Sufentanil

Background: Pulmonary thromboendarterectomy (PTE) is an effective but challenging treatment for chronic thromboembolic pulmonary hypertension (CTEPH). PTE is associated with marked hemodynamic instability in the perioperative course, suggesting the involvement of circulating mediators. The aim of this study was to characterize the expression of proinflammatory and anti-inflammatory cytokines in patients undergoing PTE.

Methods: Fourteen patients with CTEPH (mean [+ or -] SD] pulmonary vascular resistance, 1,056 [+ or -] 399 dyne * s * [cm.sup-5]) underwent PTE using cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Peripheral arterial blood samples were drawn prior to patients undergoing sternotomy, during CPB, before and after DHCA, and 0, 8, 16, 24, and 48 h after surgery. An enzyme-linked-immunosorbent assay was used to analyze the plasma levels of tumor necrosis factor (TNF)-[alpha], interleukin (IL)-6, and IL-10. Seven patients undergoing aortic arch replacement (ARCH) in DHCA served as a control group.

Results: Prior to and during PTE, the CTEPH patients exhibited elevated TNF-[alpha] levels, which decreased within the first 24 postoperative hours (p = 0.02). There was no TNF-[alpha] release among patients in the ARCH group. IL-6 levels were similar in both groups throughout the perioperative course. A profound anti-inflammatory response was observed in the PTE group, which was reflected by elevated IL-10 levels prior to surgery and a marked peak level immediately after surgery. A positive correlation was found between maximum vasopressor support and peak levels of IL-6 (r = 0.82) in the PTE patients.

Conclusion: Heart failure due to CTEPH appears to generate a pronounced inflammatory response with the release of proinflammatory and anti-inflammatory cytokines. PTE results in the rapid normalization of preoperatively elevated TNF-[alpha] levels. IL-6-mediated systemic inflammatory cascades may be involved in the regulation of peripheral vascular tone after PTE.

Key words: heart failure; pulmonary vascular resistance; right ventricle; surgery

Abbreviations: ARCH = aortic arch replacement; CPB = cardiopulmonary bypass; CTEPH = chronic thromboembolic pulmonary hypertension; DHCA = deep hypothermic circulatory arrest; IL = interleukin MPAP = mean pulmonary artery, pressure; NYHA = New York Heart Association; PTE = pulmonary thromboendarterectomy; PVR = pulmonary vascular resistance; TNF = tumor necrosis factor

**********

Pulmonary thromboendarterectomy (PTE) is an effective and specific therapeutic approach in patients with chronic thromboembolic pulmonary hypertension (CTEPH). (1) It drastically reduces pulmonary vascular resistance (PVR) and leads to a striking improvement in or elimination of heart failure. (1-9) Compared to the natural prognosis of CTEPH, PTE provides a survival advantage that is even better than that of lung transplantation. (1,4,5)

The postoperative course after PTE is associated with marked morbidity, which not only leads to the prolonged need for intensive care, but may also contribute to mortality. The hospital mortality rate is considerable and ranges from 5 to 23%. [3,5-9] Common causes of death are massive hemoptysis, pulmonary reperfusion edema, right ventricular failure, or multiple organ failure. Even in the absence of major complications, the intraoperative and postoperative hemodynamic management of PTE patients can be difficult. The most striking phenomenon is a combination of profound systemic vasodilation and a reversible component of pulmonary hypertension. These hemodynamic alterations commonly subside 24 to 72 h after surgery but may be responsible for the development of the major complications mentioned above.

The lung, and especially the endothelial lining of the pulmonary circulation, play an active role in hemodynamic and immunologic processes, including the production and action of various inflammatory mediators. (10) In addition, certain cytokines have been demonstrated to be involved in chronic heart failure. (11-15) Proinflammatory cytokines have been shown to be part of the physiologic response to cardiopulmonary bypass (CPB) (16) and ischemia/ reperfusion injury. (16,17) Since PTE is a major insult to the pulmonary vascular endothelium, is a long operative procedure, and requires long CPB times, (2,3,6,7,9) we hypothesized that cytokines should be released from the pulmonary circulation in response to the pulmonary endarterectomy. These cytokines might contribute to the marked hemodynamic alterations in the postoperative course by cytokine-triggered vasoregulation.

