Preoperative Optimization of the Heart Failure Patient Undergoing Cardiac Surgery

Accepted Manuscript Pre-operative Optimization of the Heart Failure Patient Undergoing Cardiac Surgery Maxime Pichette, M.D., Mark Liszkowski, M.D., Anique Ducharme, M.D., M.Sc. PII:

S0828-282X(16)30833-9

DOI:

10.1016/j.cjca.2016.08.004

Reference:

CJCA 2237

To appear in:

Canadian Journal of Cardiology

Received Date: 7 June 2016 Revised Date:

27 July 2016

Accepted Date: 1 August 2016

Please cite this article as: Pichette M, Liszkowski M, Ducharme A, Pre-operative Optimization of the Heart Failure Patient Undergoing Cardiac Surgery, Canadian Journal of Cardiology (2016), doi: 10.1016/ j.cjca.2016.08.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Pre-operative Optimization of the Heart Failure Patient Undergoing Cardiac Surgery

a

RI PT

Maxime Pichette, M.D.a; Mark Liszkowski, M.D.a; Anique Ducharme, M.D., M.Sc.a;

Department of medicine, Montreal Heart Institute, Université de Montréal,

M AN U

SC

Montréal, Québec, Canada

Short title: Heart failure optimization before cardiac surgery

AC C

EP

TE D

Word count: 3239 excluding references and tables

Corresponding authors:

Drs Anique Ducharme or Mark Liszkowski Department of Medicine Montreal Heart Institute 5000 Belanger east, Montreal, Quebec, H1T 1C8 [email protected] or [email protected]

1

ACCEPTED MANUSCRIPT

Brief summary

RI PT

Cardiac surgery in heart failure patients carries significant risks, which can be alleviated by preoperative optimization. Investigations and therapeutic adjustments should be performed to

achieve hemodynamic goals and optimize end-organ function. Quantitative risk stratification by

SC

the assessment of nutritional status, renal and hepatic function and goal-directed medical therapy

AC C

EP

TE D

M AN U

are some of the main pre-operative interventions that can improve the outcomes in these patients.

2

ACCEPTED MANUSCRIPT

Abstract

Heart failure (HF) patients undergoing cardiac surgery are exposed to significant perioperative

RI PT

complications and high mortality. We herein review the literature concerning pre-operative optimization of these patients. Salient findings are that end-organ dysfunction and medication should be optimized before surgery. Specifically: (i) reversible causes of anemia should be

SC

treated and a pre-operative hemoglobin level of 100 g/L obtained; (ii) renal function and volume status should be optimized; (iii) liver function must be carefully evaluated; (iv) nutritional status

M AN U

should be assessed and cachexia treated to achieve a preoperative albumin level of at least 30 g/L and a body mass index higher than 20 kg/m2 and (v) medication adjustments performed, such as withholding inhibitors of the renin-angiotensin-aldosterone system before surgery and continuing, but not starting, beta-blockers. Levels of natriuretic peptides (BNP and NT-proBNP)

TE D

provide additional prognostic value and therefore should be measured. In addition, individual patient’s risk should be objectively assessed using standard formulas such as the Euroscore-II or STS risk scores, which are simple and validated for various cardiac surgeries, including left

EP

ventricular assist device implantation. Once patients are identified as high risk, pre-operative hemodynamic optimization may be achieved with the insertion of a pulmonary artery catheter

AC C

and hemodynamic-based tailored therapy. Finally, a prophylactic intra-aortic balloon pump may be considered in certain circumstances to decrease morbidity and even mortality, like in some high risk HF patients undergoing cardiac surgery, while routine pre-operative inotropes are not recommended and should be reserved for patients in shock, except maybe for levosimendan.

3

ACCEPTED MANUSCRIPT

Abbreviations

Angiotensin-converting enzyme inhibitor

ACS

Acute coronary syndrome

ARNi

Angiotensin receptor-neprilysin inhibitor

ARB

Angiotensin II receptor blocker

BNP

Brain natriuretic peptides

BMI

Body mass index

CABG

Coronary artery bypass grafting

CVP

Central venous pressure

EPO

Erythropoietin

HF

Heart failure

HFrEF

Heart failure with reduced ejection fraction

IABP

Intra-aortic balloon pump

LFT

Liver function tests

RASi STS

SC

Model for end-staged liver disease

AC C

RCT

Left ventricular assist device

EP

MELD

PAC

M AN U

Left ventricular ejection fraction

LVAD

NP

TE D

LVEF

RI PT

ACEi

Natriuretic peptides

Pulmonary artery catheter Randomized controlled trial Renin-angiotensin system inhibitor Society of Thoracic Surgeons

4

ACCEPTED MANUSCRIPT

Introduction

Heart failure (HF) is a growing epidemic currently affecting 600,000 Canadians with more than

RI PT

50,000 new cases being diagnosed annually.(1) Cardiologists are frequently referring their HF patients for various types of cardiac surgery but few see the pre-operative period as a window of opportunity for optimization before surgery. This period is a privileged time to act upon

SC

modifiable risk factors and potentially lower the operative risk. The bulk of literature on

perioperative optimization in HF patients mainly comes from anesthesiology and hence focuses

M AN U

on intra- and immediate post-operative management, when it may be too late to intervene and alter the outcome of a patient entering the operating room in a decompensated state. Consequently, we believe that specific pre-operative goals to optimize volemia, nutritional state and end-organ function should be achieved before sending a HF patient for surgery.

TE D

Interestingly, guidelines on the cardiovascular evaluation and management of patients prior to non-cardiac surgery are available, but no such recommendations have been published concerning cardiac surgery.(2, 3) The objectives of this article are to review the recent literature concerning

EP

the pre-operative optimization of HF patients and to suggest practical tips and numeric goals to

AC C

be achieved before surgery.

