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Systemic inflammatory response syndrome predicts increased mortality in patients after transcatheter aortic valve implantation

Jan-Malte Sinning, Anne-Cathérine Scheer, Viktoria Adenauer, Alexander Ghanem, Christoph Hammerstingl, Robert Schueler, Cornelius Müller, Mariuca Vasa-Nicotera, Eberhard Grube, Georg Nickenig, Nikos Werner
DOI: http://dx.doi.org/10.1093/eurheartj/ehs002 1459-1468 First published online: 27 January 2012

Abstract

Aims The outcome of patients undergoing surgical or interventional therapy is unfavourably influenced by severe systemic inflammation. We assessed the impact of a systemic inflammatory response syndrome (SIRS) on the outcome after transcatheter aortic valve implantation (TAVI).

Methods and results One hundred and fifty-two high-risk patients (mean age: 80.5 ± 6.5 years, mean logistic EuroSCORE: 30.4 ± 8.1%) with symptomatic severe aortic stenosis underwent TAVI. Proinflammatory cytokines [interleukin-6 (IL-6) and interleukin-8 (IL-8)], and acute phase reactants [C-reactive protein (CRP) and procalcitonin (PCT)] were measured at baseline and 1, 4, 24, 48, 72 h, and 7 days after TAVI. Sixty-one of 152 patients developed SIRS during the first 48 h after TAVI. Systemic inflammatory response syndrome patients were characterized by leucocytosis ≥12 × 109/L (83.6 vs. 12.1%; P < 0.001), hyperventilation (80.3 vs. 35.2%; P < 0.001), tachycardia (37.7 vs. 9.9%; P < 0.001), and fever (31.1 vs. 3.3%; P < 0.001) compared with patients without SIRS. Furthermore, the occurrence of SIRS was characterized by a significantly elevated release of IL-6 and IL-8 with subsequent increase in the leucocyte count, CRP, and PCT. Major vascular complications [odds ratio (OR) 5.1, 95% confidence interval (CI): 1.3–19.6; P = 0.018] and the number of ventricular pacing runs (OR 1.7, 95% CI: 1.1–2.8; P = 0.025) were independent predictors of SIRS. The occurrence of SIRS was related to 30-day and 1-year mortality (18.0 vs. 1.1% and 52.5 vs. 9.9%, respectively; P < 0.001) and independently predicted 1-year mortality risk (hazard ratio: 4.3, 95% CI: 1.9–9.9; P < 0.001).

Conclusions SIRS may occur after TAVI and is a strong predictor of mortality. The development of SIRS could be easily identified by a significant increase in the leucocyte count shortly after TAVI.

  • SIRS
  • Inflammation
  • Acute kidney injury
  • Vascular complications
  • Aortic stenosis
  • TAVI

See page 1434 for the editorial comment on this article (doi:10.1093/eurheartj/ehs033)

Introduction

With >40 000 implantations worldwide, transcatheter aortic valve implantation (TAVI) has established as an alternative treatment strategy to open heart surgery for patients with symptomatic severe aortic stenosis and high or prohibitive operative risk.18 Recently, the PARTNER trial has shown that TAVI is non-inferior to surgical aortic valve replacement for all-cause mortality at 1 year in such patients, although important differences in peri-procedural risks have been identified.1 Pre-existing comorbidities and peri-procedural complications such as stroke, acute kidney injury (AKI), and vascular complications aggravate the post-interventional course of TAVI patients.1,913 Emerging data suggest that an elevated leucocyte count during the first 72 h after TAVI might be associated with a post-procedural systemic inflammatory response syndrome (SIRS) which unfavourably impacts the outcome after TAVI.913

It is widely accepted that cardiac surgery and cardiopulmonary bypass (CPB) activate a systemic inflammatory response that is associated with adverse outcome.1417 Several studies suggest that suboptimal organ perfusion during the procedure with subsequent tissue ischaemia–reperfusion (I/R) injury rather than CPB itself leads to a release of various inflammatory mediators into the systemic circulation with the development of SIRS.1820

The aim of our study was (i) to characterize the inflammatory response after TAVI and (ii) to assess the impact of SIRS on the outcome in TAVI patients.

