Eur J Cardiothorac Surg 2008;34:820-825. doi:10.1016/j.ejcts.2008.07.012
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Is incidence of postoperative vasoplegic syndrome different between off-pump and on-pump coronary artery bypass grafting surgery?
Xiumei Sun*,
Li Zhang,
Peter C. Hill,
Robert Lowery,
Anne T. Lee,
Robert E. Molyneaux,
Paul J. Corso,
Steven W. Boyce
Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center, 110 Irving Street, N.W., Suite 1E3, Washington, DC 20010-2975, United States
Received 12 February 2008;
received in revised form 9 July 2008;
accepted 14 July 2008.
* Corresponding author. Tel.: +1 202 877 0277; fax: +1 202 291 1436. (Email: xiumei.sun{at}medstar.net).
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Abstract
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Objective: Postoperative vasoplegic syndrome (PVS) is a potentially lethal condition with increased mortality and other postoperative morbidities. Many previous studies have examined the outcomes associated with on-pump coronary artery bypass grafting (CABG) surgery, little is known about the incidence of PVS after off-pump CABG. Methods: From November 21, 2005 to June 9, 2006, 334 patients underwent isolated on-pump CABG and 362 had off-pump CABG surgery. Perioperative variables were retrospectively compared between on-pump and off-pump CABG surgery using univariate analysis. Significant variables were included into a stepwise regression model to ascertain their independent impact on the incidence of PVS. Results: The incidence of PVS in isolated on-pump CABG was 6.9%; in off-pump CABG was 2.8% (p
= 0.01). However, in multivariable models adjusted for confounders, on-pump CABG did not reach statistical significance as a risk factor of PVS (OR = 2.3, 95% CI 0.94–5.78; p
= 0.07). In on-pump CABG, preoperative left ventricular EF less than 35% (OR = 3.6; p
= 0.02) and increased body mass index (OR = 1.1; p
= 0.04) were identified as risk predictors of PVS; whereas elective surgery (OR = 0.2; p
= 0.02) and preoperative use of β-blockers (OR = 0.21; p
= 0.02) were associated with a decreased rate of PVS. PVS was associated with longer ICU stay (OR = 6.0; p
< 0.01), postoperative ventilation (OR = 4.6; p
< 0.01), and hospital stay (OR = 2.62; p
= 0.03). There was a stronger association between preoperative ACE inhibitors therapy and increased risk of PVS in off-pump CABG surgery (OR = 4.52, 95% CI 0.95–21.67; p
= 0.06) than in on-pump CABG surgery (OR = 1.06, 95% CI 0.35–3.19; p
= 0.91), but neither of them reaches statistical significance. Conclusions: The incidence of PVS after off-pump CABG surgery was significantly lower than after on-pump CABG surgery.
Key Words: Postoperative vasoplegic syndrome • Off-pump • On-pump • Coronary artery bypass grafting
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1. Introduction
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Postoperative vasoplegic syndrome (PVS) is a potentially lethal complication with recognized characteristics of low systemic vascular resistance (SVR), normal or elevated cardiac output and poor response to volume substitution. The incidence of PVS following on-pump cardiac surgery has been reported to be 8–26% [1–4]. Although numerous pathophysiologic mechanisms for PVS have been suggested, the most widely accepted cause is inflammatory cytokines released during cardiopulmonary (CPB). Off-pump coronary artery bypass grafting (CABG) surgery has gained popularity in recent decades. Whether off-pump CABG reduces the incidence of PVS remains unknown. We conducted this study to evaluate the influence of off-pump CABG surgery on PVS by comparison with isolated on-pump CABG surgery.
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2. Patients and methods
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2.1 Patient population and design
Between November 21, 2005 and June 9, 2006, 334 patients underwent isolated on-pump CABG surgery and 362 patients had off-pump CABG surgery in our institution. Baseline, intraoperative and postoperative outcome variables were recorded and entered concurrently to the cardiac surgery database as part of our routine clinical practice. Patients were contacted routinely by telephone 30 days after hospital discharge. All data were defined according to the Society of Thoracic Surgeons national database (V 2.52). Guidelines and definitions are available at http://www.sts.org/sections/stsnationaldatabase/datamanagers. All adverse clinical events were source documented and adjudicated. Parsonnet's bedside risk score was calculated with methods described by Parsonnet et al. [5]. The institutional review Board approved our study protocol.