Optimization of specific organ systems

Anemia

Pre-operative anemia is present in approximately 25% of patients undergoing cardiac surgery and is an independent predictor of perioperative complications, especially for high-risk patients.(4-6) In 2750 patients undergoing coronary artery bypass grafting (CABG) with a EuroSCORE-II higher than 4, a pre-operative hemoglobin value lower than 110 g/L was 5

ACCEPTED MANUSCRIPT

associated with an increased risk of post-operative HF, myocardial infarction and cardiovascular mortality with a three-fold increase in mortality reported by another group.(4, 7) Two small trials suggested that erythropoietin (EPO) and iron supplementation may decrease transfusion

RI PT

requirements and complications after cardiac surgery, while a large randomized controlled trial (RCT) of EPO in ambulatory patients with heart failure and reduced ejection fraction (HFrEF), but not undergoing surgery, failed to demonstrate any clinical benefit overall.(8-10) In view of

SC

these apparently conflicting data, we cannot recommend routine pre-operative EPO in anemic patients undergoing cardiac surgery. Nevertheless, targeting a post-operative hemoglobin of 90

M AN U

g/L after cardiac surgery has been shown to decrease mortality when compared to a threshold of 75 g/L.(11) Consequently, it seems reasonable to draw a pre-operative complete blood count in all HF patients in order to treat possibly reversible causes of anemia, such as iron deficiency.(12) Experts’ opinion suggests that the pre-operative hemoglobin level should be above 100 g/L,

TE D

particularly for high risk surgery, and transfusions could be considered to achieve this level.(4, 6, 7, 13) The suggested pre-operative goals to achieve in HF patients before cardiac surgery are presented in Table 1. Of note, these goals should be viewed as general suggestions given that

AC C

Kidney function

EP

pre-operative optimization should always be individualized for specific patients.

The presence of even mild renal dysfunction pre-operatively predicts the occurrence of acute kidney injury and the need for dialysis after cardiac surgery and is associated with worse outcomes.(14, 15) In addition, patients are often exposed to consecutive renal insults such as iodinated-contrast agent use for coronary angiogram and the systemic inflammatory response syndrome caused by cardiopulmonary bypass. Unfortunately, pre-operative administration of

6

ACCEPTED MANUSCRIPT

sodium bicarbonates has failed to show benefit and even increased the duration of mechanical ventilation and length of stay in intensive care unit.(16) Thus, in acute or chronic kidney failure, surgery should be deferred in order to let the kidneys recover of iodinated-contrast exposure

RI PT

whenever possible.(17, 18) Data from observational studies and small RCTs suggest that preoperative statin therapy is associated with reduced post-operative renal dysfunction after cardiac surgery.(19) Statins should therefore be started pre-operatively when appropriate and continued

SC

perioperatively.(20) In HF patients, volume status and hemodynamics should be optimized in order to improve renal function pre-operatively, using pulmonary artery catheter (PAC) as

M AN U

needed for hemodynamic-tailored therapy (see below). The data on pre-operative interruption of diuretics are limited and should therefore be individualized; we believe that mineralocorticoid receptor antagonists should be suspended 24 to 48 hours prior to surgery. Other diuretics and fluid restriction should be continued preoperatively in order to maintain a euvolemic state at the

Liver function

TE D

time of surgery, therefore avoiding pre-operative congestion and cardiac decompensation.

EP

Liver function tests (LFT) may reflect hypervolemia and right-sided HF. Elevated transaminases usually reveal a low cardiac output, whereas increased bilirubin and alkaline phosphatase are

AC C

associated with congestion.(21, 22) Interestingly, the Model for End-Stage Liver Disease (MELD) score and Child-Pugh class, two risk scores originally designed for stratification of cirrhotic patients, predicted morbidity and mortality in cardiac surgery, the MELD score being particularly useful for cardiac transplantation and LVAD implantation and complementary to the EuroSCORE-II and Society of Thoracic Surgeon (STS) risk score.(23-25) Similarly to renal dysfunction, patients with abnormal LFTs must have a thorough evaluation, pre-operative

7

ACCEPTED MANUSCRIPT

hemodynamic optimization and aggressive decongestion. In patients with persistently elevated LFTs, cardiac cirrhosis should be ruled-out prior to considering surgery. Poor nutritional status, coagulopathy, risk of encephalopathy, immune dysfunction, and vasoplegia are amongst the

RI PT

many factors that increase perioperative risk of cirrhotic patients and have to be taken into

consideration.(26) Coagulopathic patients should receive vitamin K (oral or IV) and possibly fresh frozen plasma or factors concentrate to reduce the risk of perioperative bleeding. In patients

SC

with severe hepatic dysfunction, it might not be possible to completely normalize their

coagulation parameters; consequently, the use of functional assays such as thromboelastometry

M AN U

and thromboelastography should be considered for adequacy of hemostasis.(26, 27) LFTs should therefore be measured in HF patients before cardiac surgery to guide hemodynamic optimization and improve risk stratification. Ideal cut-offs have yet to be determined but targeting transaminases levels less than 2 times the normal value and a bilirubin lower than 40 µmol/L

TE D

seem reasonable pre-operative goals.(13) It might not be possible to reach these targets in cirrhotic patients despite adequate optimization and euvolemia. If cirrhosis is suspected, consultation with a gastroenterologist should be performed beforehand to confirm the diagnosis

EP

and discuss whether the benefits of the surgery outweigh the risks, the perioperative mortality

AC C

with advanced cirrhosis being as high as 66%.(28)

