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Ann Thorac Surg 1997;63:971-974
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Circulatory Resuscitation With Left Ventricular Assist Device Support Reduces Interleukins 6 and 8 Levels

Departments of Surgery and Medicine, College of Physicians & Surgeons, Columbia University, New York, New York

Accepted for publication October 19, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Background. Elevated tumor necrosis factor serum levels have been reported in patients with severe congestive heart failure. This study was designed to characterize the cytokine profile in patients with acute circulatory collapse.

Methods. Blood drawn from 14 consecutive patients within 24 hours before undergoing left ventricular assist device placement and after at least 30 days of mechanical assistance or before transplantation was assayed for levels of interleukin 6, interleukin 8, and tumor necrosis factor-.

Results. Interleukin 6 level was elevated in 11 (79%), interleukin 8 in 10 (71%), and tumor necrosis factor in 2 (14%) of the 14 patients. After hemodynamic recovery, interleukin 6 levels decreased from 33.6 +/- 9 pg/mL to 11.3 +/- 4 pg/mL (p = 0.05) and interleukin 8 levels decreased from 122 +/- 34 pg/mL to 19.7 +/- 8 pg/mL (p = 0.005). Tumor necrosis factor- levels did not vary significantly; they were associated with infection in 2 left ventricular assist device recipients and normalized after left ventricular assist device support. All patients had resolution of circulatory shock after mechanical support and had improvement in parameters of end-organ function.

Conclusions. Circulatory shock treated with left ventricular assist device placement is associated with a proinflammatory response similar to that seen in septic shock. The decrease in cytokine serum levels that follows hemodynamic recovery suggests that these cytokines may be markers of tissue damage and may modulate cardiac dysfunction.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
A growing body of experimental and clinical evidence suggests that proinflammatory cytokines may play a fundamental role in modulating cardiac function during disease states [1]. In fact, these peptides have been implicated recently in mediating stunned myocardium [2, 3], possessing negative inotropic effects [4], and appearing in the serum of patients with chronic congestive heart failure and cachexia [5]. Furthermore, these cytokines have also been associated with the myocardial dysfunction that commonly follows cardiopulmonary bypass [6–9].

The proinflammatory response in patients with acute circulatory collapse has not been well characterized. To assess the potential role of proinflammatory cytokines during acute circulatory shock, we measured the serum levels of tumor necrosis factor-alpha (TNF-), interleukin 6 (IL-6), and interleukin 8 (IL-8) in patients undergoing left ventricular assist device (LVAD) placement. Measurements were made at the time of implantation and after 30 days of mechanical assistance or just before cardiac transplantation.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Study Population
Between August 1, 1994, and April 30, 1995, 14 patients underwent implantation of the Thermo Cardiosystems (Woburn, MA) HeartMate 1000 IP (n = 11) or 1205 VE (n = 3) as a bridge to transplantation at our institution. There were 12 men and 2 women with a mean (+/- SD) age of 52 +/- 6 years (range, 45 to 62 years). The most common cause of end-stage heart failure was coronary artery disease (10 patients, 71%). At the time of implantation, 7 patients (50%) were receiving intraaortic balloon pump support, 4 patients (29%) were on mechanical ventilation, and all 14 were on intravenous inotropic support (dobutamine or phosphodiesterase inhibitor, or a combination of both). Mean cardiac index was 1.8 +/- 0.1 L • min^-1 • m^-2, mean pulmonary capillary wedge pressure was 26 +/- 1.6 mm Hg, and mean arterial blood pressure was 60 +/- 12 mm Hg. All patients resided in our intensive care unit until the time of LVAD implantation. Duration of LVAD implantation ranged from 24 to 135 days (mean, 64 days).

Eight men and 2 women without evidence of cardiovascular disease served as normal controls. All patients and normal subjects gave informed consent before the study.

	Cytokine Measurements

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Approximately 20 mL of blood was collected from each patient within 24 hours before implantation and again after at least 30 days of mechanical support or just before cardiac transplantation. Blood was also collected from 10 healthy individuals to serve as controls. Serum was separated from blood elements by centrifugation, and aliquots were stored at -70°C until the time of the assay.

