Determinants of Clinical Right Ventricular Failure After Congenital Heart Surgery in Adults

Mark J. Schuuring, MD,*, E. Charlotte van Gulik,* Dave R. Koolbergen, MD, PhD,z Mark G. Hazekamp, MD, PhD,z Wim K. Lagrand, MD, PhD,y Ad P.C.M. Backx, MD, PhD,* Barbara J.M. Mulder, MD, PhD,*, and Berto J. Bouma, MD, PhD*
Objectives: Right ventricular (RV) failure after cardiac surgery is a clinical entity with high morbidity and mortality. Patients with congenital heart disease (CHD) often undergo right-sided cardiac surgery. The authors aimed to identify determinants of RV failure after cardiac surgery to differentiate patients with increased risk. Design: A retrospective chart review. Setting: University hospital. Participants: Adults with CHD operated on between January 2001 and January 2011. Interventions: Clinical characteristics, laboratory tests, surgical data, and intensive care unit outcome were obtained from medical records. Measurements and Main Results: The diagnosis of clinical RV failure was made by careful review of the medical records by 2 independent physicians. Patients only were identied as having RV failure if (1) they had elevated jugular venous pressure, (2) they had impaired postoperative RV function on transthoracic echocardiography, and (3) a diagnosis of RV failure was documented clearly in the medical charts by the treating physician. Data of 412 consecutive patients (median age 36 [range 18-74] years, 56% male) were studied. Eighteen patients had clinical RV failure (4.4%) postoperatively, of whom 6 patients died. Patients undergoing left- and bothsided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. In multivariate logistic regression analysis, preoperative impaired RV function, supraventricular tachycardia, and cardiopulmonary bypass time 4150 minutes were the strongest determinants of clinical RV failure (p o 0.05, for all). Conclusions: RV failure after cardiac surgery is a serious complication, and occurs regardless of the side of surgery. A tailored approach in patients with CHD at highest risk of RV failure should be considered. & 2013 Elsevier Inc. All rights reserved. KEY WORDS: right ventricular failure, cardiac surgery, congenital heart disease, adult CHD

ATIENTS WHO UNDERGO CARDIAC surgery are at risk of developing right ventricular (RV) failure. This clinical entity is characterized by edema, elevated jugular venous pressure, hypotension, and, in worst cases, shock or multiorgan failure. RV failure often is difcult to diagnose and to treat. Cardiac surgery relieves symptoms and increases life expectancy in cardiac patients. However, postoperative morbidity is signicant and inuenced by the patients conditions (male, chromosomal abnormalities), history (cyanosis, New York Heart Association [NYHA] class), and underlying morphology (systemic RV).1 Cardiac surgery has been demonstrated to affect RV function (RVF) in adults who undergo coronary artery bypass grafting2 and correction of congenital heart disease (CHD).3 The decline in RVF persists up to 18 months and is associated with impaired clinical status and reduced long-term prognosis in patients with CHD.4,5 In children, both systolic and diastolic biventricular performances were impaired shortly after CHD correction.6 The literature lacks data on risk factors of RV failure in patients with CHD. The authors aimed to identify determinants of RV failure after cardiac surgery. The results will be of help to identify patients at highest risk and to establish an early diagnosis to improve clinical outcome. Ultimately, early anticipation and early start of supportive therapy might lead to reduction of intensive care unit and hospitalization time, as well as risk of death.
METHODS Adult patients with CHD who had surgery between January 2001 and January 2011 in the Academic Medical Center in Amsterdam were studied. Clinical characteristics, laboratory tests, and surgical data were obtained from medical records. This retrospective chart analysis did not require permission from the institutional ethics committee.

Echocardiography was performed with a Vivid 7 ultrasound system (General Electric, Milwaukee, WI). All echocardiographic images were acquired and recorded digitally. All studies were analyzed by a single observer with more than 10 years experience in echocardiography in adult patients with CHD, who was blinded to clinical information. Parasternal and apical views were obtained and valve regurgitation was quantied according to the guidelines.7 Echocardiographic assessment of the right8 and left heart9 in adults was performed according to the guidelines. RVF was evaluated by means of tricuspid annular plane systolic excursion (TAPSE) and tissue Doppler imaging (RV S). TAPSE was obtained from the apical 4-chamber view. The difference in the displacement of the RV base from end-diastole to end-systole at the junction of the tricuspid valvular plane was used to determine TAPSE.10 Tissue Doppler imaging S (RV S) was measured using a pulsed-wave Doppler sampling gate of 6 to 6 mm and a sweep of 100 mm/s. RVF was found to be normal for levels of TAPSE and tissue Doppler imaging S above 15 mm and 11 cm/s, respectively. The study population was divided into 2 groups representing preserved or impaired ventricular function. Analysis of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was performed using a sandwich technique using 2 antibodies and a chemiluminescence signal for determination of the concentration of the analyte. Lithium heparin plasma was used for sample material.

