2009; 87(3): 988 - 988. [Full Text] [PDF]

				M. Siepe, C. Schlensak, and U. Goebel Reply. Ann. Thorac. Surg., March 1, 2009; 87(3): 989 - 989. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Matthias Siepe Torsten Doenst Friedhelm Beyersdorf Christian Schlensak Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siepe, M. Articles by Schlensak, C. Search for Related Content PubMed PubMed Citation Articles by Siepe, M. Articles by Schlensak, C. Related Collections Extracorporeal circulation