Nutrition status

Malnutrition can affect up to 50% of HF patients and 15% of them are overtly cachectic, due to their catabolic state, bowel hypoperfusion, congestive hepatopathy, and systemic inflammation among other causes.(29) Body mass index (BMI) and albumin levels are independent predictors of morbidity and mortality after CABG and valve surgeries.(30, 31) In patients undergoing

8

ACCEPTED MANUSCRIPT

LVAD implantation, a low pre-operative albumin is associated with prolonged hospitalization and development of acute kidney injury.(32) Also, a low prealbumin level provides incremental information over BMI and albumin and is associated with prolonged intubation and post-

RI PT

operative infections.(33) A pre-operative nutritional assessment must therefore be performed in all HF patients undergoing cardiac surgery, with at least a serum albumin, prealbumin and BMI calculation, using the “dry” weight. Once identified, severe malnutrition is a potentially

SC

modifiable risk factor that should be addressed before surgery. Doing so in collaboration with a nutritionist would allow patients to build protein reserves and reach targeted albumin levels

M AN U

higher than 30 g/L, prealbumin higher than 20 mg/dL and BMI higher than 20 kg/m2. An option is to consider nocturnal enteral feeding if supplements and standard nutritional measures failed. (30-33) In stable patients, sufficient time for optimization of the nutritional status should be

TE D

allowed, which can be up to several weeks in severely malnourished patients.

Cardiovascular medication management

EP

ACEi, ARB and ARNi

Angiotensin-converting enzyme inhibitors (ACEi), angiotensin-II receptor blockers (ARB) or

AC C

angiotensin receptor-neprilysin inhibitors (ARNi) should be prescribed in patients with HFrEF as they improve survival and decrease morbidity when used chronically.(34) However, reninangiotensin-system inhibitors (RASi) associated with anesthesia induction and cardiopulmonary bypass can have adverse hemodynamic consequences.(35) Results from observational studies are inconsistent but a large propensity-matched study suggested that continuing ACEi just prior to surgery increases mortality after CABG.(36-41) In HF patients undergoing LVAD implantation

9

ACCEPTED MANUSCRIPT

or cardiac transplantation, RASi are associated with an increased risk of post-operative acute kidney injury with up to 3.5-fold increased risk of dialysis.(42, 43) RASi should therefore be interrupted in HF patients before cardiac surgery. Although the exact timing is unknown, we

RI PT

believe that stopping them 2 to 3 days prior to cardiac surgery is sufficient, depending on the half-life of the agent used. However, discontinuing RASi in patients with HFrEF could

potentially cause a deleterious increase in afterload. Patients should then be closely monitored

SC

and if signs of decompensation occur, bridging with other vasodilators such as hydralazine

and/or nitrates before surgery can be considered. Table 2 summarizes our recommendations

M AN U

concerning the perioperative management of cardiovascular medication.

Beta-blockers

As for RASi, beta-blockers have important clinical benefits in HFrEF and the majority of HF

TE D

patients should already be chronically on these agents before surgery.(34) Evidence from large observational studies demonstrated that the use of perioperative beta-blockers improves survival in patients with ischemic cardiomyopathy, a benefit that seems limited to those with a left

EP

ventricular ejection fraction (LVEF) < 40%, although a recent analysis of the STS database questioned this finding.(44-46) Nevertheless, we believe that beta-blockers should be continued

AC C

throughout the operative period in HF patients already receiving these agents, provided there is no contraindication such as cardiogenic shock or acutely decompensated HF. However, there is no data to support their introduction for those not already receiving beta-blockers prior to cardiac surgery.(47)

10

ACCEPTED MANUSCRIPT

The role of biomarkers and risk scores Biomarkers Levels of natriuretic peptides (NP, BNP and NT-proBNP) are powerful predictors of mortality in

RI PT

patients with HF.(48) Their utility for risk stratification before cardiac surgery has also been confirmed in observational studies, pre-operative BNP levels independently predicting long-term mortality even for elective CABG.(49, 50) In ACS patients undergoing CABG, pre-operative

SC

NT-ProBNP levels have incremental prognostic value to the EuroScore-II.(51) Since, NP are often chronically elevated in HF patients, even when compensated, it is difficult to determine a

M AN U

threshold beyond which surgical risk would be prohibitive. Therefore, goals should be individualized, aiming at the lowest level obtained in the previous year and considering delaying surgery in patients with rapidly increasing NP levels.(52, 53) If no baseline values are available, targets for BNP could be lower than 300 pg/mL and 1000 pg/mL for NT-proBNP, although these

TE D

goals are highly controversial.(49-51) Nonetheless, the NP should never be taken in isolation as they reflect filling pressures that might also influence both renal and hepatic function.

EP

Risk scores

Post-operative outcomes in HF patients undergoing cardiac surgery are determined by interplay

AC C

of numerous modifiable and non-modifiable patient-related and technique-related factors. No single factor can accurately predict mortality. Therefore, various composite risk scores have been developed to improve pre-operative stratification. These scores can be useful to identify patients in whom a rigorous pre-operative optimization will be the most beneficial. In studies comparing different scoring systems, the EuroScore, EuroScore-II and the STS risk score are the three models that demonstrated the best predictive accuracy.(54, 55) Even though some important

11

ACCEPTED MANUSCRIPT

variables such as frailty are not included in these scores, they are easy to use and well validated in contemporary cohorts.(56, 57) In a recent small study, the EuroScore-II demonstrated very good accuracy in predicting one-year mortality in patients undergoing LVAD implantation.(58)

RI PT

Therefore, risk scores, particularly EuroScore-II and STS, should be calculated in all HF patients before cardiac surgery as they are easily available and provide good risk stratification,

complementary to the NP levels. A perioperative mortality risk lower than 2% is generally

SC

considered as low risk and an estimated mortality higher than 5% as high risk. High risk patients can therefore be objectively identified and substantial efforts should be made to try to optimize

M AN U

these patients. Even though some parameters are not modifiable, small improvements in multiple modifiable factors may translate into fewer clinical events. For example, based on EuroScore-II, the risk of mortality in a 75 years-old diabetic patient with ischemic cardiomyopathy and a LVEF of 35% undergoing redo CABG surgery is 16% when the pre-operative creatinine level is

TE D

150 µmol/L. After optimization of renal function and a decrease of the creatinine level to 120 µmol/L, the peri-operative risk could potentially be reduced to 10%. Noteworthy, there is no published prospective study to confirm that lowering EuroSCORE-II translates into fewer

EP

clinical events, but considering the prognostic impact of renal function before cardiac surgery,

AC C

such a decrease in peri-operative mortality could be expected.

