ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Yoichi Kawahira
Hideki Uemura
Toshikatsu Yagihara
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kawahira, Y.
Right arrow Articles by Yagihara, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kawahira, Y.
Right arrow Articles by Yagihara, T.
Related Collections
Right arrow Congenital - acyanotic

Ann Thorac Surg 2006;81:685-689
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Impact of the Off-Pump Fontan Procedure on Complement Activation and Cytokine Generation

Yoichi Kawahira, MD a , Hideki Uemura, MD b , Toshikatsu Yagihara, MD c , *

a Department of Pediatric Cardiovascular Surgery, Osaka City General Hospital, Osaka, Japan
b Department of Cardiothoracic Surgery, Royal Brompton Hospital, London, England
c Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan

Accepted for publication July 13, 2005.

* Address correspondence to Dr Yagihara, Department of Cardiovascular Surgery, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (Email: yagihara{at}hsp.ncvc.gojp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: To investigate whether the Fontan procedure in an off-pump fashion is less invasive in terms of the systemic inflammatory reaction.

METHODS: Plasma levels of complement and cytokines were measured during and after the Fontan procedure in consecutive 38 patients. Of these, 16 underwent the extracardiac method without use of cardiopulmonary bypass (off-pump group), while the machine was used in the remaining 22 because of intracardiac maneuvers concomitantly needed (CPB group).

RESULTS: There was no difference, between these two groups, in any value of plasma complement or cytokines after anesthetic induction. Immediately after commencement of the Fontan circulation, however, plasma concentration was significantly lower in the off-pump group for activated complement 3 (C3a), interleukin-6, interleukin-8, and polymorphonuclear elastase. The C3a value was also lower at 2 hours later in the off-pump group than in the CPB group. Furthermore, the values even stayed within the normal ranges, in the off-pump group, for tumor necrosis factor alpha (TNF{alpha}) and thrombomodulin. A pulmonary venous oxygen tension divided by an inspired oxygen tension (PpvO2/FiO2) ratio immediately after commencement of the Fontan circulation was 528 ± 93 mm Hg (410 to 580 mm Hg) in the off-pump group, and 258 ± 167 mm Hg (86 to 540 mm Hg) in the CPB group (p = 0.01). Duration of drainage for fluid sequestration was shorter in the former group (6.3 ± 0.7 days versus 13.9 ± 2.5 days, p = 0.02).

CONCLUSIONS: Inflammatory reactions were attenuated when the Fontan procedure was employed in an off-pump fashion compared with the usual procedure on bypass.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
It is well known that cardiopulmonary bypass activates the complements system and induces a systemic inflammatory reaction [1, 2], which can be a cause of dysfunction of the bodily organs [3, 4]. Since April 1996, we have striven to establish the Fontan circulation in an off-pump fashion when intracardiac maneuvers are not needed at the time of Fontan completion [5, 6]. We speculated that this approach would be beneficial when earlier Fontan establishment is sought [7], and that inflammatory response could be less with no use of cardiopulmonary bypass. The purpose of this study is to investigate whether this is really the case or not, because no scientific report is available in the literature about this particular form of the Fontan procedure.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patient Profile
Thirty-eight patients underwent the Fontan operation at the National Cardiovascular Center of Japan between February 1998 and April 2000. Of these, 16 underwent the extracardiac Fontan procedure in an off-pump fashion (off-pump group), and cardiopulmonary bypass was used in the remaining 22 (CPB group). The off-pump maneuver was chosen whenever feasible technically. The reason for using cardiopulmonary bypass was intracardiac procedures concomitantly needed, extensive reconstruction of the pulmonary arteries, or anatomical features posing technical difficulties during the anastomosis between an extracardiac conduit and the inferior caval vein. Age at the Fontan procedure ranged from 10 months to 19 years (mean, 4.6 ± 5.5) in the off-pump group, and 1 to 22 years (mean, 3.6 ± 4.7) in the CPB group. Body weight ranged from 7.4 to 51.3 kg (mean, 16.2 ± 14.4 kg), and 6.8 to 51.0 kg (mean 12.7 ± 10.0 kg), respectively. Cardiac diagnoses are listed in Table 1.