2.2 Definition of postoperative vasoplegic syndrome
Based on previous studies [2–4,6,7], PVS was defined using the following criteria: mean arterial pressure (MAP) 
70 mmHg, indexed SVR (SVRI) 1400 dynes s cm–5
m–2, cardiac index (CI) 
2.5 min–1
m–2, and central venous pressure (CVP) 10 mmHg. Patients with PVS occurring within 24 h and supported by norepinephrine and/or vasopressin were included. Patients receiving milrinone, dobutamine within 24 h postoperatively were excluded. Patients with preoperative endocarditis or other severe infections (e.g. pneumonia, intraabdominal abscess) were also excluded.
2.3 Anesthesia, surgery and cardiopulmonary bypass
Routine preoperative cardiac medications, including nitrates, β-blockers, calcium-channel blockers, and ACE inhibitors were maintained until the day before surgery. Standard institutional guidelines of anesthesia, surgical selection and techniques, and myocardial protection protocol were performed. CPB was conducted under moderate systemic hypothermia (30–34 °C). Perfusion pressure was maintained between 60 and 80 mmHg by a 2.4 l min m–2 nonpulsatile pump flow. Myocardial protection was achieved using repetitive doses of antegrade and/or retrograde cold blood (4:1) cardioplegia at 20 min intervals. Hemoglobin (Hgb) was maintained more than 7 g/dl. All patients were operated on through a median sternotomy. Anticoagulation was provided by intravenous heparin and protamine was administered at the end of the operation to fully reverse the heparin effect.
2.4 Postoperative treatments and hemodynamic monitoring
When preoperative ejection fraction (EF) was greater than 40% as diagnosed by preoperative echocardiogram or left ventriculogram, the selection of intraoperative hemodynamic monitoring (pulmonary artery pressure or CVP) was dependent upon the preference of the attending anesthesiologist. When preoperative EF was less than 40% a Swan-Ganz catheter was inserted in the operating room (OR) regularly. Despite fluid administration, when postoperative hemodynamic instability occurred in the intensive care unit but without the Swan-Ganz catheter being inserted in the OR, hemodynamic monitoring by a Swan-Ganz catheter was initiated and vasoactive agents were infused according to the cardiac output and SVR. Only those patients who met the vasoplegic criteria were included in the vasoplegic group for final analysis.
MAP, mean pulmonary arterial pressure, CVP, pulmonary capillary wedge pressure, and cardiac output were recorded, and SVRI, CI were calculated by the Edwards Lifesciences vigilance monitor (Edwards Lifesciences Co., USA) simultaneously.
2.5 Data analysis
The primary aim of this study was to compare any existing differences of risk factors in the occurrence of PVS between on-pump and off-pump CABG surgery; the secondary aim was to examine the association between PVS and major outcomes.
Data are expressed as percentages, mean value with standard deviation, or median (minimum, maximum 25th to 75th percentile). Continuous variables were compared using Student's t-test for normally distributed data and Wilcoxon rank-sum test for non-normally distributed data. Categorical variables were compared via a chi-square test or via Fisher's exact test for expected cell counts less than 5.
A stepwise logistic regression analysis was used to identify significant covariates that predicted PVS in on-pump and off-pump CABG surgery, as well as to assess the association between PVS and each outcome and to adjust crude outcomes rates for potentially confounding variables. Variables that met a significance level of 0.15 in the univariate analysis or were previously reported as important determinants of the outcome of interest were included in the multivariate models. The candidate confounding variables entered in the model included age, gender, body mass index (BMI), EF, hypertension, diabetes, peripheral vascular disease (PVD), chronic heart failure (CHF), hypercholesteremia, history of myocardial infarction (MI), premedications, and surgical characteristics. The CPB characteristics were included in on-pump CABG surgery. Hosmer and Lemeshow goodness-of-fit statistics was conducted to examine the calibration of the model.
All statistical analysis was performed with SAS for Windows Version 9.1 (Cary, N.C.). A p value of 0.05 or less was considered significant.
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3. Results
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The overall incidence of PVS was 4.7% (33 patients), with 23 patients in the on-pump CABG group (6.9%) and 10 patients in the off-pump group (2.8%) (p
= 0.01, Table 1
).