The role of pulmonary artery catheter and goal-directed therapy

HF patients undergoing cardiac surgery are at risk of inadequate organ perfusion because of the stress imposed by cardiopulmonary bypass and limited cardiac reserves. They should therefore enter the operating room with optimal filling pressures and cardiac output in order to limit

12

ACCEPTED MANUSCRIPT

hypoperfusion in the perioperative period. Pulmonary artery catheters (PAC) have been criticized in the past because RCT failed to show benefits in acutely decompensated HF patients or in high risk patients undergoing non-cardiac surgery.(59, 60) Some studies even suggested increased

RI PT

perioperative mortality with the use of PAC during cardiac surgery.(61) However, a major

limitation of the surgical studies is that PAC was often used in compensated HF patients or in patients without HF at all. In the RCT on the use of PAC for non-cardiac surgery,(60) high risk

SC

patients were defined as being American Society of Anesthesiologists class III or IV, but only 11% had a history of congestive HF and the New York Heart Association functional class was I

M AN U

or II in 87% of the patients. It is therefore not surprising that the use of PAC did not affect clinical outcomes in these patients with normal hemodynamics. Other limitations of these reports include the intra-operative use of PAC, rather than pre-operatively, and the absence of standardized treatment algorithm for the optimization of hemodynamics. Achieving targeted

TE D

hemodynamic parameters in HF patients requires thorough treatment adjustment and can extend over of a few days. If a patient is sent to surgery with a very high central venous pressure (CVP) and a decreased cardiac output, it is unlikely that intra-operative management will suffice to

EP

optimize hemodynamics and allow optimal oxygen delivery. A recent meta-analysis including high risk patients, defined among other criteria as a EuroSCORE higher than 6, demonstrated a

AC C

reduction in perioperative complications and length of hospital stay in patients randomized to goal-directed therapy.(62) In patients with acute decompensated HF or those undergoing LVAD implantation, pre-operative PAC insertion could therefore be considered. Most importantly, hemodynamic parameters should be measured at regular intervals and treatment adjustments made accordingly. The hemodynamic goals should aim for normal filling pressures, that is CVP < 8mmHg, pulmonary capillary wedge pressure < 16mmHg and a cardiac index > 2.2

13

ACCEPTED MANUSCRIPT

L/min/m2.(59, 63) Therapy should be tailored not only for hemodynamic goals but also to optimize end-organ function, such as creatinine, LFT and lactate levels. Diuretic therapy and

and even temporary mechanical support should be considered.

RI PT

vasodilators should be carefully titrated and if the goals are not reached, pre-operative inotropes

SC

Temporary mechanical support and inotropes

Temporary mechanical support

M AN U

In patients with severe volume overload and shock, medication titration and goal-directed therapy might not be sufficient to optimize the hemodynamic state and end-organ dysfunction. Different forms of hemodynamic support can then be offered. Intra-aortic balloon pump (IABP) increases coronary artery perfusion, decreases afterload and provides a modest increase in

TE D

cardiac output.(64) Pre-operative insertion of IABP has been studied in numerous small RCT involving high risk patients with ischemic cardiomyopathy, such as those with HFrEF and left main coronary artery stenosis. A recent meta-analysis of 17 trials including a total of 2539

EP

patients found a significant short-term mortality reduction (OR=0.35, p<0.0001).(65) Preoperative IABP is also associated with favourable outcomes in small trials involving HF patients

AC C

undergoing LVAD implantation and cardiac transplantation.(66, 67) In the latter scenario, an axillary approach can be used to allow prolonged support and ambulation. However, IABP can be associated with complications(65) and should not be routinely used for all HF patients undergoing cardiac surgery, but rather reserved for patients with ischemic cardiomyopathy undergoing CABG for whom goal-directed therapy failed and for patients with acute mitral regurgitation undergoing mitral surgery.(68) Other types of temporary mechanical supports such

14

ACCEPTED MANUSCRIPT

as Impella, TandemHeart and extra-corporeal membrane oxygenation (ECMO) provide higher cardiac output to offer complete circulatory support for patients in cardiogenic shock. They have been successfully used in patients with adavnced HF (INTERMACS profiles 1 and 2) as a bridge

RI PT

to LVAD or cardiac transplantation but there is not enough data to recommend their routine use.(69-71) In high risk HF patients undergoing CABG or valve surgery who otherwise would be good candidates, consultation with the heart transplant team pre-operatively should be

SC

considered. Advanced HF therapies such as LVAD and cardiac transplantation should be

discussed beforehand in order to establish a plan in the event of perioperative complications and

therapies are considered.(72)

Inotropes

M AN U

postcardiotomy shock. An appropriate work-up should be completed pre-operatively if advanced

TE D

Intravenous inotropes cause an acute rise in cardiac output, help achieve hemodynamic goals and improve end-organ perfusion in HF patients. This may reduce the risk of worsening organs’ ischemic injury in the peri-operative period. However, routine pre-operative administration of