Methods

Patient population

From January 2008 to June 2011, 155 patients with severe, symptomatic aortic stenosis, and high or prohibitive operative risk underwent TAVI at our institution and were included into this prospective study after written informed consent was obtained. Transcatheter aortic valve implantation was performed with the third generation 18-F CoreValve prosthesis (CoreValve Revalving Technology, Medtronic, Minneapolis, MN, USA). Procedural success was achieved in 152/155 (98%) patients with one peri-procedural death (1%) due to cardiogenic shock after balloon valvuloplasty (BAV) and two conversions to open heart surgery (1%). In this analysis, patients with conversion to open heart surgery (n = 2) were excluded as the surgical trauma itself and extracorporeal circulation lead to an inflammatory response.15,19,20 Details about patient screening, valve implantation techniques, and adjunctive medication have been described previously in detail.9

Primary endpoint of the study was the occurrence of SIRS which was defined according to existing guidelines as fulfilling at least two of the following criteria during the first 48 h after TAVI as assessed by monitoring on ICU:21,22 temperature <36.0 or >38.0°C, heart rate >90 beats/min, respiratory rate >20 breaths/min, or PaCO2 <32 mmHg, leucocyte count >12 or <4 (109/L). Secondary clinical outcomes were assessed in accordance with the standardized endpoint definitions for TAVI of the Valve Academic Research Consortium (VARC).23

Information about the cause of death was obtained from the treating hospital, referring cardiolgist, or general practitioner. The study was approved by the local ethics committee of the University of Bonn.

Laboratory methods

Blood samples were obtained pre-procedurally and at 1, 4, 24, 48, 72 h, and 7 days after TAVI. Leucocyte count was measured using fluorescence flow cytometry and electrical impedance (Sysmex XE-2100, Kobe, Japan). High-sensitive C-reactive protein (CRP) levels were determined nephelometrically (hsCRP Flex reagent cartridge, Dimension Vista System, Siemens Healthcare Diagnostics GmbH, Munich, Germany). These measurements were performed in all 152 patients.

Procalcitonin levels were measured with the use of an immunoluminometric assay (Liaison Brahms PCT, DiaSorin S.p.A., Saluggia, Italy). Interleukin-6 (IL-6) and interleukin-8 (IL-8) levels were measured using an immunoluminometric sandwich-assay (IL-6 and IL-8 Immulite Test, Siemens Healthcare Diagnostics GmbH, Munich, Germany). Procalcitonin and IL levels were determined in 98 consecutive patients from January 2010 to June 2011.

Estimated glomerular filtration rate (eGFR) was calculated by the simplified Modification of Diet in Renal Disease formula. Chronic renal failure was defined as GFR ≤60 mL/min/1.73 m2. Acute kidney injury was defined according to the VARC consensus as an increase in serum creatinine to 150–200% (1.5–2.0 × compared with baseline) or increase of ≥0.3 mg/dL (≥26.4 μmol/L) in up to 72 h after TAVI.23

Since packed red blood cell (RBC) transfusions influence the post-TAVI haemoglobin (Hb) measurements, the modified Landefeld equation was used to estimate the corrected nadir Hb level and the net Hb drop after the procedure.24,25 The corrected nadir Hb level was calculated according to the following formula:25Embedded Image

Statistical analysis

Data are presented as mean ± standard deviation if normally distributed or as median and interquartile range (quartile 1/quartile 3) if not normally distributed. Continuous variables were tested for normal distribution with the use of the Kolmogorov–Smirnov test. Categorical variables are given as frequencies and percentages. For continuous variables, a Student's t-test or a Mann–Whitney U-test, as appropriate, was performed for comparison between two groups. When comparing more than two groups, ANOVA or the Kruskal–Wallis test was used. A χ2 or Fisher's exact test was used for analysis of categorical variables. Logistic regression modelling was used to assess the short-term technical outcome and to determine independent predictors of SIRS. We performed univariate Cox proportional hazard models to examine the association of SIRS and other clinical characteristics with cumulative 1-year mortality and to evaluate the impact on long-term clinical outcome. In a multivariate regression analysis, we adjusted for all independent predictors of 1-year mortality of the univariate analysis. We confirmed that the proportionality of hazards assumption was met. Survival according to the occurrence of SIRS was determined with the use of the Kaplan–Meier method. The log-rank test was used to determine statistical differences in terms of survival.

Statistical significance was assumed when the null hypothesis could be rejected at P< 0.05. All P-values are results of two-sided tests. Statistical analyses were conducted with PASW Statistics version 18.0.3 (IBM Corporation, Somer, NY, USA) and MedCalc version 11.1.1.0 (MedCalc Software, Mariakerke, Belgium).