Thus, we sought to characterize the expression of proinflammatory and anti-inflammatory cytokines in patients undergoing PTE, and to analyze the potential effect of cytokines Oil hemodynamic alterations after surgery.

PATIENTS AND METHODS

Patients

Fourteen patients with right heart failure (mean [[+ or -] SD] New York Heart Association [NYHA] class, 3.4 [+ or -] 0.5) due to CTEPH (mean pulmonary artery pressure [MPAP], 48 [+ or -] 8 mm Hg; mean PVR, 1,056 [+ or -] 399 dyne * s * [cm.sup.-5]) were studied in conjunction with PTE (Table 1). Seven patients with aneurysmal dilatation of the aortic arch (Table 1) underwent aortic arch replacement (ARCH) and served as a control group. The study was approved by a University Hospital Ethics Review Committee. and in formed consent was obtained from all patients.

A triple-lumen central venous line was placed for the IV administration of drugs. Arterial BP was continously recorded after cannulation of a radial artery. Hemodynamic monitoring included a surgically placed 3.6F left atrial catheter in all patients and a 7.5F flow-directed Swan-Ganz-catheter (Baxter catheter; Edwards; Irvine, CA) in the PTE patients. In all patients, anesthesia was introduced by the IV application of etomidate and sufentanil, and was maintained by the administration of propofol and sufentanil.

Surgical Procedures

After undergoing a median sternotomy, the patients were placed on CPB by aortic and bicaval cannulation (PTE group) or right atrial cannulation (ARCH group) and were cooled to a nasopharyngeal temperature of 18 to 20[degrees]C. Cardiac arrest was induced by the infusion of cold blood cardioplegia into the aortic root (PTE group) or directly into the coronary ostia (ARCH group) after aortic crossclamping.

For PTE patients, the central pulmonary arteries were opened within the pericardium. A dissection plane was developed, which was followed to segmental levels as described previously. (2) Repeated periods of deep hypothermic circulatory arrest (DHCA) limited to 20 min were utilized to achieve accurate visualization during peripheral dissection. After the completion of the pulmonary endarterectomy, CPB was resumed, and the patient was rewarmed. Concomitant cardiac procedures (Table 2) were performed during the cooling and rewarming periods. Weaning from CPB was started after rewarming to a rectal temperature of 34[degrees]C. Before reducing pump flow, the mean arterial BP was regulated to approximately 60 mm Hg using IV infusion of norepinephrine if vascular resistance was low. Weaning from CPB was accomplished by the stepwise reduction of pump flow, the monitoring of mean pulmonary artery pressures (MPAPs), and the careful administration of volume to maintain at cardiac index of > 2.2 [L/min/m.sup.2]. If MPAP exceeded 30 mm Hg, nitroglcyerine was utilized via IV infusion to reduce preload.

For ARCH, one period of DHCA was used. Utilizing standard techniques, either partial arch replacement (two patients) or total arch replacement (five patients) was peformed. Concomitant procedures (Table 2) also were performed during the rewarming period. Before reducing pump flow, mean systemic arterial pressure was regulated to 50 to 70 mm Hg, using either norepinephrine or nitroglycerine infusion depending on systemic vascular resistance. Weaning from CPB was accomplished by the stepwise reduction of pump flow, keeping the blood volume of the patient constant.

Cytokine Analysis

Arterial blood samples were drawn from the radial artery catheter prior to surgery (after the induction of anesthesia and line placement, and before sternotomy), during CPB before DHCA (cooling period, approximately 28[degrees]C nasopharyngeal) and after DHCA (rewarming period, approximately 28[degrees]C nasopharyngeal) as well as 0, 8, 16, 24, and 48 h postoperatively after arrival at the ICU. Blood samples were centrifuged at 1,200 revolutions per minute for 10 min, and the plasmatic supernatant was analyzed for tumor necrosis factor (TNF)-[alpha], interleukin (IL)-6, and IL-10 utilizing commercially available enzyme-linked immunosorbent assay kits (Boche Molecular Biochemicals; Mannheim, Germany). Recombinant human TNF-[alpha], IL-6, and IL-10 served as standard controls.