From the *Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; yInteruniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands; and the Departments of zCardiothoracic Surgery and yIntensive Care, Academic Medical Center, Amsterdam, The Netherlands. Address reprint requests to Mark Schuuring, Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: m.j.schuuring@amc.uva.nl & 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.10.022
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The main outcome measure for this study was clinical RV failure. The diagnosis of clinical RV failure was made by careful review of the medical records by 2 independent physicians. Patients were identied only as cases with RV failure if (1) they had elevated jugular venous pressure, (2) they had impaired postoperative RVF on transthoracic echocardiography, and (3) a diagnosis of RV failure clearly was documented in the medical charts by the treating physician. Moreover, 2 independent physicians discussed each case and selected appropriate cases if both physicians agreed on the diagnosis of RV failure. When needed, cases were discussed with the treating clinician. These criteria uniformly were used for all patients. Creatinine clearance was calculated using the CockcroftGault formula. Pulmonary hypertension was dened as systolic pulmonary artery pressure above 37 mmHg at rest with a tricuspid regurgitation velocity of more than 2.8 m/s measured on transthoracic echocardiography, according to the guidelines of the European Society of Cardiology.11 For statistical analysis, SPSS 19.0 (SPSS Inc, Chicago, IL) was used. Normally distributed continuous variables were compared with the Students t-test and skewed distribution with the Wilcoxon ranksum test. Categoric variables were compared with the chi-square test. Cutoff values for EuroSCORE and cardiopulmonary bypass time were based on the optimal point of the individual determinant levels in receiver operating characteristic curves. Univariate statistics applied to the preoperative and perioperative characteristics identied signicant determinants for inclusion in multivariate analysis. RESULTS

Data of 412 consecutive patients with CHD (median age 36 [range 18-74] years, 56% male) were studied. Table 1 summarizes patients baseline characteristics. None of the patients had clinical RV failure preoperatively. Right-sided surgery was performed 121 times, involving pulmonary valve surgery (n 104)

and tricuspid valve surgery (n 65). Left-sided surgery was performed 160 times, involving aortic valve surgery (n 106) and mitral valve surgery (n 58). A combination of right- and left-sided surgery was performed 131 times. Patients diagnosed with clinical RV failure were signicantly older; were more often in NYHA class III/ IV; had higher NT-pro-BNP levels, higher logistic EuroSCORE, longer cardiopulmonary bypass time, and lower creatinine clearance; had more frequent episodes of supraventricular tachycardia preoperatively; and had undergone tricuspid and mitral valve surgery more often as compared to patients who did not have RV failure (Table 1). Of all patients studied, 18 were diagnosed with clinical RV failure (4.4%) after cardiac surgery. In the present study, 4 patients died during hospitalization. These patients had surgery in 2004, 2006 (2 patients), and 2010. Table 2 shows detailed information on these patients. In univariate analyses, clinical RV failure rates increased signicantly in patients with NYHA class Z II, supraventricular tachycardia, creatinine clearance below 85 mL/min, impaired RVF, cardiopulmonary bypass time 4150 minutes, higher NT-pro-BNP, and logistic EuroSCORE above 2.5% (Table 3). Patients undergoing left- and both-sided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. Multivariate analyses also are shown in Table 3. Logistic EuroSCORE in multivariate analysis was not associated with clinical RV failure and was excluded from the nal model. NTpro-BNP was available only in 123 patients. For that reason, NT-pro-BNP was excluded for multivariate analysis. In the nal model, preoperative impaired RVF, supraventricular tachycardia,

Table 1. Baseline Characteristics

Variables All Patients RV Failure Patients Nonfailing Patients p*

Number Died, n Age, median (range), y Body mass index, mean (SD), kg Male, % NYHA class III/IV, % Prior cardiac surgery, % Logistic EuroSCORE, median (range), % Treatment for pulmonary disease, % Supraventricular tachycardia, % QRS duration, mean (SD), ms NT-pro-BNP, median (range) Creatinine clearance, mean (SD), mL/min Right ventricular dilatation, % Impaired right ventricular function, % Pulmonary arterial hypertension, % Type of surgery Pulmonary valve, n Tricuspid valve, n Closure atrial septal defect, n Closure ventricular septal defect, n Aortic valve surgery, n Mitral valve surgery, n Cardiopulmonary bypass time, mean (SD), min

412 15 36 (18-74) 25 4 56 12 51 2.4 (0.9-37.2) 7 8 116 30 186 (53-2716) 102 23 38 19 1 104 64 101 33 106 58 134 64

18 6 49 24 39 33 38 3.5* 17 33 125 1272 86 56 53 6 4 9 4 0 4 6 178

394 9 36 25 57 11 51 2.4 6 7 116 177 103 37 18 o1 99 55 97 33 102 52 132

o0.01 o0.01 0.80 0.14 o0.01 0.29 0.02 0.09 o0.01 0.28 0.01 o0.01 0.18 o0.01 0.01 0.78 o 0.01 0.82 0.20 0.73 0.02 o0.01

Abbreviations: ng/L, nanogram per liter; mmol/L, micromol/L; SD, standard deviation. * Signicant values (po.05) are set in bold.

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Died

and cardiopulmonary bypass time 4150 minutes were the strongest determinants of clinical RV failure (p o 0.05, for all).

DISCUSSION

To the authors knowledge, this is the rst report of determinants of RV failure after congenital cardiac surgery. Patients undergoing left- and both-sided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. The clinical syndrome of RV failure was described rst by Cohn et al,12 and was associated with a native transmural postero-inferior myocardial infarction. The latter process involves contiguous areas of the right ventricle, left ventricle, and interventricular septum. In addition to the ischemic element, other factors such as pre-existing or acquired pulmonary hypertension and an altered interventricular balance also may contribute to the genesis of RV failure.13 In this group of patients, both short- and long-term survival were determined by RV performance. Especially in patients with CHD, contribution of the RV to cardiac pump function is essential. Adults with CHD undergo right-sided surgery more often. However, the literature lacks data on RV failure after cardiac surgery in patients with CHD. Various hypotheses regarding change in RV performance after cardiac surgery have been put forward. However, no clear cause is known. Prospective studies are needed to reveal potential mechanisms and identify patients at risk. Acute ischemia or air emboli may relate to RV failure. It is possible that the thin-walled RV may be more susceptible to dysfunction secondary to inammation or effusions postoperatively.3 These effusions may result from local tissue damage or from a systemic inammatory response. Another theory revolves around cytokines affecting RV performance. While undergoing cardiopulmonary bypass, the body releases cytokines, which initiate inammation and pulmonary vasoconstriction.14 One of these cytokines is endothelin-1, which has a vasoconstrictive effect on the pulmonary arterioles and, consequently, might inuence RV afterload.15 In the present study, patients undergoing left- and both-sided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. This might indicate a central role of cardiopulmonary bypass in the development of RV failure. Other hypotheses, such as perioperative temperature variations and the deleterious effects of pericardial disruption on RV lling and function, are plausible, but require further investigation. Another theory suggested pericardial adhesions that impair ventricular lling.16 However, the decline in RV performance manifested very rapidly after cardiac surgery. Change in RV performance also occurs when off-pump coronary artery bypass grafting surgery is used. This suggests that changes in RV failure might not be associated with techniques used for cardioplegia.17 Preoperative supraventricular tachycardia might have caused chamber dilatation and ventricular dysfunction resulting from structural and cellular changes that occur as a result of the rapid heart rates.18 This could be the reason that in the present study preoperative supraventricular tachycardia was found to be a strong determinant of postoperative RV failure. In the Society of Thoracic Surgeons Congenital Heart

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Abbreviations: ASD, atrial septal defect; CPB, cardiopulmonary bypass; ICU, intensive care unit; TvF, tetralogy of Fallot; TVP, tricuspid valvuloplasty; MVP, mitral valvuloplasty; AF, atrial brillation; PVR, pulmonary valve replacement; TVR, tricuspid valve replacement; MV, mitral valve; RF, radiofrequency; AVP, aortic valvuloplasty; RCA, right coronary artery; PV, pulmonary vein; APS, artery pulmonalis sinistra.

Follow-up, m ICU, d CK-MB Max CPB, min

Table 2. Patients With Right Ventricular Failure After Cardiac Surgery

Side Surgery Re-OK EuroSCORE NYHA Age Sex RVF Pre Procedure

M F F M M M M F F F M F F F F F F M

59 63 49 48 29 35 20 56 28 42 36 55 68 54 66 46 25 66

III I II IV I III I III III III I I II II II II III IV

Poor Good Good N/A Moderate Good Moderate Moderate Moderate Poor Good Moderate Good Good Good N/A Moderate Moderate

4.4 3.0 3.7 6.6 2.4 3.6 0.9 3.5 6.1 9.6 0.9 6.1 2.2 4.9 3.6 2.3 3.0 2.6

Gore-tex graft closure pulmonary artery TVP Closure ASD MVP TVP AF-ablation Bentall procedure prox archreplacement Bentall procedure PVR TVP ablation Corcap device Closure ASD MV repair TVR TVR PVR MVP Carpentierring RF ablation AVP David PVR TVP AVP TVP MVP MAZE Closure ASD MVP TVP Closure ASD Commissurotomy PV MAZE Correction RCA and APS TVP MVP Correction TvF

Yes No No Yes Yes Yes No No Yes Yes No Yes No No No No No No

Right Left Both Both Both Right Both Left Left Right Left Right Both Both Both Right Left Both

257 141 175 185 150 220 162 175 289 109 196 188 110 305 82 165 102 198

257 141 175 185 150 220 162 175 289 109 196 188 110 305 82 165 102 198

5 6 66 15 4 1 3 N/A 1 3 1 3 5 4 3 2 2 2

0 0 2 4 5 5 6 9 11 13 22 26 30 37 38 43 54 93

Yes Yes Yes Yes No No Yes No No No No No No No Yes No No No

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Table 3. Univariate and Multivariate Analyses on Determinants of Right Ventricular Failure

Univariate OR 95% CI p OR Multivariate 95% CI p

Age NYHA Z II Prior cardiac surgery Treatment for pulmonary disease Supraventricular tachycardia QRS duration Creatinine clearance o85 mL/min NT-pro-BNP* Right ventricular dilatation Impaired right ventricular function Pulmonary arterial hypertension Logistic EuroSCORE 42.5 Male Body mass index Side of surgery Cardiopulmonary bypass time 4150 min

2.5 3.31 0.6 3.08 7.13 1.00 4.95 1.00 1.42 4.14 11.53 4.18 0.49 0.98 1.4 4.03

0.87-7.14 1.16-9.46 0.23-1.58 0.78-12.17 2.45-20.77 0.99-1.02 1.89 - 12.96 1.00-1.00 0.84-2.41 1.45-11.82 1.00-133.48 1.45-11.97 0.19-1.29 0.86-1.12 0.79-2.46 1.48-11.00

0.08 0.03 0.30 0.11 o0.01 0.47 o0.01 o0.01 0.19 0.01 0.05 o0.01 0.15 0.8 0.25 0.01

9.80 3.44

2.53-37.96 1.00-11.88

o0.01 0.05

5.70

1.64-19.76

o0.01

5.09

1.40-18.54

0.01

Abbreviations: OR, odds ratio; CI, condence interval. * Available in 123 patients.

Surgery Database, preoperative arrhythmia was found to be a common risk factor for more postoperative complications.19 It is important to establish an early diagnosis in RV failure and to start supportive therapy. This minimizes the risk of endorgan damage.13 However, a diagnosis of RV failure often is difcult. The earliest indication of this problem after cardiac surgery is elevated jugular venous pressure. At an early stage, echocardiographic ndings may help to identify patients with RV failure. NT-pro-BNP was only available in a small number of patients. Preoperative NT-pro-BNP was in univariate analysis a signicant determinant of postoperative RV failure in this study. Prospective studies are needed to draw denitive conclusions on the role of NT-pro-BNP in preoperative risk stratication of postoperative RV failure. When the RV fails acutely, preservation of hemodynamic status depends on the contractile state of the left ventricle and the septum, and also on right atrial contractility and atrioventricular synchronization.13 In most cases, a robust or a wellsupported left ventricle is capable of maintaining satisfactory hemodynamic status, provided there is no signicant element of pulmonary hypertension. In the present study, 4 patients died during hospitalization. To the authors knowledge, no literature exists on prevention of RV failure in patients with CHD. Studies are needed to explore effective management strategies. Potentially, RV afterload-reducing therapies might decrease the risk of developing RV failure perioperatively. The present study reported clinical RV failure after cardiac surgery in adult patients with CHD. Observational studies

always have limitations. It can therefore be difcult to relate causes (cardiac surgery) to effects (changes in RV function). However, the cohort of 412 consecutive patients who underwent cardiac surgery was large for studies performed in adults with CHD. Another limitation was the heterogeneity of underlying diagnoses and procedures performed. However, the authors chose to study a nonselected, typical, and realistic population of patients who had undergone consecutive surgeries for CHD. Finally, identication of patients was performed by careful review of medical records. Potentially, more patients with CHD had RV failure that was missed by their treating physician. RV failure is difcult to dene and lacks a universal diagnosis. Lastly, the authors were unable to include NT-pro-BNP in the multivariate model because of a high number of missing values and potential selection bias. Available NT-pro-BNP samples were taken with a median difference of 84 days (2.7 months) from the day of echocardiography. The authors did not collect transesophageal echocardiography data because transesophageal echocardiography was not performed in all patients preoperatively and, especially, not postoperatively. They chose to use transthoracic instead of transesophageal echocardiography, a rapid, simple, and inexpensive technique. Transthoracic echocardiography is performed easily at bedside in a postoperative setting, and is used often according to the literature.6 RV failure after cardiac surgery is a serious complication, and occurs regardless of the side of surgery. A tailored approach in patients with CHD at highest risk of RV failure should be considered.

REFERENCES newald S, et al: Independent risk factors 1. Vogt MO, H orer J, Gru for cardiac operations in adults with congenital heart disease: A retrospective study of 543 operations for 500 patients. Pediatr Cardiol 33(1):75-82, 2012 2. Yadav H, Unsworth B, Fontana M, et al: Selective right ventricular impairment following coronary artery bypass graft surgery. Eur J Cardiothorac Surg 37(2):393-398, 2010 3. Schuuring MJ, Bolmers PPM, Mulder BJM, et al: Right ventricular function declines after cardiac surgery in adult patients with congenital heart disease. Int J Cardiovasc Imaging 28:755-762, 2012 4. Tulevski II, Romkes H, Dodge-Khatami A, et al: Quantitative assessment of the pressure and volume overloaded right ventricle: Imaging is a real challenge. Int J Cardiovasc Imaging 18(1): 41-51, 2002

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5. Tulevski II, Dodge-Khatami A, Groenink M, et al: Right ventricular function in congenital cardiac disease: Noninvasive quantitative parameters for clinical follow-up. Cardiol Young 13(5):397-403, 2003 6. Klitsie LM, Hazekamp MG, Roest AAW, et al: Tissue Doppler imaging detects impaired biventricular performance shortly after congenital heart defect surgery. Pediatr Cardiol. [Epub ahead of print], 2012 7. Lancellotti P, Tribouilloy C, Hagendorff A, et al: European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 1: Aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr 11(3):223-244, 2010 8. Rudski LG, Lai WW, Alalo J, et al: Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 23(7):685-713. [quiz 786-788], 2010 9. Baumgartner H, Bonhoeffer P, De Groot NMS, et al: ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 31(23):2915-2957, 2010 10. Kaul S, Tei C, Hopkins JM, et al: Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 107(3): 526-531, 1984  N, Hoeper MM, Humbert M, et al: Guidelines for the 11. Galie diagnosis and treatment of pulmonary hypertension: The task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society

(ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30(20):2493-2537, 2009 12. Cohn JN, Guiha NH, Broder MI, et al: Right ventricular infarction. Clinical and hemodynamic features. Am J Cardiol 33(2):209-214, 1974 13. Kaul TK, Fields BL: Postoperative acute refractory right ventricular failure: Incidence, pathogenesis, management and prognosis. Cardiovasc Surg 8(1):1-9, 2000 14. Bond BR, Dorman BH, Clair MJ, et al: Endothelin-1 during and after cardiopulmonary bypass: Association to graft sensitivity and postoperative recovery. J Thorac Cardiovasc Surg 122(2):358-364, 2001 15. Schuuring MJ, Vis JC, Duffels MG, et al: Adult patients with pulmonary arterial hypertension due to congenital heart disease: A review on advanced medical treatment with bosentan. Ther Clin Risk Manag 6:359-366, 2010 16. Wranne B, Pinto FJ, Hammarstr om E, et al: Abnormal right heart lling after cardiac surgery: Time course and mechanisms. Br Heart J 66(6):435-442, 1991 17. Diller G-P, Wasan BS, Kyriacou A, et al: Effect of coronary artery bypass surgery on myocardial function as assessed by tissue Doppler echocardiography. Eur J Cardiothorac Surg 34(5): 995-999, 2008 18. Houmsse M, Tyler J, Kalbeisch S: Supraventricular tachycardia causing heart failure. Curr Opin Cardiol 26(3):261-269, 2011 19. Mascio CE, Pasquali SK, Jacobs JP, et al: Outcomes in adult congenital heart surgery: Analysis of the Society of Thoracic Surgeons database. J Thorac Cardiovasc Surg 142(5):1090-1097, 2011