The investigators initiated the study, had full access to and analysed the data, and wrote the manuscript. All authors vouch for the data and analysis.

Results

Baseline characteristics

Transcatheter aortic valve implantation was performed in 152 patients at high risk for open heart surgery as reflected by a mean STS mortality score of 9.8 ± 7.3% and a mean logistic EuroSCORE of 30.4 ± 18.1%. Baseline characteristics are summarized in Table 1.

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Table 1

Baseline characteristics according to the occurrence of systemic inflammatory response syndrome

All patients (n = 152)No SIRS (n = 91)SIRS (n = 61)P-value
Age (years)80.5 ± 6.580.8 ± 6.180.1 ± 7.20.51
Male gender [n (%)]75 (49.3)45 (49.5)30 (49.2)0.97
Logistic EuroSCORE (%)30.4 ± 18.129.1 ± 18.232.4 ± 17.90.28
STS mortality score (%)9.8 ± 7.38.8 ± 6.311.4 ± 8.40.030
Body mass index (kg/m2)24.9 (22.5/28.1)24.8 (22.6/27.7)25.2 (22.3/31.1)0.29
Coronary artery disease [n (%)]93 (61.2)51 (56.0)42 (68.9)0.11
Peripheral artery disease [n (%)]59 (38.8)32 (35.2)27 (44.3)0.28
Previous MI [n (%)]46 (30.3)23 (25.3)23 (37.7)0.11
Previous PCI [n (%)]62 (40.8)35 (38.5)27 (44.3)0.48
Previous CABG [n (%)]19 (12.5)13 (14.3)6 (9.8)0.42
Previous stroke [n (%)]37 (24.3)24 (26.4)13 (21.3)0.48
Chronic renal failure [n (%)]87 (57.2)51 (56.0)36 (59.0)0.63
Serum creatinine (mg/dL)1.24 (1.01/1.60)1.22 (1.00/1.60)1.27 (1.05/1.61)0.68
eGFR (mL/min/1.73 m2)51.9 ± 21.452.5 ± 22.451.0 ± 20.30.69
COPD [n (%)]43 (28.3)22 (24.2)21 (34.4)0.17
Pulmonary hypertension [n (%)]55 (36.2)29 (31.9)26 (42.6)0.18
Left ventricular EF (%)44.2 ± 14.545.6 ± 13.742.2 ± 15.60.17
Aortic valve area (mm2)0.67 ± 0.150.66 ± 0.160.69 ± 0.150.38
Mean gradient (mmHg)38.0 (29.0/51.0)40.0 (30.0/51.0)35.0 (25.0/47.0)0.16
Annulus diameter (mm)23.6 ± 2.223.9 ± 2.223.3 ± 2.10.13
  • CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; EuroSCORE, European System for Cardiac Operative Risk Evaluation score; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; NT-proBNP, N-terminal pro-hormone brain natriuretic peptide; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons; EF, ejection fraction.

Systemic inflammatory response syndrome after transcatheter aortic valve implantation

Systemic inflammatory response syndrome developed in 61 of 152 patients (40.1%) during the first 48 h after TAVI. These patients were characterized by leucocytosis ≥12 × 109/L (83.6 vs. 12.1%; P < 0.001), hyperventilation with a respiratory rate ≥20/min (80.3% vs. 35.2%; P < 0.001), tachycardia with a heart rate ≥90 b.p.m. (37.7 vs. 9.9%; P < 0.001), and fever with a temperature ≥38.0°C (31.1 vs. 3.3%; P < 0.001) compared with patients without SIRS (Figure 1). Patients who developed a post-procedural SIRS had a higher mean STS mortality score at baseline compared with patients without SIRS (11.4 ± 8.4 vs. 8.8 ± 6.3%; P = 0.030). Concerning other baseline characteristics, no significant differences were observed (Table 1).

Figure 1

Parameters of systemic inflammatory response syndrome (SIRS) in patients after transcatheter aortic valve implantation. Systemic inflammatory response syndrome patients (green bars) fulfilled at least two of the following criteria during the first 48 h after TAVI as assessed on ICU: fever or hypothermia (temperature <36.0°C or >38.0°C), tachycardia (heart rate >90 beats/min), hyperventilation (respiratory rate >20 breaths/min or PaCO2 <32 mmHg), leucocytosis or leucopenia (leucocyte count >12 or <4 × 109/L). Non-systemic inflammatory response syndrome patients (blue bars) did not fulfil more than one criterion.