Statistical Analysis

Data are given as the mean [+ or -] SD. Statistical differences were assessed with standard statistic software (SigmaStat, version 2.0; Jandel Scientific; San Rafael CA) using the paired t test if normal distribution had been confirmed by the Kolmogorov-Smirnov test. In case of the violation of parametric testing, the Wilcoxon signed rank test was performed. A p value of < 0.05 was considered to indicate a significant difference. Nonparametric correlation (Spearman) was applied to correlate cytokine levels in peripheral plasma to hemodynamic parameters and vasopressor support.

RESULTS

PTE included a mean duration of 142 [+ or -] 21 min of CPB, 81 [+ or -] 15 min of myocardial ischemia, and 40 [+ or -] l0 min of DHCA. PTE significantly decreased the MPAP (p < 0.001) and PVR (p < 0.001) within the first 48 h after surgery (Table 2). Two patients with residual pulmonary hypertension after surgery died in the early postoperative course dim to multiple organ failure (one patient) and massive reperfusion edema (one patient). All other PTE patients were discharged from the hospital in good condition. ARCH was associated with a mean duration of 114 [+ or -] 30 min of CPB, 56 [+ or -] 13 min of myocardial ischemia, and 21 [+ or -] 8 min of DHCA. All patients in the ARCH group were discharged from the hospital.

The mean preoperative plasma level of TNF-[alpha] in ARCH group patients was 1.8 [+ or -] 3.3 pg/mL (Fig 1). In the PTE patients, the plasma levels of TNF-[alpha] were elevated prior to surgery in 8 of 14 patients (57%; NYHA class III, 4 of 9 patients; NYHA class IV, 4 of 5 patients) with a resulting mean level of 9.1 [+ or -] 15.5 pg/mL (Fig 1). There was no correlation between TNF-[alpha] level and preoperative pulmonary hemodynamics (TNF-[alpha] vs MPAP, r = 0.48; TNF-[alpha] vs PVR, r = 0.21). Following PTE, plasma levels of TNF-[alpha] decreased significantly within 24 h (p = 0.02 vs preoperative levels at 24 and 48 h before surgery). Interestingly, TNF-[alpha] levels did not decrease postoperatively in the two patients who died in the hospital. Both of these patients had a persistence of pulmonary hypertension during the postoperative period and died at persistently high TNF-[alpha] levels of 11.0 pg/mL at 48 h postoperatively and 17.9 pg/mL directly after surgery, respectively.

[FIGURE 1 OMITTED]

IL-6 levels were elevated prior to surgery in 36% of the PTE patients (IL-6 levels: PTE group, 4.4 -4- 5.7 pg/mL; ARCH group, 2.0 [+ or -] 3.5 pg/mL) [Fig 2]. Both groups exhibited a sharp peak in IL-6 plasma levels immediately after surgery (p < 0.001 vs preoperative levels). The levels decreased during the postoperative period but remained elevated throughout the observation period (Fig 2). A positive correlation was found between peak IL-6 levels and preoperative pulmonary hemodynamics (peak IL-6 vs preoperative MPAP, r = 0.65 and p = 0.02; peak IL-6 vs preoperative PVR, r = 0.54 and p = 0.05).

[FIGURE 2 OMITTED]

Elevated levels of IL-10 were found in 29% of the PTE patients prior to surgery, all of which also had preoperative elevation of TNF-[alpha] levels (PTE group, 4.4 [+ or -] 5.7 pg/mL; ARCH group, 1.3 [+ or -] 3.5 pg/mL) [Fig 3]. During PTE, a marked increase in IL-10 was observed with a mean peak level of 593 [+ or -] 307 pg/mL at 0 h (p < 0.001 vs preoperative levels) [Fig 3], followed by a drastic decrease. Within 8 h after surgery, IL-10 levels were similar in both groups.

[FIGURE 3 OMITTED]

During the early postoperative course, systemic vasodilation was observed in all PTE patients, requiring a mean peak dose of norepinephrine of 0.6 [+ or -] 0.5 [micro]g/kg/min. A mean peak of only 0.1 [+ or -] 0.2 [micro]g/kg/min was required in ARCH patients during the postoperative period. The dose of vasopressor support did not correlate with preoperative MPAP or PVR levels. Statistical analysis revealed a strong correlation between the maximum norepinephrine dosage and the peak plasma levels of circulating IL-6 in the PTE group (r = 0.82; p = 0.0003) [Fig 4]. There was no such correlation in the ARCH group (r = 0.49; p = not significant). No correlation was found between vasopressor support and peripheral plasma levels of TNF-[alpha] and IL-10 in the PTE or the ARCH groups.

[FIGURE 4 OMITTED]

DISCUSSION

Patients with CTEPH have a poor prognosis, which is primarily determined by the degree of pulmonary artery hypertension. (1) Affected patients commonly receive diagnoses after symptoms of heart failure already have developed, and almost all patients are in NYHA class III or IV at the time of diagnosis and consecutive surgery. (1) The treatment of such patients with PTE is an effective therapeutic approach, but implies a hospital mortality rate between 5% and 23%. (3,5-9) The risk of postoperative death appears to correlate with the severity of preoperative heart failure. (5,6.8,9) The initial perioperative period is frequently associated with hemodynamic instability, including systemic vasodilation and a reversible component of pulmonary vasoconstriction. These observations indicate an effect of systemic factors, either related to preexisting heart failure or the operative procedure itself.

Chronic heart failure has been found to involve changes in neuroendocrine, vasoactive, and inflammatory mediators. Among the inflammatory mediators, TNF-[alpha] and IL-6 have been found to correlate with functional status. (11) Patients with heart failure in NYHA classes III and IV have been shown to exhibit high plasma levels of TNF-[alpha] and its soluble receptors, indicating a functional association between cytokine-triggered inflammation and the development of chronic heart failure. (11-15,18) Similar to the situation with TNF-[alpha], elevated plasma levels of IL-6 have been uniformly identified in patients with chronic heart failure. [11,13,14,18] The production source of inflammatory mediators in patients with chronic heart failure may be the myocardium itself (15,19) or the lung. (20)

Cytokine production also has been shown to be influenced by CPB. (16) Blood contact with the CPB circuit initiates a systemic inflammatory response, including leukocyte activation and the release of both proinflammatory and anti-inflammatory cytokines. (21) Increased cytokine production has additionally been shown to be triggered by myocardial ischemia (22) and during DHCA (23) as part of cardiac surgical procedures. Typical pathophysiologic effects are capillary leakage, an increase in body temperature, and a decrease in systemic vascular resistance. (24) Organ dysfunction may occur, and can lead to increased mobidity and mortality.

In many investigations dealing with heart failure and CPB, the parameters TNF-[alpha], IL-6, and IL-10 have been identified as the key indicators of proinflammatory and anti-inflammatory cytokine responses. (11,13,15,18,21,22,25,26) Therefore, we decided to determine the expression of these parameters in patients undergoing PTE.

Our data demonstrated a marked elevation of plasma levels of TNF-[alpha] preoperatively in patients with right heart failure due to CTEPH, with levels corresponding with those reported in studies on left heart failure. (11) This increase in proinflammatory cytokines most likely reflects the extent of CTEPH-associated right heart failure, which has not been described previously.

PTE not only effectively reduced MPAP and PVR, but also was associated with a reduction in plasma levels of TNF-[alpha]. This most likely indicates a rapid improvement of right heart failure after PTE. This observation is comparable with those in reports showing decreased plasma levels of inflammatory mediators in parallel to clinical improvement after the implantation of left ventricular assist devices in patients with severe left heart failure. (27-29) In this context, it is interesting to note that the two PTE patients in our series who died within the early postoperative course exhibited persisting pulmonary hypertension paralleled by a constant elevation of TNF-[alpha]. Both died at their maximum TNF-[alpha] levels, possibly indicating persisting right heart failure.

Previous investigations have demonstrated an increased production of IL-6 in response to surgical trauma and CPB. (16) Comparing coronary bypass surgery with and without CPB, a higher release of IL-6 was observed after the use of CPB. (25, 26) In addition, DHCA has been demonstrated to increase IL-6 release, even though it is not clear whether the DHCA itself or the prolonged CPB times necessary for cooling and sufficient rewarming are primarily responsible. (23) It has uniformly been reported (23,25,26,30) that perioperative cytokine production peaks early after surgery. As expected, we found that both procedures, PTE and ARCH, were associated with a similar rise in IL-6 plasma levels within 0 to 8 h after surgery, which is comparable to the levels reported in other studies involving CPB. (23,25,26,30)

Studies focusing on cytokine expression in heart failure (18, 31) as well as in response to CPB (32-34) have documented a compensatory expression of IL-10 as an anti-inflammatory response to the initiated proinflammatory process. This has been considered to be of crucial importance for patient outcome. (34) Our data also indicate increased anti-inflammatory activity in CTEPH patients. Already in the preoperative period expression was increased (elevated preoperative IL-10 levels were found only in PTE patients with relevant TNF-[alpha] release), and in addition there was a sharp peak IL-10 level immediately after surgery. The expression of IL-10 during and early after surgery otherwise paralleled the expression of IL-6 in both groups, most likely indicating a concomitant proinflammatory and anti-inflammatory cytokine response.

As mentioned above, postoperative patient management after PTE is frequently aggravated by profound systemic vasodilation that is sometimes unresponsive to therapy with vasopressors. Because the avoidance of positive inotropic catecholamines appears to be important, (35) the maintenance of adequate systemic BP requires careful titration with vasopressors such as norepinephrine. Since PTE is a major insult to the pulmonary vascular endothelium, which is known to be a source of IL-6 release, (20) we hypothesized that IL-6 expression may be responsible for the systemic vasoplegia in CTEPH patients after undergoing PTE. In fact, statistical analysis revealed a positive correlation between postoperative peak IL-6 levels and the severity of CTEPH (compared to preoperative MPAP and PVR levels). Most interestingly, there was a strong positive correlation between the postoperative peak IL-6 plasma levels and the maximum vasopressor support early after PTE (Fig 4). There was no such correlation in the ARCH group, even though this group exhibited similar peak IL-6 levels in response to the operative procedure. Furthermore, no such correlation was found for TNF-[alpha] or IL-10 levels in either patient group. We hypothesize that the IL-6 release may promote systemic vasodilation/vasoplegia by inducing an altered pattern of secondary vasoactive mediator release. This alteration of a secondary mediator network may be influenced by the preexisting inflammation in response to the heart failure associated with CTEPH. We did not attempt to uncover specific secondary substances that are directly responsible for such hemodynamic phenomena associated with PTE. Nevertheless, our findings suggest a further involvement of vasoactive mediators (36) such as nitric oxide or arachidonic acid metabolites, which are well-known to be regulated on their transcriptional level by cytokines. (37-39)

In summary the present study analyzes the expression of inflammatory cytokines in patients with CTEPH undergoing PTE. Our data outline the fact that the PTE procedure improves right heart failure in these patients, as indicated by TNF-[alpha] expression. Moreover, the PTE-associated expression of IL-6 may contribute to severe vasoplegia during the early postoperative course.

* From the Departments of Thoracic and Cardiovascular Surgery (Drs. Langer, Schramm, Tscholl, Kunihara, and Schafers) and Anesthesiology and Critical Care (Dr. Bauer) University Hospitals Homburg, Homburg, Germany.

This research was supported by departmental funding from the University Hospitals Homburg.

Manuscript received October 7, 2003; revision accepted February 13, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:permissions@chestnet.org).

Correspondence to: Hans-Joachim Schafers, MD, FCCP, Department of Thoracic and Cardiovascular Surgery, University Hospitals Homburg/Saar University of Saarland, Kirrberger Str D-66421, Homburg/Saar, Germany; e-mail: chhjsc@uniklinik-saarland.de

REFERENCES

(1) Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345: 1465-1472

(2) Daily PO, Dembitsky WP, Jamieson SW. The evolution and the current state of the art of pulmonary thromboendarterectomy. Semin Thorac Cardiovasc Surg 1999; 11:152-163

(3) Jamieson SW, Auger WR, Fedullo PF, et al. Experience and results with 150 pulmonary thromboendarterectomy operations over a 29-month period. J Thorac Cardiovasc Surg 1993; 106:116-126

(4) Archibald CJ, Auger WR, Fedullo PF, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999; 160:523-528

(5) Daily PO, Dembitsky WP, Iversen S, et al. Risk factors for pulmonary thromboendarterectomy. J Thorac Cardiovasc Surg 1990; 99:670-678

(6) Thistlethwaite PA, Mo M, Madani MM, et al. Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg 2002; 124:1203-1211

(7) Masuda M, Nakajima N. Our experience of surgical treatment for chronic pulmonary thromboembolism. Ann Thorac Cardiovasc Surg 2001; 7:261-265

(8) Tscholl D, Langer F, Wendler O, et al. Pulmonary thromboendarterectomy-risk factors for early survival and hemodynamic improvement. Eur J Cardiothorac Surg 2001; 19:771-776

(9) Hartz RS, Byrne JG, Levitsky S, et al. Predictors of mortality in pulmonary thromboendarterectomy. Ann Thorac Surg 1996; 62:1255-1259

(10) Toews GB. Cytokines and the lung. Eur Respir J Suppl 2001; 34:3s-17s

(11) Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27:1201-1206

(12) Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323:236-241

(13) Munger MA, Johnson B, Amber IJ, et al. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996; 77:723-727

(14) Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000; 102:3060-3067

(15) Testa M, Yeh M, Lee P, et al. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 1996; 28:964-971

(16) Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996; 111:469-477

(17) Pham SM, Yoshida Y, Aeba R, et al. Interleukin-6, a marker of preservation injury in clinical lung transplantation. J Heart Lung Transplant 1992; 11:1017-1024

(18) Aukrust P, Ueland T, Lien E, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999; 83:376-382

(19) Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996; 93:704-711

(20) Mabuchi N, Tsutamoto T, Wada A, et al. Relationship between interleukin-6 production in the lungs and pulmonary vascular resistance in patients with congestive heart failure. Chest 2002; 121:1195-1202

(21) Wan S, LeClere JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest 1997; 112:676-692

(22) Wan S, DeSmet JM, Barvais L, et al. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996; 112:806-811

(23) Ashraf S, Bhattacharya K, Tian Y, et al. Cytokine and S100B levels in paediatric patients undergoing corrective cardiac surgery with or without total circulatory arrest. Eur J Cardiothorac Surg 1999; 16:32-37

(24) Christakis GT, Fremes SE, Koch JP, et al. Determinants of low systemic vascular resistance during cardiopulmonary bypass. Ann Thorac Surg 1994; 58:1040-1049

(25) Diegeler A, Doll N, Rauch T, et al. Humoral immune response during coronary artery bypass grafting: a comparison of limited approach, "off-pump" technique, and conventional cardiopulmonary bypass. Circulation 2000; 102(suppl):III95-III100

(26) Struber M, Cremer JT, Gohrbandt B, et al. Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 1999; 68:1330-1335

(27) Clark AL, Loebe M, Potapov EV, et al. Ventricular assist device in severe heart failure: effects on cytokines, complement and body weight. Eur Heart J 2001; 22:2275-2283

(28) Hasper D, Hummel M, Kleber FX, et al. Systemic inflammation in patients with heart failure. Eur Heart J 1998; 19:761-765

(29) Torre-Amione G, Stetson SJ, Youker KA, et al. Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: a potential mechanism for cardiac recovery. Circulation 1999; 100:1189-1193

(30) Wan S, Izzat MB, Lee TW, et al. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68:52-56

(31) Yamaoka M, Yamaguchi S, Okuyama M, et al. Anti-inflammatory cytokine profile in human heart failure: behavior of interleukin-10 in association with tumor necrosis factor-alpha. Jpn Circ J 1999; 63:951-956

(32) Tabardel Y, Duchateau J, Schmartz D, et al. Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men. Surgery 1996; 119:76-80

(33) Kawamura T, Wakusawa R, Inada K. Interleukin-10 and interleukin-1 receptor antagonists increase during cardiac surgery. Can J Anaesth 1997; 44:38-42

(34) Taniguchi T, Koido Y, Aiboshi J, et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med 1999; 27:1262-1264

(35) Mares P, Gilbert TB, Tschernko EM, et al. Pulmonary artery thromboendarterectomy: a comparison of two different postoperative treatment strategies. Anesth Analg 2000; 90:267-273

(36) Sharma R, Coats AJ, Anker SD. The role of inflammatory mediators in chronic heart failure: cytokines, nitric oxide, and endothelin-1. Int J Cardiol 2000; 72:175-186

(37) Marsden PA, Brenner BM. Transcriptional regulation of the endothelin-1 gene by TNF-alpha. Am J Physiol 1992; 262(suppl):C854-C861

(38) Lamas S, Michel T, Brenner BM, et al. Nitric oxide synthesis in endothelial cells: evidence for a pathway inducible by TNF-alpha. Am J Physiol 1991; 261(suppl):C634-C641

(39) Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999; 159:1925-1932

COPYRIGHT 2004 American College of Chest Physicians
COPYRIGHT 2004 Gale Group