View this table:
[in this window]
[in a new window]
  		Table 1. Major Cardiac Malformation of Patients and Operative Procedures Concomitantly Employed at the Time of the Fontan Procedure
 
The bidirectional Glenn procedure had been carried out before the Fontan procedure in 5 patients (31%) of the off-pump group and 14 (64%) of the CPB group.

Preoperative cardiac catheterization showed that mean pulmonary arterial pressure was 12 ± 2 mm Hg for the off-pump group and 14 ± 5 mm Hg for the CPB group. Pulmonary vascular resistance was calculated as 1.4 ± 0.9 Um2 and 1.9 ± 1.1 Um2, respectively. End diastolic volume of the systemic ventricle was 179% ± 71% and 186% ± 87%, respectively, of the anticipated normal value based on the body surface area. These preoperative data did not significantly differ between the two groups.

Operative Methods
In patients undergoing cardiopulmonary bypass, a hollow fiber oxygenator (Dideco, Mirandola, Italy) was used. The bypass circuit was not heparin coated. The priming solution for the cardiopulmonary circuit contained 5% albumin and predonisolone (30 mg/kg). Heparinization (0.3 mL/kg) was carried out before commencement of cardiopulmonary bypass, and protamine was given 0.15 mL/kg approximately 10 minutes after coming off bypass. Under moderate hypothermia, cardiac arrest was induced using crystalloid cardioplegia. Operative procedures concomitantly employed are shown in Table 1. Cardiopulmonary bypass time was 113 ± 63 minutes, and aortic cross-clamp time was 34 ± 28 minutes.

In contrast, no oxygenator or perfusion pump was used in the off-pump group. Instead, after infusion of heparin (0.2 mL/kg), one or two venous cannula tubes were used as a temporary bypass. This was firstly placed between the superior caval vein and the atrial chamber for superior cavopulmonary anastomosis in a bidirectional fashion, and eventually placed between the inferior caval vein and the atrial chamber for construction of the extracardiac inferior venous channel [5, 6]. During the superior cavopulmonary anastomosis, pulmonary perfusion was maintained through a systemic-pulmonary shunt or the pulmonary trunk from the ventricle. Subsequently, under the unilateral Glenn physiology, another anastomosis was carried out between the central part of the pulmonary artery and a tube graft to be used for the extracardiac channel. Eventually, under the bilateral Glenn physiology, the opposite end of the graft was anastomosed to the inferior caval vein. The extracardiac channel was constructed using an ePTFE tube in 9 cases and exclusively using autologous tissues in the others. Protamine was given (0.1 mL/kg) approximately 10 minutes after commencement of the Fontan circulation.

Harvesting Samples and Quantitative Analysis
Six blood samples (6 mL each) were obtained through an arterial line of the patients; after anesthetic induction as a reference point, just after and 2 hours after commencement of the Fontan circulation, and at 1 day, 3 days, and 7 days after the procedure. The samples were drawn into a tube containing ethylenediamine tetra-acetic acid. The plasma fraction was immediately separated and stored at –30°C for subsequent quantitative analysis. Activated complement 3 (C3a) was measured by radioimmunoassay. The serum complement titer (CH50) was measured by the modified Meyer method. Tumor necrosis factor-alpha (TNF{alpha}), interleukin-1-beta (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), polymorphonuclear (PMN) elastase, and thrombomodulin were measured by enzyme immunoassay. Each value was corrected by hematocrit value of each patient.

Statistical Analysis
The values were reported as a mean plus or minus a standard error of the absolute values. Comparisons between groups over time were performed by two-way analysis of variance with repeated measures. Data were further compared by post hoc test if significance was indicated (p < 0.05). The Mann-Whitney U test was used to compare differences in continuous variables in the two groups and the {chi}2 test for proportions. The p value of less than 0.05 was considered significant. Statistical analysis was performed using a program of StatView version 5.0 (SAS Institute, Cary, North Carolina).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
No patients have died either in the short term or the longer term, irrespective of the groups.

Measured consecutive values for complement activation and cytokines are shown in Table 2. The concentration of C3a was considerably higher at just after, as well as 2 hours after, major surgical maneuvers for Fontan procedure when compared with the reference value within each group. These values were significantly lower in the off-pump group than in the CPB group.