3.1 Perioperative risk factors
Univariate analysis of preoperative patients’ demographics, comorbidities and surgical characteristics are presented in Table 1. Patients who underwent off-pump surgery were older (p
< 0.01) and tended to have lower BMI (p
= 0.06). Patients undergoing both of on-pump and off-pump CABG surgery showed similar frequencies in the administration of preoperative angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARB), β-blockers, calcium-channel blockers, lipid lowering medications, and steroids. Fewer patients in the off-pump CABG group received preoperative heparin treatment (p
< 0.01) and inotropes (p
< 0.01). Patients undergoing off-pump CABG surgery were less likely to have recent MI, reduced EF, and more likely to have hypercholesterolemia. Elective surgery was more common in the off-pump group (p
< 0.01). When evaluating non-elective CABG patients only, PVS occurred in 19 of 190 patients (11.1%) after on-pump surgery and in 6 of 141 patients (4.2%), p value is 0.037.
3.2 The impact of CPB on PVS
We did univariate and multivariate analysis to elucidate the role of CPB on PVS in on-pump CABG surgery (Table 2
). There was no significant difference between PVS and non-PVS patients in regard to bypass time, body core temperature, cardioplegia, hemoglobin concentration during CPB, and heparin usage; however, the average amount of protamine use was significantly higher in PVS patients (p
= 0.02). There were trends toward an increased risk of PVS with longer CPB (p
= 0.07) and lower core body (p
= 0.09) (Table 6).
3.3 PVS and postoperative outcomes
Postoperative outcomes are detailed in Table 3
. The mechanical ventilation time, ICU hours and hospital stay were significantly longer in the on-pump CABG group. We have noted a higher incidence of MI, renal failure, ventricular arrhythmias, and infections after on-pump surgery. The in-hospital mortality after off-pump surgery was lower (p
= 0.02), but 30-day postoperative mortality (p
= 0.16) was not. Logistic regression models showed PVS was associated with longer postoperative mechanical ventilation time, hospital stay, and ICU stays (p
< 0.01). The association between PVS and increased operative mortality did not reach statistic significance (OR = 3.4, 95% CI 0.78–14.7; p
= 0.1) (Table 4
).
3.4 Risk factors of PVS
With adjustment for confounding variables, multivariable regression analysis showed on-pump surgery tended to increase the incidence of PVS, but did not demonstrate statistically significant (OR = 2.3; p
= 0.07). Increased BMI (OR = 1.1; p
= 0.01) and EF less than 35% (OR = 4.22; p
0.01) were concurrent predictors; β-blockers use (OR = 0.24; p
= 0.01) and elective surgery (OR = 0.3; p
= 0.01) were protectors for PVS in all CABG surgery patients (Table 5
). In on-pump CABG, larger BMI (OR = 1.1; p
= 0.04) and EF less than 35% (OR = 3.93; p
= 0.02) were significant predictors of PVS; elective surgery (OR = 0.21; p
= 0.02), female gender (OR = 0.18; p
= 0.05), and preoperative β-blockers therapy (OR = 0.21; p
= 0.02) were PVS protectors (Table 6
). In off-pump surgery, redo-CABG was identified as an independent predictor of PVS (OR = 9.9; p
= 0.05); preoperative ACE inhibitors therapy demonstrated a strong tendency to increase the risk of PVS (OR = 4.52, 95% CI 0.95–21.67; p
= 0.06) (Table 7
).
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4. Discussion
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Previous studies have investigated the incidence of PVS in cardiac surgery performed with the use of CPB. The underlying mechanisms of PVS were proposed to be poor preoperative cardiac function, vasodilators tissue accumulation due to preoperative long-term usage [2,6,7], CPB-mediated inflammatory cytokines release [8–10], and poor end-organ response to vasopressor support after cardiac surgery.
CPB as a cause of PVS has been extensively studied [3,11]. CPB generates hemodynamic and inflammatory disorders involving changes in vascular permeability, regional blood flow and alterations of coagulation and complementary systems [8,9]. The avoidance of CPB in off-pump surgery may attenuate the systemic inflammatory response. Our study showed a significantly decreased incidence of PVS after off-pump CABG surgery by univariable analysis. However, we only found a trend toward decreasing incidence of PVS after off-pump surgery in a multivariable logistic model, which did not reach statistical significance (p
= 0.07). It is important to specify this finding. In our study, the risk of PVS in on-pump CABG surgery was more than double that of off-pump CABG surgery after adjustment for other risk predictors. The borderline association between decreased PVS and off-pump surgery may be related to the very small number of patients with PVS. This occurs frequently when the incidence of a clinical event is very low.