In patients with post-procedural SIRS, an elevated leucocyte count was already observed 4 h after TAVI (10.6 ± 4.6 vs. 8.3 ± 2.4 × 109/L; P = 0.015). The leucocyte count reached its maximum level at 48 h after TAVI (13.6 ± 5.5 vs. 9.1 ± 2.4 × 109/L; P < 0.001) and was significantly increased in patients with SIRS compared with patients without until Day 7 after TAVI (Figure 2).

Figure 2

Leucocyte count according to the occurrence of systemic inflammatory response syndrome (SIRS) after transcatheter aortic valve implantation (TAVI). Mean leucocyte count (109/L) before and at 1, 4, 24, 48, 72 h, and 7 days after transcatheter aortic valve implantation according to the occurrence of systemic inflammatory response syndrome.

The lactate level decreased after the procedure but was significantly higher at 4 h [0.85 (0.60/1.95) vs. 0.70 (0.50/1.00) mmol/L; P = 0.037] and 24 h [1.20 (0.80/1.74) vs. 0.90 (0.80/1.10) mmol/L; P = 0.028] in patients with the development of SIRS.

Inflammatory biomarkers after transcatheter aortic valve implantation

The increase in inflammatory biomarkers after TAVI is summarized in Figure 3. The proinflammatory cytokines IL-6 and IL-8 were significantly increased at 4 h after TAVI and reached their maximum level in SIRS patients compared with patients with uneventful course after 24 h [IL-6: 46.6 (32.8/100.9) vs. 32.4 (22.5/53.0) pg/mL; P = 0.006 and IL-8: 18.8 (14.1/28.7) vs. 13.2 (8.8/17.7) pg/mL; P = 0.001]. Procalcitonin and CRP levels subsequently increased after 24 h in SIRS patients and peaked on Day 2 [procalcitonin (PCT): 0.17 (0.10/0.57) vs. 0.10 (0.07/0.11) µg/L; P < 0.001] and Day 3 [CRP: 89.4 (59.9/123.0) vs. 57.3 (37.7/81.2) mg/L; P = 0.001], respectively.

Figure 3

Inflammatory biomarker increases after transcatheter aortic valve implantation. Median interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), and procalcitonin (PCT) levels in patients after transcatheter aortic valve implantation according to the occurrence of systemic inflammatory response syndrome (SIRS).

Since the PCT level was below the detection limit in most of the TAVI patients without the development of SIRS, we calculated an receiver operating characteristic-curve based cut-off value for PCT (>0.11 µg/L). The occurrence of SIRS was significantly associated with an elevation of the PCT level above this cut-off at 48 h after TAVI (69.2 vs. 30.8%; P < 0.001). However, the PCT level was not superior to the SIRS definition in identifying patients at high risk for 1-year mortality [area under the curve (AUC): 0.75 (0.64–0.87) vs. AUC: 0.74 (0.63–0.85); P = 0.69].

Predictors of systemic inflammatory response syndrome

The development of SIRS was significantly related to the occurrence of major vascular complications (16.4 vs. 3.3%; P = 0.003), major bleeding (14.8 vs. 5.5%; P = 0.042), and AKI (45.9 vs. 7.7%; P < 0.001; Table 2). The amount of contrast dye was significantly higher in SIRS patients [187 (154/246) mL vs. 165 (134/199) mL; P = 0.019]. In addition, SIRS occurred more frequently in patients with the need for repeated ventricular pacing runs (1.5 ± 0.9 vs. 1.1 ± 0.6; P = 0.016) and post-dilation of the valve prosthesis (37.7 vs. 22.0%; P = 0.035). Systemic inflammatory response syndrome patients received more units of packed RBC [2(0/2) vs. 0(0/2); P = 0.019] (Table 2).