Concentrations of TNF-, IL-6, and IL-8 were measured with commercially available enzyme-linked immunoabsorbent assay kits (R&D Systems, Minneapolis, MN) (in picograms per milliliter) following the manufacturer's instructions. Briefly, samples were diluted 1:1 in appropriate diluent and incubated for 2 hours at room temperature in wells coated with anticytokine antibodies. Wells were washed and incubated similarly with polyclonal anticytokine antibody conjugated to horseradish peroxidase. After further washing, a solution of tetramethylbenzidine and hydrogen peroxide was added and the reaction was then quenched after 20 minutes with sulfuric acid. Plates were then submitted to spectrophotometric analysis at 450 nm with wavelength correction set to 570 nm. Lower limits of detection in these assays were less than 4.4 pg/mL for TNF-, 18.1 pg/mL for IL-8, and 0.7 pg/mL for IL-6. Undetectable serum levels were assigned a value of zero. All samples were run in duplicate; the average value of the two measurements is reported.

	Data Analysis

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
All values are reported as mean +/- standard error of the mean unless otherwise specified. Preimplantation serum cytokine levels, hemodynamic profiles, and end-organ function tests were compared with those after at least 30 days of mechanical support (or before cardiac transplantation) with the Wilcoxon signed rank test and Student's t-test for paired observations (InStat software package for MacIntosh). A two-tailed probability value of 0.05 or less was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Cytokine Levels
Proinflammatory cytokine serum concentration changes after circulatory resuscitation are depicted in Figure 1. At the time of LVAD implantation, the mean serum concentration of IL-6 was 33.6 +/- 9 pg/mL (range, 1.07 to 106.9). In 11 patients, levels were above the detection limits of the assay, and in 10 patients, serum concentrations were more than 10 pg/mL. Preoperative IL-8 concentration averaged 122 +/- 34 pg/mL (range, 0 to 350.76 pg/mL) and was not detectable in 4 patients. Mean serum TNF- concentration was 9.8 +/- 7 pg/mL, but was above the detection limit of the assay in only 2 patients. Two patients underwent emergent LVAD implantation in the setting of active clinical infection (active infection was defined as positive urine, sputum, or blood cultures, in conjunction with a temperature of >38.0°C, or leukocytosis >11,000/mL) (Table 1). Interleukin-6, IL-8, and TNF- levels were not detected in the serum of any of the 10 healthy controls.

View larger version (18K): [in this window] [in a new window]   Fig 1. . Mean preimplantation and postresuscitation interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor- (TNF) serum levels among left ventricular assist device (LVAD) recipients. Error bars represent +/- standard error of the mean.

	Hemodynamics and End-Organ Function

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
The hemodynamic profile of all 14 LVAD recipients improved over the study period. Mean cardiac index rose from 1.8 +/- 0.1 L • min^-1 • m^-2 (95% confidence interval, 1.5 to 2.1 L • min^-1 • m^-2) to 2.8 +/- 0.2 L • min^-1 • m^-2 (95% confidence interval, 2.5 to 3.2 L • min^-1 • m^-2; p = 0.0007) and mean blood pressure increased from 60 +/- 3 mm Hg (95% confidence interval, 53 to 68 mm Hg) to 83 +/- 3 mm Hg (95% confidence interval, 76 to 90 mm Hg; p = 0.002). A statistically significant improvement in renal and liver function tests was observed (Table 1). At the time of the second blood draw (30-day support or just before transplantation), none of the patients required mechanical ventilation, inotropic support, or balloon counterpulsation.

	Follow-up

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Mean follow-up after LVAD implantation is 311 +/- 18 days (range, 214 to 453 days). All 14 patients are alive and well. Ten patients have undergone successful transplantation and 1 has had the device explanted after 101 days of support and is currently in New York Heart Association functional class II. Routine cultures of the explanted devices were positive in 3 of these patients (Table 2). Of the 3 patients awaiting transplantation, 1 remains hospitalized with a pneumatic device and the remaining 2 patients have been discharged home with implantable devices.

	Comment

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

In addition to their roles as mediators of numerous inflammatory, immune, and septic responses, increasing evidence suggests that proinflammatory cytokines may modulate cardiac function [1]. Tumor necrosis factor has been identified as a myocardial depressant substance in sepsis [11, 12], and its concentration has been found to be elevated in the serum of patients with advanced congestive heart failure [5]. Moreover, it has recently been demonstrated to possess direct cardiotoxic effects [13]. In our group, only 2 patients had detectable levels of TNF- before LVAD implantation. Both of these patients had clinically active infection, which may explain the observed elevated levels. Unlike patients with severe chronic heart failure, our cohort of patients presented with acute cardiogenic shock.