View this table:
[in this window]
[in a new window]
  		Table 2. Changes of Complements and Cytokines in Both Groups
 
Plasma concentration of TNF{alpha} increased during cardiopulmonary bypass, whereas it did not increase during temporary bypasses. Change in the IL-6 level was different between the two groups. In the off-pump group, IL-6 increased even during the first 2 hours after the major surgical maneuver, whereas the peak was at the time of coming off bypass in the CPB group. Change in plasma IL-8 concentration was milder in the off-pump group, and did not show a sharp peak as seen in the CPB group. The PMN elastase level demonstrated its maximal value just after the bypass, and the value in the off-pump group was less than half of that in the CPB group. The thrombomodulin level remained within the preoperative range throughout the postoperative period examined in the off-pump group. The level showed a trend of slight raise in the CPB group.

The so-called PF ratio (PpvO2/FiO2) was calculated immediately after coming off bypass or removal of a temporary bypass. Oxygen content was measured in blood derived from the pulmonary vein. The calculated value was 528 ± 93 mm Hg (range, 410 to 580 mm Hg) in the off-pump group, and 258 ± 167 mm Hg (range, 86 to 540 mm Hg) in the CPB group. There was a significant difference between these groups (p = 0.01).

The amount of blood loss during the procedure and overall blood transfusion in the off-pump group were 120 ± 39 mL and 200 ± 77 mL, respectively, and no blood transfusion was needed in 5 patients in this group. However, in the CPB group, these amounts were 470 ± 117 mL and 540 ± 189 mL, respectively, and all patients needed blood transfusion during or after procedure. The amount of blood loss and overall blood transfusion in the off-pump group was significantly smaller than in CPB group (p = 0.03 and p = 0.02, respectively).

Mean pressure of the superior caval vein after commencement of the Fontan circulation was 14.4 ± 0.5 mm Hg in the off-pump group and 15.5 ± 0.4 mm Hg in the CPB group (p = 0.08). Inhalation of nitric oxide (our criteria for this equipment being transpulmonary pressure gradient of 10mm Hg or greater) was carried out in 4 of 16 (25%) of the off-pump group and in 14 of 22 (64%) of the CPB group (p = 0.02). Duration for this treatment was 2.1 ± 1.3 hours in the no-CPB group and 14.3 ± 6.2 hours in the CPB group (p = 0.06); and duration of endotracheal intubation in the intensive care unit was 5.4 ± 0.8 hours in the off-pump group and 12.5 ± 3.5 hours in the CPB group (p = 0.09).

Overall amount of fluid sequestration drainage was 996 ± 276 mL/m2 in the off-pump group and 2,291 ± 468 mL/m2 in the CPB group (p = 0.08). Duration of drainage for fluid sequestration was 6.3 ± 0.7 days and 13.9 ± 2.5 days, respectively (p = 0.02). Duration of drainage for 1 week or longer was needed in 4 of 16 patients (25%) in the off-pump group versus 14 of 22 (64%) in the CPB group (p = 0.02).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
The contact of blood with artificial materials activates the complement system, initiating a cascade of inflammatory pathways. Activated complement 3 contributes to monocyte activation and causes adherent monocytes to synthesize TNF{alpha} and IL-1ß [8]. These cytokines affect activity of fibroblasts and endothelial cells. Activated complement 5 also contributes to PMN and platelet activation and IL-6 production by monocytes [9]. Neutrophils and monocytes/macrophages respond to these activated complements, and react in many ways; enhanced chemotactic migration and adherence to the endothelial cells, secretion of lysosomal enzymes, and increased oxidative and arachidonic acid metabolisms [10]. In consequence, various inflammatory cytokines, such as IL-1ß, IL-6, or IL-8, are released and often related to dysfunction of the bodily organs after CPB [11, 12].

Not only complement activation but also contact activation stimulates PMN to release toxic oxygen species and granule contents including elastase [13, 14]. These two manners of activation were nominated as playing a synergistic role for PMN activity during CPB [15], and products from PMN were related to the respiratory dysfunction after CPB [16]. Tumor necrosis factor-alpha is another vital cytokine indicating the degree of tissue injury [17], and regarded as an important variable in the pathogenesis of the systemic inflammatory response syndrome induced by CPB [18]. Tumor necrosis factor-alpha also induces endothelial dysfunction with enhanced vascular permeability [19]. Thrombomodulin is released in excessive amounts when the endothelium is injured, and is a marker of endothelial cell injury [20, 21].