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Table 2

Peri-procedural characteristics according to the occurrence of systemic inflammatory response syndrome

All patients (n = 152)No SIRS (n = 91)SIRS (n = 61)P-value
Access site0.11
 Trans-femoral [n (%)]140 (92.1)87 (95.6)53 (86.9)
 Trans-subclavian, percutaneous [n (%)]8 (5.3)2 (2.2)6 (9.8)
 Trans-subclavian, surg. cutdown [n (%)]4 (2.6)2 (2.2)2 (3.3)
Anesthesia type0.99
 Local [n (%)]142 (93.4)85 (93.4)57 (93.4)
 General [n (%)]10 (6.6)6 (6.6)4 (6.6)
Post-dilatation [n (%)]43 (28.3)20 (22.0)23 (37.7)0.035
Pacing runs [n (%)]1.3 ± 0.71.1 ± 0.61.5 ± 0.90.016
Valve-in-valve implantation [n (%)]5 (3.3)1 (1.1)4 (6.6)0.06
Intervention time (min)60.0 (45.0/80.0)60.0 (45.0/77.3)70.0 (45.0/95.0)0.09
Contrast dye (mL)172 (140/205)165 (134/199)187 (154/246)0.004
Red blood cell transfusion [n (%)]82 (53.9)43 (46.7)39 (63.9)0.02
Units of RBC transfusion [n (%)]1 (0/2)0 (0/2)2 (0/2)0.019
Baseline Hb (g/dL)12.1 ± 1.612.2 ± 1.712.1 ± 1.50.69
Net Hb drop (g/dL)4.6 (3.0/7.1)3.8 (2.7/6.4)5.4 (3.4/7.6)0.07
Corrected nadir Hb (g/dL)a7.2 (4.8/9.8)8.7 (4.9/9.9)6.0 (4.3/9.7)0.14
Post-procedural AR0.08
 None53 (34.9)35 (38.5)18 (29.5)
 Mild76 (50.0)45 (49.5)31 (50.8)
 Moderate19 (12.5)11 (12.1)8 (13.1)
 Severe4 (2.6)0 (0)4 (6.6)
  • AR, aortic regurgitation; Hb, haemoglobin; RBC, red blood cell.

  • aCorrected nadir was calculated according to the Landefeld equation, as suggested by Van Mieghem et al.25

In the multivariate regression analysis, we entered procedural variables which were associated with the occurrence of SIRS (major vascular complications, major bleeding events, post-dilatation of the valve prosthesis, units of packed RBC, amount of contrast dye, and the number of ventricular pacing runs). The occurrence of major vascular complications [odds ratio (OR): 5.1, 95% confidence interval (CI): 1.3–19.6; P = 0.018] and the number of ventricular pacing runs for balloon and/or post-dilatation (OR: 1.7, 95% CI: 1.1–2.8; P = 0.025) were independent predictors for the development of SIRS after TAVI (Table 3).

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Table 3

Multivariate logistic regression analysis for predictors of systemic inflammatory response syndrome after transcatheter aortic valve implantation

OR (95% CI)P-value
Post-dilatation1.2 (0.4–3.2)0.78
Amount of contrast dye (Q4 vs. Q1–Q3)1.9 (0.9–4.2)0.11
Major vascular complications5.1 (1.3–19.6)0.018
Major bleeding0.6 (0.1–3.6)0.59
RBC transfusion (per unit)1.1 (0.9–1.4)0.17
Pacing runs (no.)1.8 (1.1–2.8)0.025
  • Q, quartile. Other abbreviations as in Tables 1 and 2.

The number of RBC transfusions was not an independent predictor for the occurrence of SIRS. Furthermore, we calculated the net Hb drop according to the Landefeld equation24,25 which showed a trend but was not significantly associated with the occurrence of SIRS: 5.4 (3.4/7.6) g/dL vs. 3.8 (2.7/6.4) g/dL; P = 0.07. Furthermore, the corrected nadir Hb was also not associated with SIRS: 6.0 (4.3/9.7) vs. 8.7 (4.9/9.9); P = 0.14.

Clinical outcomes and the occurrence of systemic inflammatory response syndrome after transcatheter aortic valve implantation

Twelve of 152 patients (7.9%) died within the first 30 days after TAVI, 41 of 152 patients (27.0%) during a follow-up of 1 year (Table 4). The causes of death for these patients were pneumonia (n = 12), congestive heart failure (n = 9), septicaemia with multiple organ failure (n = 7), acute cardiorenal syndrome (n = 5), chronic cardiorenal syndrome (n = 4), fatal myocardial infarction (n=1), non-procedure-related stroke during follow-up (n = 1), intracerebral bleeding (n = 1), and unknown (n = 1).