Preoperative decreased EF is one of the most documented predictors for PVS after on-pump cardiac surgery [1,12–14]. This conclusion was confirmed by our study in the on-pump CABG group. Weis et al. [13] found more than half of patients developed postoperative vasopressor dependency when the preoperative EF was less than 37%, whereas in patients with normal left ventricular function only 25% did so. Preoperative heart failure is associated with marked activation of inflammatory factors, the rennin–angiotensin system, and a higher vasopressin level. The stress of CPB and cardiac surgery stimulate another increase of the inflammatory response, and these lead to an altered vascular responsiveness. Furthermore, patients with preoperative left ventricular dysfunction are known to have decreased myogenic reactivity to circulating catecholamines [15].
Recent studies have established preoperative ACE inhibitors as independent risk factors for PVS [3,6]. The long-term use of long acting ACE inhibitors leads to tissue accumulation, contributing to a decrease in SVR in the postoperative period. Our study only showed a borderline association between preoperative uses of ACE inhibitors and increased risk of PVS after off-pump surgery. In a recent review of eleven articles published from 1950 through 2007, Raja and Fida found that seven large cohort and case–control studies were consistent with the conclusion that preoperative ACE inhibitors administration resulted in PVS, but three small randomized controlled trials provided conflicting results [16].
Non-elective surgery is an independent risk factor for vasoplegia in on-pump CABG in our study. Emergent/urgent CABG is consistently associated with a higher preoperative risk profile and worse outcomes than elective surgery. Recent studies reported significantly reduced perioperative mortality and other outcomes in emergency off-pump CABG than in on-pump CABG [17]. We hope further prospective study will evaluate the difference of troponin and other inflammation response cytokines level between on-pump and off-pump emergency CABG.
Increased BMI showed a tendency to be a significant risk factor for PVS in on-pump CABG surgery. No previous study has reported an association between BMI and PVS. Increased BMI may incur a greater myocardial workload and inadequate myocardial protection of hypertrophied heart. CPB may more frequently elicit the imbalance between vascular resistance and body volume in obese patients. In addition, Esposito and Cottam found obese patients with coronary disease already have a high level of proinflammatory cytokines in adipose tissue preoperatively [18].
Our data showed that preoperative β-blocker therapy provided protection against development of PVS after on-pump surgery. The mechanism remains unclear. Booth established a theory that CPB results in a significant impairment on β-adrenergic receptor function; β-blockers may attenuate acute β-adrenergic receptor desensitization, and preserve the sensitivity of myocardium to catecholamine after CPB [19].
It is well known that female gender carries increased mortality and morbidities after cardiac surgery. Therefore, the clinical significance of our data that female gender conferred protection against PVS remains to be redefined.
Our results extended the findings of previous studies by demonstrating that PVS was associated with more adverse comorbidities [2,6,7]. In our study, patients with vasoplegia tend to have longer ICU stays, mechanical ventilation time and hospital stay. Conclusions about the associations between PVS and operative mortality may be limited because of the relatively small patient numbers of mortality in the group; nevertheless, we believe the trend correlations between PVS and mortality indicate PVS is a risk factor for mortality.
In summary, our study is significant in identifying the difference of incidence and risk factors for PVS between on-pump and off-pump CABG. The incidence of PVS after off-pump CABG was significantly lower. Patients with preoperative EF less than 35% and increased BMI are at increased risk for PVS after on-pump CABG surgery.
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5. Study limitations
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Despite the limitations inherent in a retrospective single-institution study, we did not test the serum level of inflammatory cytokines for patients who developed PVS simultaneously. With respect to the statistical power, the small number of patients in the mortality and PVS after off-pump CABG surgery group failed to present statistical significance in a logistic regression model.
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Acknowledgments
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We thank Nancy J. Kershner, MedStar Research Institute, for editing the manuscript.
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Abstract
1. Introduction