In all these respects, our results in plasma measurements of C3a and cytokines support that the off-pump maneuver was less invasive when compared with the usual Fontan procedure on CPB. Of course, even in the off-pump fashion, some artificial materials are used, such as Polystan tubes or an expanced polytetrafluoroethylene tube. Changes in complements suggest this aspect. Nonetheless, exposure of blood to artificial materials was unequivocally much less in this fashion than when CPB was used. In particular, no oxygenator was involved.

Another potential advantage of the off-pump procedure in terms of cytokine generation is reduction in reperfusion injury of the lung. It is known that this tissue injury subsequent to ischemia is mediated by activated macrophages, products of activated, and recruited neutrophils in the lung [22, 23]. In the off-pump Fontan procedure, the lungs are perfused throughout, or for a short duration, ischemia of a unilateral lung, if any, is employed. During CPB, in contrast, pulmonary perfusion is almost always diminished. That can be one of the factors that affect change in the thrombomodulin level and, eventually, lung function for blood oxygenation (PF ratio). The postoperative course clinically easier and shorter to handle in the off-pump group reflected the better lung condition.

It should be noted that there are many factors potentially present that affect the status of compliments and cytokines. Drugs that can induce release of histamine, for example, Protamin or other anestatic agents, could influence inflammatory reaction. Duration of overall surgical procedure is another crucial factor. Blood transfusion will also introduce immunological reactions. Even under such a multifactorial circumstances, however, dispersion of the measured values in this study was relatively small, for clinical data, within either the off-pump group or the CPB group. No more obvious difference was demonstrated, in terms of inflammatory reaction, under any heading other than whether CPB was used or not.