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Table 4

Clinical outcomes according to the occurrence of systemic inflammatory response syndrome

All patients (n = 152)No SIRS (n = 91)SIRS (n = 61)P-value
30-day mortality [n (%)]12 (7.9)1 (1.1)11 (18.0)<0.001
1-year mortality, [n (%)]41 (27.0)9 (9.9)32 (52.5)<0.001
Stroke [n (%)]8 (5.3)5 (5.5)3 (4.9)0.88
Myocardial infarction [n (%)]4 (2.6)1 (1.1)3 (4.9)0.15
Any vascular complications [n (%)]39 (25.8)18 (19.8)21 (34.4)0.028
Major vascular complications [n (%)]13 (8.6)3 (3.3)10 (16.4)0.003
Major bleeding [n (%)]14 (9.2)5 (5.5)9 (14.8)0.042
Acute kidney injury [n (%)]35 (23.0)7 (7.7)28 (45.9)<0.001
Pacemaker implantation [n (%)]35 (23.0)19 (20.9)16 (26.2)0.44
Moderate/severe periAR [n (%)]23 (15.1)11 (12.1)12 (19.7)0.16

The development of SIRS after TAVI was strongly associated with 30-day (18.0 vs. 1.1%; P < 0.001) and 1-year mortality (52.5 vs. 9.9%; P < 0.001; Figure 4). During the first 30 days of follow-up, patients suffering from SIRS after TAVI did not die significantly more often from infectious causes: acute cardiorenal syndrome (n = 5), pneumonia (n = 2), septicemia with multi-organ failure (n = 2), fatal myocardial infarction (n=1) and congestive heart failure (n = 1).

Figure 4

One-year mortality according to the development of systemic inflammatory response syndrome I (SIRS).

Even after exclusion of patients (n = 45) suffering from peri-procedural complications such as major vascular complications, major bleeding events, and AKI which might have synergistically affected the mortality in SIRS patients, the development of SIRS was still related to 1-year survival (75.0 vs. 93.7%, P = 0.004; Figure 5).

Figure 5

One-year mortality according to the development of systemic inflammatory response syndrome (SIRS) after exclusion from patients (n = 45) suffering from periprocedural complications (major vascular complications, major bleeding events, and acute kidney injury).

Patients suffering from SIRS had a 7.4-fold increased risk for 1-year mortality [hazard ratio (HR): 7.4, 95% CI: 3.5–15.6; P < 0.001] (Table 5). In a multivariate Cox regression analysis with adjustment for the three strongest univariate predictors of outcome such as pulmonary hypertension, the occurrence of AKI, and moderate/severe peri-prosthetic aortic regurgitation, SIRS after TAVI was independently associated with a 1-year outcome and increased the 1-year mortality risk by a factor of 4 (HR 4.0, 95% CI: 1.8–9.2: P = 0.001).

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Table 5

Cox regression analysis of the association between clinical characteristics and 1-year mortality

Univariate HR (95% CI)P-valueMultivariate HR (95% CI)P-value
Acute kidney injury7.0 (3.8–13.2)<0.0013.9 (2.0–7.7)<0.001
Pulmonary hypertension2.8 (1.5–5.3)0.0012.4 (1.3–4.6)0.007
Moderate/severe periAR4.0 (2.1–7.5)<0.0014.9 (2.5–9.6)<0.001
SIRS7.4 (3.5–15.6)<0.0014.0 (1.8–9.2)0.001
Coronary artery disease2.6 (1.3–5.5)0.01
Ejection fraction ≤30%2.7 (1.4–5.0)0.002
Chronic renal failure2.1 (1.0–4.2)0.039
Logistic EuroSCORE1.0 (1.0–1.0)<0.001
STS score mortality1.1 (1.0–1.1)<0.001
  • CI, confidence interval; HR, hazard ratio; other abbreviations as in Table 1.

Discussion

Our prospective study of 152 percutaneous TAVI patients demonstrates that SIRS occurs after TAVI. During the first 48 h after TAVI, 61 patients developed post-procedural SIRS and were characterized by leucocytosis, hyperventilation, tachycardia, and fever compared with patients without SIRS. This systemic inflammatory response was preceded by a significant release of the proinflammatory cytokines IL-6 and IL-8 with subsequent elevation of leucocyte count and the acute phase reactants CRP and PCT. Patients with peri-procedural complications such as major vascular complications and the need for repeated ventricular pacing were at high risk for the development of SIRS. The development of SIRS after the procedure was related to a significantly increased risk of short- and long-term mortality, even after the exclusion of patients with peri-procedural complications that might have synergistically affected the mortality.

Mechanisms of systemic inflammatory response syndrome

Systemic inflammatory response syndrome occurs in the setting of a number of non-infectious, major systemic insults, including cardiac surgery, cardiopulmonary bypass, trauma, and cardiogenic shock.15,26 Several mechanisms contribute to the pathophysiology of SIRS: tissue I/R injury caused by suboptimal organ perfusion during CPB and the surgical trauma represent the predominant factors resulting in immunologic changes after cardiac surgery that may culminate in the development of a systemic inflammatory reaction.14,1720

The SHOCK trial demonstrated that patients with a large myocardial infarction often have elevation of body temperature, leucocyte count, complement, interleukins, CRP, and other inflammatory markers and, thus, fulfil the clinical criteria of SIRS. This vicious circle is initially triggered by infarction-related, systemic hypotension with suboptimal organ perfusion and consecutive I/R injury which leads to leucocyte and endothelial activation with cytokine release and finally to the development of SIRS.2729 In the CARDINAL trial and the COMMA trial, this pathomechanism could be confirmed and it was shown that increased leucocyte count and elevated temperature also predicted clinical outcome in patients suffering from myocardial infarction.30,31 The kidneys and myocardium itself have been identified as the origin of cytokine release after hypoperfusion and I/R injury.28,3135 A few studies even hypothesized that inadequate gut perfusion and resulting ischaemia impair the gastrointestinal tract barrier function which might facilitate the passage of enteric bacterial endotoxin.28,35

Systemic inflammatory response syndrome in transcatheter aortic valve implantation patients

Considering suboptimal organ perfusion with a subsequent release of cytokines as the major common pathomechanism of SIRS in both—cardiac surgery and myocardial infarction—this might also contribute to the development of a systemic inflammatory reaction after TAVI. A transient drop in total or regional blood flow with consecutive hypotension occurs during several steps of the TAVI procedure: in the initial phase during rapid pacing and BAV, deployment, post-dilatation, or repositioning of the valve prosthesis, and potentially as a consequence of vascular complications and/or major bleeding events. In our study, peri-procedural characteristics such as repeated ventricular pacing, the performance of post-dilatation, and complications with consecutive hypotension were related to the development of SIRS. The hypothesis of transient hypoperfusion with ischaemia was further supported by increased lactate levels in our study which we observed in SIRS patients at 4 and 24 h.

Another factor, which might contribute to the development of SIRS in TAVI patients, is the transfusion of RBC units. Red blood cell transfusion is associated with the co-administration of e.g. IL-8 which accumulates in the stored packed RBCs and might also be associated with pyrexia and leucocytosis.36 Blood transfusion has been shown to be a predictor of inflammation and adverse outcome in cardiac surgery patients.37 However, in our study cohort, the number of RBC transfusions as well as the net Hb drop according to the Landefeld equation did not independently predict the occurrence of SIRS in the multivariate regression analysis.24,25 This underscores again that the administration of packed RBC was only a minor contributor to the development of SIRS in the TAVI patients of our study cohort.

The RBC transfusion policy in our study supported a pre- and post-procedural Hb level of ≥10 g/dL and haematocrit <30%. Thus, 53.9% (82/152) of our patients received RBC transfusions. However, our RBC transfusion rate is in accordance with a recent TAVI series reporting an in-hospital transfusion rate of 70% (83/118).25 The administration of RBC transfusion, which was associated with SIRS and AKI in a univariate analysis in our study, might have been more a surrogate for haemodynamic impairment of our TAVI patients due to procedure-related hypotension with consecutive hypoperfusion as a consequence of vascular complications, bleeding events, etc.913

The occurrence of vascular complications with the need for stenting of the femoral access vessel might also explain the increased amount of contrast dye, which was used in SIRS patients. Albeit, the amount of contrast dye in our study (172 (140/205) mL) is in line with data from the German TAVI registry8 (169.2 ± 68.3 mL) and a CoreValve series from Rotterdam10 (199 ± 81 mL).