Interleukin-6, a pleiotropic peptide involved in diverse biologic processes [14], has been shown to be a mediator of stunned myocardium after cardiopulmonary bypass [2, 8] and to have negative inotropic effects in vitro [4]. Elevated levels of this cytokine have been reported recently after myocardial infarction [3]. Furthermore, increasing IL-6 levels have been detected in septic patients and it has been suggested to be a sensitive marker of tissue damage [15–18]. In 11 (79%) of the patients, elevated serum IL-6 levels were detected. Only 2 of these patients had clinical evidence of active infection. This observation suggests that IL-6 levels may be elevated in the absence of culture-positive sepsis in patients with circulatory shock. Given the experimental data implicating the role of IL-6 in cardiac dysfunction, the intriguing possibility exists that IL-6 may modulate the cardiac dysfunction of acute circulatory failure.

Interleukin-8, an important neutrophil chemotactic and degranulating agent [7], has also received attention as a potential mediator of myocardial stunning after cardiopulmonary bypass [6–8, 19]. Experimental models of cardiac reperfusion injury suggest that myocardial infiltration with neutrophils followed by degranulation and generation of superoxide free radicals are related to the pathogenesis of myocardial injury [20]. In fact, neutrophil-free blood may protect the ischemic myocardium during reperfusion [21]. Given that IL-8 was not detected in any of the healthy individuals and yet 10 (71%) of our patients had elevated serum levels of this cytokine, we postulate that IL-8 may yet be another element contributing to cardiac dysfunction during acute circulatory failure.

The results of this study should be interpreted cautiously given several limitations. First, only a single blood specimen was drawn from each patient and, therefore, transient or late increases may have been missed. Second, levels of cytokines may vary because of binding of cytokines to plasma proteins, rapid clearance by circulating receptors, or degradation by plasma proteases [22]. Furthermore, within the limit of our assay, a number of patients did not have increased levels of IL-6 and IL-8 before LVAD placement. We cannot rule out the possibility that these cytokines might have been acting locally at low concentrations that do not spill over to plasma for detection. Finally, our results are only observational in nature. Indeed, based on these data, it is difficult to assert whether elevated cytokines are a marker of circulatory failure or, on the other hand, are implicated in its pathogenesis.

All of the patients in the study showed significant hemodynamic improvement after LVAD placement. Concomitant with hemodynamic improvement, IL-6 and IL-8 levels significantly decreased. We were unable to establish that elevated preoperative levels of IL-6 or IL-8 correlated with active infection, except in the 2 patients who also exhibited elevated TNF- levels. The low number of clinically detectable infections suggests that a stimulus other than an infection triggered the elevated levels of these cytokines. Finally, presence of elevated pre-LVAD or pretransplantation IL-6 and IL-8 levels were not correlated with increased morbidity.

In summary, we have observed that patients with acute circulatory shock have elevated levels of IL-6 and IL-8. Unlike patients with chronic heart failure, elevation in TNF- was not observed preoperatively except in the setting of active infection. All patients had their cytokine profile determined at the peak of hemodynamic instability, as judged by low cardiac index and systemic pressure with associated poor end-organ perfusion. The coexistence of poor end-organ function, hemodynamic deterioration, and elevated inflammatory cytokine profile in this group of patients mimics the hemodynamic scenario of gram-negative septic shock, a state in which all three studied cytokines have been implicated in the pathogenic process [16, 18, 25–28]. However, unlike septic shock, the hemodynamic characteristics of these patients was not related to an infectious cause.

We conclude that the circulatory shock that precedes ventricular assist device placement is associated with elevated IL-6 and IL-8 serum levels in the absence of overt clinical infection. The decrease in cytokine serum levels that follows hemodynamic recovery suggests that these cytokines may be markers of tissue damage. Whether IL-6 and IL-8 modulate cardiac dysfunction in this setting remains unsettled.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 
Address reprint requests to Dr Goldstein, Department of Surgery, College of Physicians & Surgeons, 622 W 168 St, PH Box 268, New York, NY 10032.

	References

Top Footnotes Abstract Introduction Material and Methods Cytokine Measurements Data Analysis Results Hemodynamics and End-Organ... Follow-up Comment References

 

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This Article Abstract 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): Daniel J. Goldstein Robert C. Ashton, Jr David J. Pinsky Mehmet C. Oz Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldstein, D. J. Articles by Oz, M. C. Search for Related Content PubMed PubMed Citation Articles by Goldstein, D. J. Articles by Oz, M. C.