In conclusion, inflammatory reactions were attenuated when the Fontan procedure was employed in the off-pump fashion rather than by usual establishment with the aid of CPB.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Seghaye MC, Grabitz RG, Duchateau J, et al. Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations J Thorac Cardiovasc Surg 1996;112:687-697.[Abstract/Free Full Text]
  2. Mainwaring RD, Lamberti JJ, Hugli TE. Complement activation and cytokine generation after modified Fontan procedure Ann Thorac Surg 1998;65:1715-1720.[Abstract/Free Full Text]
  3. Ohata T, Sawa Y, Kadoba K, Masai T, Ichikawa H, Matsuda H. Effect of cardiopulmonary bypass under tepid temperature on inflammatory reactions Ann Thorac Surg 1997;64:124-128.[Abstract/Free Full Text]
  4. Kirklin JK. The postperfusion syndromeinflammation and the damaging effects of cardiopulmonary bypass. In: Tinker JH, editor. Cardiopulmonary bypass. current concepts and controversies. Philadelphia: Saunders; 1989. pp. 131-146.
  5. Uemura H, Yagihara T, Yamashita K, Ishizaka T, Yoshizumi K, Kawahira Y. Establishment of total cavopulmonary connection without use of cardiopulmonary bypass Eur J Cardiothorac Surg 1998;13:504-508.[Medline]
  6. Uemura H, Yagihara T, Kawahira Y. The extracardiac Fontan procedure using a pedicled pericardial roll without cardiopulmonary bypass [letter] J Thorac Cardiovasc Surg 1999;117:1046-1047.[Free Full Text]
  7. Uemura H, Yagihara T. Less invasive establishment of the Fontan circulation in terms of earlier farewell to a cyanotic circulation [in Japanese] Kyobu Geka 2003;56:309-315.[Medline]
  8. Takabayashi T, Vannier E, Clark B, et al. A new role for C3a and C3adesArg J Immunol 1996;156:3455-3460.[Abstract]
  9. Fletcher MP, Stahl G, Longhurst J. C5a-induced myocardial ischemia Am J Physiol 265 (Heart Circ Physiol) 1993;34:H1750-H1761.
  10. Goldstein IM. Complementbiologically active products. In: Ballin JI, Goldstein IM, Snyderman R, editors. Inflammation. basic principles and clinical correlates. New York: Raven Press; 1992. pp. 63.
  11. Kunkel SL, Standiford T, Kasahara K, Strieter RM. Interleukin-8 (IL-8)the major neutrophil chemotactic factor in the lung. Exp Lung Res 1991;17:17-23.[Medline]
  12. Faymonville ME, Princemail J, Duchateau J, et al. Myeloperoxidase and elastase as markers of leukocyte activation during cardiopulmonary bypass in humans J Thorac Cardiovasc Surg 1991;102:309-317.[Abstract]
  13. Vogt W. Anaphylatoxinspossible roles in disease. Complement 1986;3:177-188.[Medline]
  14. Wachtfogel YT, Boscoff R, Bauer R, et al. Alpha 1-antitrypsin (Met358-Arg) inhibits the contact pathway of intrinsic coagulation and alters human neutrophil elastase release during SDCC Thromb Haemost 1994;72:843-847.[Medline]
  15. Rinder CS, Rinder HM, Johnson K, et al. Role of C3 cleavage in monocyte activation during extracorporeal circulation Circulation 1999;100:553-558.[Abstract/Free Full Text]
  16. Komai H, Yamamoto F, Tanaka K, et al. Increased lung injury in pulmonary hypertensive patients during open heart operations Ann Thorac Surg 1993;55:1147-1152.[Abstract]
  17. Casey WF, Hauser GJ, Hanrallah RS, Midgle FM, Khan WN. Circulating endotoxin and tumor necrosis factor during pediatric cardiac surgery Crit Care Med 1992;20:1090-1096.[Medline]
  18. Jansen NJG, van Oeveren W, Gu YJ, van Vliet MH, Eijsman L, Wildevuur CRH. Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass Ann Thorac Surg 1992;54:744-748.[Abstract]
  19. Starnes Jr HF, Warren RS, Jeevanandam M, et al. Tumor necrosis factor and the acute metabolic response to tissue injury in man J Clin Invest 1988;82:1321-1325.[Medline]
  20. MacGregor IR, Perrie AM, Donnelly SC, Haslett C. Modulation of human endothelial thrombomodulin by neutrophils and their release products Am J Respir Crit Care Med 1997;155:47-52.[Abstract]
  21. Welters I, Menges T, Ballesteros M, et al. Thrombin generation and activation of the thrombomodulin protein C system in open heart surgery depend on the underlying cardiac disease Thromb Res 1998;92:1-9.[Medline]
  22. Yamazaki T, Ooshima H, Usui A, Watanabe T, Yasuura K. Protective effects of ONO-5046Na, a specific neutrophil elastase inhibitor, on postperfusion lung injury Ann Thorac Surg 1999;68:2141-2146.[Abstract/Free Full Text]
  23. Eppinger MJ, Deeb GM, Bolling SF, Ward PA. Mediators of ischemia-reperfusion injury of rat lung Am J Pathol 1999;150:1773-1784.



This article has been cited by other articles:


Home page
 Eur. J. Cardiothorac. Surg.Home page
F. Shikata, T. Yagihara, K. Kagisaki, I. Hagino, S. Shiraishi, J. Kobayashi, and S. Kitamura
Does the off-pump Fontan procedure ameliorate the volume and duration of pleural and peritoneal effusions?
Eur. J. Cardiothorac. Surg., September 1, 2008; 34(3): 570 - 575.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
A. Castellheim, T. N. Hoel, V. Videm, E. Fosse, A. Pharo, J. L. Svennevig, A. E. Fiane, and T. E. Mollnes
Biomarker Profile in Off-Pump and On-Pump Coronary Artery Bypass Grafting Surgery in Low-Risk Patients
Ann. Thorac. Surg., June 1, 2008; 85(6): 1994 - 2002.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
O. S. Goksel and E. Tireli
Factors influencing early and late outcome following Fontan procedure in the current era
Eur. J. Cardiothorac. Surg., September 1, 2007; 32(3): 553 - 553.
[Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
I. Adachi, T. Yagihara, K. Kagisaki, I. Hagino, T. Ishizaka, J. Kobayashi, S. Kitamura, and H. Uemura
Preoperative small pulmonary artery did not affect the midterm results of Fontan operation
Eur. J. Cardiothorac. Surg., July 1, 2007; 32(1): 156 - 162.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Yoichi Kawahira
Hideki Uemura
Toshikatsu Yagihara
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kawahira, Y.
Right arrow Articles by Yagihara, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kawahira, Y.
Right arrow Articles by Yagihara, T.
Related Collections
Right arrow Congenital - acyanotic

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS