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(Chest. 2004;126:135-141.)
© 2004 American College of Chest Physicians

Cytokine Response to Pulmonary Thromboendarterectomy*

Frank Langer, MD; Rene Schramm, MD; Michael Bauer, MD; Dietmar Tscholl, MD; Takashi Kunihara, MD and Hans-Joachim Schäfers, MD, FCCP

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

Correspondence to: Hans-Joachim Schäfers, 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{at}uniklinik-saarland.de


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
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 [± SD] pulmonary vascular resistance, 1,056 ± 399 dyne · s · cm–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


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
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.123456789 Compared to the natural prognosis of CTEPH, PTE provides a survival advantage that is even better than that of lung transplantation.145

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%.356789 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.1112131415 Proinflammatory cytokines have been shown to be part of the physiologic response to cardiopulmonary bypass (CPB)16 and ischemia/reperfusion injury.1617 Since PTE is a major insult to the pulmonary vascular endothelium, is a long operative procedure, and requires long CPB times,23679 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 on hemodynamic alterations after surgery.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients
Fourteen patients with right heart failure (mean [± SD] New York Heart Association [NYHA] class, 3.4 ± 0.5) due to CTEPH (mean pulmonary artery pressure [MPAP], 48 ± 8 mm Hg; mean PVR, 1,056 ± 399 dyne · s · cm–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 informed consent was obtained from all patients.


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  		Table 1. Demographic Data*

 
A triple-lumen central venous line was placed for the IV administration of drugs. Arterial BP was continuously 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°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°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 a cardiac index of > 2.2 L/min/m2. If MPAP exceeded 30 mm Hg, nitroglcyerine was utilized via IV infusion to reduce preload.


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  		Table 2. Operative Data*

 
For ARCH, one period of DHCA was used. Utilizing standard techniques, either partial arch replacement (two patients) or total arch replacement (five patients) was performed. 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°C nasopharyngeal) and after DHCA (rewarming period, approximately 28°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 (Roche 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 ± 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
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
PTE included a mean duration of 142 ± 21 min of CPB, 81 ± 15 min of myocardial ischemia, and 40 ± 10 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 due 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 ± 30 min of CPB, 56 ± 13 min of myocardial ischemia, and 21 ± 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 ± 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 ± 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.



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  		Figure 1. Mean (± SEM) TNF-{alpha} levels in the PTE and ARCH groups. preop = preoperative; postop = postoperative.

 
IL-6 levels were elevated prior to surgery in 36% of the PTE patients (IL-6 levels: PTE group, 4.4 ± 5.7 pg/mL; ARCH group, 2.0 ± 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).



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  		Figure 2. Mean (± SEM) IL-6 levels in the PTE and ARCH groups. See the legend of Figure 1 for abbreviations not used in the text.

 
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 ± 5.7 pg/mL; ARCH group, 1.3 ± 3.5 pg/mL) [Fig 3 ]. During PTE, a marked increase in IL-10 was observed with a mean peak level of 593 ± 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.



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  		Figure 3. Mean (± SEM) IL-10 levels in the PTE and ARCH groups. See the legend of Figure 1 for abbreviations not used in the text.

 
During the early postoperative course, systemic vasodilation was observed in all PTE patients, requiring a mean peak dose of norepinephrine of 0.6 ± 0.5 µg/kg/min. A mean peak of only 0.1 ± 0.2 µg/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.



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  		Figure 4. Correlation of peak plasma IL-6 levels and peak norepinephrine dosage in the PTE group.

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
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%.356789 The risk of postoperative death appears to correlate with the severity of preoperative heart failure.5689 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.111213141518 Similar to the situation with TNF-{alpha}, elevated plasma levels of IL-6 have been uniformly identified in patients with chronic heart failure.11131418 The production source of inflammatory mediators in patients with chronic heart failure may be the myocardium itself1519 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 ischemia22 and during DHCA23 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 morbidity 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 pro-inflammatory and anti-inflammatory cytokine responses.1113151821222526 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.272829 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.2526 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 reported23252630 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.23252630

Studies focusing on cytokine expression in heart failure1831 as well as in response to CPB323334 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 mediators36 such as nitric oxide or arachidonic acid metabolites, which are well-known to be regulated on their transcriptional level by cytokines.373839

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.


   Footnotes
 
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

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

Received for publication October 7, 2003. Accepted for publication February 13, 2004.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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