Systemic inflammatory response syndrome and the occurrence of acute kidney injury

According to our data, we suggest that SIRS after TAVI—at least in part—might coincide with the development of AKI. However, the prevalence of CRF (defined as glomerular filtration rate <60 mL/min/1.73 m2), which was high in our series but in accordance with the data from the German TAVI registry (57.5 vs. 61.5%), was not associated with the occurrence of SIRS after TAVI.

Several studies showed that inflammation resulting from I/R injury plays a pivotal role in the pathophysiology of AKI.3234 Liu et al. observed that AKI after cardiac surgery is preceded by significantly increased IL-6 and IL-8 levels during the first 12 h after CPB, respectively.33 In TAVI patients, Aregger et al.11 observed fever without a focus and elevated leucocyte count in patients developing AKI after the procedure. In addition, Nuis et al.10 and van Linden et al.13 recently showed that an elevated leucocyte count after TAVI is an independent predictor of AKI. We confirmed these findings, as SIRS was strongly associated with AKI which was in turn also a predictor of 1-year mortality in our study. Temporary hypoperfusion of the kidney during the procedure might be responsible for a significant cytokine release culminating in a SIRS-like, inflammatory reaction, which might play a pivotal role in the pathophysiology of AKI, as recent data suggest.3234

In summary, our findings demonstrate that SIRS may develop after TAVI and is independently associated with outcome. Transient hypoperfusion occurs during several steps of the TAVI procedure—for example during rapid pacing and BAV or as a consequence of vascular complications, bleeding events, etc.—and might lead to ischaemia of the kidneys and the gut with a subsequent release of inflammatory mediators. Most of the SIRS patients in our study could be easily identified by an elevation of the leucocyte count (83.6%), which was already significantly increased at 4 h after TAVI compared with patients not developing SIRS, and an elevated PCT level after TAVI. Due to the frequent coincidence with AKI, patients with leucocyte increase have to be taken particular care of, since both—SIRS and AKI—have a negative impact on short- and long-term outcome.

Currently, strategies to prevent AKI and SIRS in TAVI patients remain an important challenge, as these complications are associated with a dramatic increase in mortality and hospital resource utilization. Because of the presumably multifactorial pathogenesis of SIRS in TAVI patients, every measure has to be taken to avoid or treat these complications. Restrictive blood transfusion might help to break the vicious circle of cytokine release and inflammation.36,37 Since anti-inflammatory treatment has not been established as a treatment strategy, yet,27,31,38 periods of procedure-related hypotension during rapid pacing, BAV, or deployment of the valve prosthesis should be kept as short as possible in order to prevent or ameliorate hypoperfusion with a subsequent development of SIRS and to improve operative outcomes. For the prevention of major vascular complications in patients with severe peripheral arterial disease, TAVI via a transfemoral approach with elective surgical cutdown and surgical closure of the vessel might be a more beneficial treatment strategy than accepting the risk of a major vascular complication in patients with difficult transfemoral access due to severe peripheral arterial disease. However, this remains to be elucidated in future studies, since no randomized controlled trial addressed this hypothesis, yet.

Study limitations

The results of our study should be considered hypothesis generating. A larger controlled multicentre trial is needed to further validate our data, because it might have major implications on the procedure itself as well as preventive treatment of TAVI patients. However, the exact pathomechanism of SIRS in TAVI patients remains speculative, and our hypothesis with hypoperfusion-related I/R injury and a subsequent release of cytokines playing a pivotal role have to be elucidated in further studies. In addition, it has to be tested whether our results apply to other transcatheter heart valve types than the CoreValve prosthesis. Nonetheless, the observation of a prognostic ability of the leucocyte count and inflammatory markers such as the PCT level for the development of SIRS helps to early identify TAVI patients with a high risk for an adverse outcome after the procedure. With the increasing use of TAVI, identification of clinical criteria is important to optimize post-procedural management.

Conclusions

Systemic inflammatory response syndrome may occur after TAVI and is an independent predictor of mortality. The development of SIRS could be easily identified by clinical parameters such as a significant increase in the leucocyte count shortly after TAVI. Peri-procedural hypotension and suboptimal organ perfusion with I/R injury and subsequent cytokine release might play a role in the pathogenesis of SIRS after TAVI.

Funding

J.-M.S. is supported by a research grant from the University Hospital Bonn (BONFOR).

Conflict of interest: Dr. Eberhard Grube is a proctor for CoreValve/Medtronic. The other authors report no conflicts.

Acknowledgements

We thank the staff of the catheterization laboratory for their excellent support.

References

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