EP

milrinone or dobutamine failed to improve clinical outcomes; on the contrary, a meta-analysis of 13 RCT comparing the peri-operative use of milrinone to placebo or other inotropes suggested an

AC C

increased risk of mortality (OR=2.67, p=0.04) when started immediately before or during the surgery.(73) Similarly to the use of PAC and goal-directed therapy, a benefit might be present if inotropes are used for pre-operative optimization of HF rather than intra-operatively. Noteworthy, levosimendan, a calcium sensitizer with inotropic and vasodilatory effects, seems to behave differently. In a RCT trial of 252 patients with ischemic cardiomyopathy and LVEF < 25%, routine pre-operative levosimendan was associated with a decrease in perioperative

15

ACCEPTED MANUSCRIPT

mortality.(74) When compared with milrinone, dobutamine, enoximone or placebo in a metaanalysis of 46 RCT, levosimendan was the only inotrope associated with reduced perioperative mortality.(75) A panel of European experts recently recommended levosimendan the day before

RI PT

cardiac surgery in patients with impaired left of right ventricular function (76). The results of the LEVO-CTS trial (NCT02025621) and the LICORN trial (NCT02184819), two large RCT

studying the effect of levosimendan before and during cardiac surgery respectively, will soon be

SC

published and could provide sufficient data to recommend its use in patients with HFrEF

undergoing cardiac surgery. Of note, levosimendan is not yet approved in Canada. Inotropes

M AN U

should therefore not be used routinely before cardiac surgery and ought to be reserved for patients in shock with evidence of end-organ dysfunction from hypoperfusion. In these patients, dobutamine, milrinone or epinephrine can be used. Epinephrine should be used in preference to inotropes with vasodilatory properties in patients with fixed or dynamic left ventricular outflow

AC C

EP

TE D

tract obstruction.

16

ACCEPTED MANUSCRIPT

Conclusions

For the HF patients, the period preceding cardiac surgery is a critical moment during which the

RI PT

cardiologist can intervene to improve mortality and morbidity. The pre-operative period must include investigations and treatment adjustments in order to lower that risk. Table 3 summarizes a checklist that should be performed prior sending a HF patient to surgery: End-organ

SC

dysfunction should be screened for and treated accordingly. Stratification with biomarkers and risk scores can identify patients who will benefit from pre-operative pulmonary artery catheter

M AN U

insertion and goal-directed therapy. Cardiologists and cardiac surgeons should discuss as a Heart team to establish pre-operative goals, confirm that these goals have been achieved and decide on the optimal timing of surgery. The benefits associated with each of these goals individually are small. However, pre-operative optimization should be viewed as a bundle of care in which all

AC C

EP

patients.

TE D

elements collectively contribute to improving post-operative outcome in these high risk surgical

17

ACCEPTED MANUSCRIPT

Funding sources The authors did not receive any funding for this article.

RI PT

Disclosures

AC C

EP

TE D

M AN U

SC

None

18

ACCEPTED MANUSCRIPT

Pre-operative goals before cardiac surgery in heart failure patients

Parameter

Goal

RI PT

Table 1.

> 100 g/L

Creatinine

Lowest individual value in the previous year

AST and ALT

< 2 times the normal value

Bilirubin

< 40 µmol/L

Albumin

SC

Hemoglobin

M AN U

Laboratory parameters

> 30 g/L

Prealbumin

> 20 mg/dL > 20 kg/m2

Body mass index

TE D

Biomarkers BNP

EP

NT-proBNP

Lowest individual value in the previous year or < 300 pg/mL Lowest individual value in the previous year or < 1000 pg/mL

AC C

Hemodynamic parameters Central venous pressure

< 8 mmHg

Pulmonary capillary wedge pressure

< 16 mmHg

Cardiac output

> 2.2 L/min/m2

AST = aspartate aminotransferase; ALT = alanine transaminase; BNP = brain natriuretic peptides.

19

ACCEPTED MANUSCRIPT

Table 2.

Cardiovascular medication management before surgery in heart failure patients Management

ACEi, ARB and ARNi

• Interrupt 3 days before the surgery and restart before home discharge

Beta-blockers

RI PT

Medication

• Continue until surgery if the patient is already on beta-

SC

blocker therapy at the time of admission

M AN U

• Do not start pre-operatively in patients not receiving betablocker therapy at the time of admission • Interrupt 24 to 48 hours before the surgery and restart

MRA

before home discharge

TE D

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNi = angiotensin receptor-neprilysin inhibitor; LVAD = left ventricular assist device; MRA

AC C

EP

= mineralocorticoid receptor antagonist.

20

ACCEPTED MANUSCRIPT

Table 3.

Checklist before sending a heart failure patient to surgery Item

Have modifiable parameters of

• Complete blood count and coagulogram

end-organ dysfunction been

• Creatinine, urea and electrolytes

assessed and treated?

SC

• Liver function tests

RI PT

Question

• Measure albumin and prealbumin and calculate BMI • Measure BNP or NT-proBNP levels

adequately risk stratified?

M AN U

Has the patient been

• Calculate EuroScore-II or STS risk score

Is the patient at very high risk

• Consider pulmonary artery catheter insertion and goal-

or acutely decompensated?

directed therapy

TE D

• Consider IABP and inotropes

BMI = body mass index; BNP = brain natriuretic peptides; IABP = intra-aortic balloon

AC C

EP

pump; STS = Society of Thoracic Surgeons.

21

ACCEPTED MANUSCRIPT

References

1.

Heart and Stroke Foundation. 2016 report on the health of Canadian. Available at:

HEART-REPORT.PDF. Accessed on June 4, 2016. 2.

RI PT

www.heartandstroke.com/atf/cf/%7B99452d8b-e7f1-4bd6-a57d-b136ce6c95bf%7D/2016-

Fleisher LA, Fleischmann KE, Auerbach AD, Barnason SA, Beckman JA, Bozkurt B, et

SC

al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of

M AN U

Cardiology/American Heart Association Task Force on practice guidelines. Journal of the American College of Cardiology. 2014;64(22):e77-137. 3.

Kristensen SD, Knuuti J, Saraste A, Anker S, Botker HE, Hert SD, et al. 2014 ESC/ESA

Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task

TE D

Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). European heart journal. 2014;35(35):2383-431.

Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC, Snyder-Ramos SA, et al.

EP

4.

Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft

5.

AC C

surgery. Circulation. 2007;116(5):471-9. Karkouti K, Wijeysundera DN, Beattie WS. Risk associated with preoperative anemia in

cardiac surgery: a multicenter cohort study. Circulation. 2008;117(4):478-84. 6.

Hallward G, Balani N, McCorkell S, Roxburgh J, Cornelius V. The Relationship

Between Preoperative Hemoglobin Concentration, Use of Hospital Resources, and Outcomes in Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia. 2016.

22

ACCEPTED MANUSCRIPT

7.

Boening A, Boedeker RH, Scheibelhut C, Rietzschel J, Roth P, Schonburg M. Anemia

before coronary artery bypass surgery as additional risk factor increases the perioperative risk. The Annals of thoracic surgery. 2011;92(3):805-10. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al. Treatment of

RI PT

8.

anemia with darbepoetin alfa in systolic heart failure. The New England journal of medicine. 2013;368(13):1210-9.

Weltert L, Rondinelli B, Bello R, Falco M, Bellisario A, Maselli D, et al. A single dose of

SC

9.

erythropoietin reduces perioperative transfusions in cardiac surgery: results of a prospective

10.

M AN U

single-blind randomized controlled trial. Transfusion. 2015;55(7):1644-54.

Cladellas M, Farre N, Comin-Colet J, Gomez M, Merono O, Bosch MA, et al. Effects of

preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement. The American journal of cardiology. 2012;110(7):1021-6. Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, et al. Liberal

TE D

11.

or restrictive transfusion after cardiac surgery. The New England journal of medicine. 2015;372(11):997-1008.

Qian C, Wei B, Ding J, Wu H, Wang Y. The Efficacy and Safety of Iron

EP

12.

Supplementation in Patients With Heart Failure and Iron Deficiency: A Systematic Review and

13.

AC C

Meta-analysis. The Canadian journal of cardiology. 2016;32(2):151-9. Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, et al. Clinical

management of continuous-flow left ventricular assist devices in advanced heart failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2010;29(4 Suppl):S1-39.

23

ACCEPTED MANUSCRIPT

14.

Sandner SE, Zimpfer D, Zrunek P, Rajek A, Schima H, Dunkler D, et al. Renal function

and outcome after continuous flow left ventricular assist device implantation. The Annals of thoracic surgery. 2009;87(4):1072-8. Ji Q, Xia L, Shi Y, Ma R, Wang C, Mei Y, et al. Impact of mild preoperative renal

RI PT

15.

insufficiency on in-hospital and long-term outcomes after off-pump coronary artery bypass

grafting: a retrospective propensity score matching analysis. Journal of cardiothoracic surgery.

16.

SC

2016;11:30.

Tie HT, Luo MZ, Luo MJ, Zhang M, Wu QC, Wan JY. Sodium bicarbonate in the

M AN U

prevention of cardiac surgery-associated acute kidney injury: a systematic review and metaanalysis. Critical care (London, England). 2014;18(5):517. 17.

Kim K, Joung KW, Ji SM, Kim JY, Lee EH, Chung CH, et al. The effect of coronary

angiography timing and use of cardiopulmonary bypass on acute kidney injury after coronary

18.

TE D

artery bypass graft surgery. The Journal of thoracic and cardiovascular surgery. 2016. Teo KK, Cohen E, Buller C, Hassan A, Carere R, Cox JL, et al. Canadian Cardiovascular

Society/Canadian Association of Interventional Cardiology/Canadian Society of Cardiac Surgery

EP

position statement on revascularization--multivessel coronary artery disease. The Canadian journal of cardiology. 2014;30(12):1482-91. Wang J, Gu C, Gao M, Yu W, Yu Y. Preoperative Statin Therapy and Renal Outcomes

AC C

19.

After Cardiac Surgery: A Meta-analysis and Meta-regression of 59,771 Patients. The Canadian journal of cardiology. 2015;31(8):1051-60. 20.

Anderson TJ, Gregoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012

update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of

24

ACCEPTED MANUSCRIPT

dyslipidemia for the prevention of cardiovascular disease in the adult. The Canadian journal of cardiology. 2013;29(2):151-67. 21.

Poelzl G, Ess M, Mussner-Seeber C, Pachinger O, Frick M, Ulmer H. Liver dysfunction

of clinical investigation. 2012;42(2):153-63. 22.

RI PT

in chronic heart failure: prevalence, characteristics and prognostic significance. European journal

van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA.

SC

Abnormal liver function in relation to hemodynamic profile in heart failure patients. Journal of cardiac failure. 2010;16(1):84-90.

Yang JA, Kato TS, Shulman BP, Takayama H, Farr M, Jorde UP, et al. Liver dysfunction

M AN U

23.

as a predictor of outcomes in patients with advanced heart failure requiring ventricular assist device support: Use of the Model of End-stage Liver Disease (MELD) and MELD eXcluding INR (MELD-XI) scoring system. The Journal of heart and lung transplantation : the official

24.

TE D

publication of the International Society for Heart Transplantation. 2012;31(6):601-10. Vanhuyse F, Maureira P, Mattei MF, Laurent N, Folliguet T, Villemot JP. Use of the

model for end-stage liver disease score for guiding clinical decision-making in the selection of

EP

patients for emergency cardiac transplantation. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2013;44(1):134-8. Hsieh WC, Chen PC, Corciova FC, Tinica G. Liver dysfunction as an important

AC C

25.

predicting risk factor in patients undergoing cardiac surgery: a systematic review and metaanalysis. International journal of clinical and experimental medicine. 2015;8(11):20712-21. 26.

Lopez-Delgado JC, Esteve F, Javierre C, Ventura JL, Manez R, Farrero E, et al. Influence

of cirrhosis in cardiac surgery outcomes. World journal of hepatology. 2015;7(5):753-60.

25

ACCEPTED MANUSCRIPT

27.

Deppe AC, Weber C, Zimmermann J, Kuhn EW, Slottosch I, Liakopoulos OJ, et al.

Point-of-care thromboelastography/thromboelastometry-based coagulation management in cardiac surgery: a meta-analysis of 8332 patients. The Journal of surgical research.

28.

RI PT

2016;203(2):424-33.

Modi A, Vohra HA, Barlow CW. Do patients with liver cirrhosis undergoing cardiac

surgery have acceptable outcomes? Interactive cardiovascular and thoracic surgery.

29.

SC

2010;11(5):630-4.

Rahman A, Jafry S, Jeejeebhoy K, Nagpal AD, Pisani B, Agarwala R. Malnutrition and

30.

M AN U

Cachexia in Heart Failure. JPEN Journal of parenteral and enteral nutrition. 2015. Bhamidipati CM, LaPar DJ, Mehta GS, Kern JA, Upchurch GR, Jr., Kron IL, et al.

Albumin is a better predictor of outcomes than body mass index following coronary artery bypass grafting. Surgery. 2011;150(4):626-34.

Thourani VH, Keeling WB, Kilgo PD, Puskas JD, Lattouf OM, Chen EP, et al. The

TE D

31.

impact of body mass index on morbidity and short- and long-term mortality in cardiac valvular surgery. The Journal of thoracic and cardiovascular surgery. 2011;142(5):1052-61. Go PH, Hodari A, Nemeh HW, Borgi J, Lanfear DE, Williams CT, et al. Effect of

EP

32.

Preoperative Albumin Levels on Outcomes in Patients Undergoing Left Ventricular Device

AC C

Implantation. ASAIO journal (American Society for Artificial Internal Organs : 1992). 2015;61(6):734-7. 33.

Yu PJ, Cassiere HA, Dellis SL, Manetta F, Kohn N, Hartman AR. Impact of Preoperative

Prealbumin on Outcomes After Cardiac Surgery. JPEN Journal of parenteral and enteral nutrition. 2015;39(7):870-4.

26

ACCEPTED MANUSCRIPT

34.

McKelvie RS, Moe GW, Ezekowitz JA, Heckman GA, Costigan J, Ducharme A, et al.

The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. The Canadian journal of cardiology. 2013;29(2):168-81. Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, et al.

RI PT

35.

Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. The Journal of thoracic and cardiovascular surgery.

36.

SC

1998;116(6):973-80.

Miceli A, Capoun R, Fino C, Narayan P, Bryan AJ, Angelini GD, et al. Effects of

M AN U

angiotensin-converting enzyme inhibitor therapy on clinical outcome in patients undergoing coronary artery bypass grafting. Journal of the American College of Cardiology. 2009;54(19):1778-84. 37.

Barodka V, Silvestry S, Zhao N, Jiao X, Whellan DJ, Diehl J, et al. Preoperative renin-

TE D

angiotensin system inhibitors protect renal function in aging patients undergoing cardiac surgery. The Journal of surgical research. 2011;167(2):e63-9. 38.

Benedetto U, Melina G, Capuano F, Comito C, Bianchini R, Simon C, et al. Preoperative

EP

angiotensin-converting enzyme inhibitors protect myocardium from ischemia during coronary artery bypass graft surgery. Journal of cardiovascular medicine (Hagerstown, Md).

39.

AC C

2008;9(11):1098-103.

Arora P, Rajagopalam S, Ranjan R, Kolli H, Singh M, Venuto R, et al. Preoperative use

of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery. Clinical journal of the American Society of Nephrology : CJASN. 2008;3(5):1266-73.

27

ACCEPTED MANUSCRIPT

40.

Ouzounian M, Buth KJ, Valeeva L, Morton CC, Hassan A, Ali IS. Impact of preoperative

angiotensin-converting enzyme inhibitor use on clinical outcomes after cardiac surgery. The Annals of thoracic surgery. 2012;93(2):559-64. Drenger B, Fontes ML, Miao Y, Mathew JP, Gozal Y, Aronson S, et al. Patterns of use of

RI PT

41.

perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: effects on in-hospital morbidity and mortality. Circulation.

42.

SC

2012;126(3):261-9.

Jokinen JJ, Tikkanen J, Kukkonen S, Hammainen P, Lommi J, Sipponen J, et al. Natural

M AN U

course and risk factors for impaired renal function during the first year after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2010;29(6):633-40. 43.

Hasin T, Topilsky Y, Schirger JA, Li Z, Zhao Y, Boilson BA, et al. Changes in renal

TE D

function after implantation of continuous-flow left ventricular assist devices. Journal of the American College of Cardiology. 2012;59(1):26-36. 44.

Brinkman W, Herbert MA, O'Brien S, Filardo G, Prince S, Dewey T, et al. Preoperative

EP

beta-blocker use in coronary artery bypass grafting surgery: national database analysis. JAMA internal medicine. 2014;174(8):1320-7. ten Broecke PW, De Hert SG, Mertens E, Adriaensen HF. Effect of preoperative beta-

AC C

45.

blockade on perioperative mortality in coronary surgery. British journal of anaesthesia. 2003;90(1):27-31. 46.

Lin T, Hasaniya NW, Krider S, Razzouk A, Wang N, Chiong JR. Mortality reduction

with beta-blockers in ischemic cardiomyopathy patients undergoing coronary artery bypass grafting. Congestive heart failure (Greenwich, Conn). 2010;16(4):170-4.

28

ACCEPTED MANUSCRIPT

47.

Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, et al. Effects of extended-

release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet (London, England). 2008;371(9627):1839-47. Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P, et al. Prognostic

RI PT

48.

impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart

(COPERNICUS) trial. Circulation. 2004;110(13):1780-6. 49.

SC

failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival

Fox AA, Shernan SK, Collard CD, Liu KY, Aranki SF, DeSantis SM, et al. Preoperative

M AN U

B-type natriuretic peptide is as independent predictor of ventricular dysfunction and mortality after primary coronary artery bypass grafting. The Journal of thoracic and cardiovascular surgery. 2008;136(2):452-61. 50.

Mitchell J, Webb ST. Is brain natriuretic peptide a marker for adverse postoperative

TE D

outcomes in patients undergoing cardiac surgery? Interactive cardiovascular and thoracic surgery. 2011;12(3):467-72. 51.

Holm J, Vidlund M, Vanky F, Friberg O, Hakanson E, Walther S, et al. EuroSCORE II

EP

and N-terminal pro-B-type natriuretic peptide for risk evaluation: an observational longitudinal study in patients undergoing coronary artery bypass graft surgery. British journal of anaesthesia.

52.

AC C

2014;113(1):75-82.

Michtalik HJ, Yeh HC, Campbell CY, Haq N, Park H, Clarke W, et al. Acute changes in

N-terminal pro-B-type natriuretic peptide during hospitalization and risk of readmission and mortality in patients with heart failure. The American journal of cardiology. 2011;107(8):1191-5.

29

ACCEPTED MANUSCRIPT

53.

Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-

brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168-74. Nilsson J, Algotsson L, Hoglund P, Luhrs C, Brandt J. Comparison of 19 pre-operative

RI PT

54.

risk stratification models in open-heart surgery. European heart journal. 2006;27(7):867-74. 55.

Wang TK, Choi DH, Stewart R, Gamble G, Haydock D, Ruygrok P. Comparison of four

thoracic and cardiovascular surgery. 2015;149(2):443-8.

Garcia-Valentin A, Mestres CA, Bernabeu E, Bahamonde JA, Martin I, Rueda C, et al.

M AN U

56.

SC

contemporary risk models at predicting mortality after aortic valve replacement. The Journal of

Validation and quality measurements for EuroSCORE and EuroSCORE II in the Spanish cardiac surgical population: a prospective, multicentre study. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

57.

TE D

2016;49(2):399-405.

Kirmani BH, Mazhar K, Fabri BM, Pullan DM. Comparison of the EuroSCORE II and

Society of Thoracic Surgeons 2008 risk tools. European journal of cardio-thoracic surgery :

discussion

Menon AK, Mechelinck M, Unterkofler J, Goetzenich A, Autschbach R, Tewarie L, et al.

AC C

58.

EP

official journal of the European Association for Cardio-thoracic Surgery. 2013;44(6):999-1005;

Predictive Value of EuroSCORE II in Patients Undergoing Left Ventricular Assist Device Therapy. The Thoracic and cardiovascular surgeon. 2015. 59.

Binanay C, Califf RM, Hasselblad V, O'Connor CM, Shah MR, Sopko G, et al.

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. Jama. 2005;294(13):1625-33.

30

ACCEPTED MANUSCRIPT

60.

Sandham JD, Hull RD, Brant RF, Knox L, Pineo GF, Doig CJ, et al. A randomized,

controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. The New England journal of medicine. 2003;348(1):5-14. Chiang Y, Hosseinian L, Rhee A, Itagaki S, Cavallaro P, Chikwe J. Questionable benefit

RI PT

61.

of the pulmonary artery catheter after cardiac surgery in high-risk patients. Journal of cardiothoracic and vascular anesthesia. 2015;29(1):76-81.

Osawa EA, Rhodes A, Landoni G, Galas FR, Fukushima JT, Park CH, et al. Effect of

SC

62.

Perioperative Goal-Directed Hemodynamic Resuscitation Therapy on Outcomes Following

M AN U

Cardiac Surgery: A Randomized Clinical Trial and Systematic Review. Critical care medicine. 2016;44(4):724-33. 63.

Stevenson LW. Are hemodynamic goals viable in tailoring heart failure therapy?

Hemodynamic goals are relevant. Circulation. 2006;113(7):1020-7; discussion 33. Prondzinsky R, Unverzagt S, Russ M, Lemm H, Swyter M, Wegener N, et al.

TE D

64.

Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial.

65.

EP

Shock (Augusta, Ga). 2012;37(4):378-84.

Wang J, Yu W, Gao M, Gu C, Yu Y. Preoperative Prophylactic Intraaortic Balloon Pump

AC C

Reduces the Incidence of Postoperative Acute Kidney Injury and Short-Term Death of HighRisk Patients Undergoing Coronary Artery Bypass Grafting: A Meta-Analysis of 17 Studies. The Annals of thoracic surgery. 2016;101(5):2007-19. 66.

Imamura T, Kinugawa K, Nitta D, Hatano M, Kinoshita O, Nawata K, et al. Prophylactic

Intra-Aortic Balloon Pump Before Ventricular Assist Device Implantation Reduces Perioperative Medical Expenses and Improves Postoperative Clinical Course in INTERMACS Profile 2

31

ACCEPTED MANUSCRIPT

Patients. Circulation journal : official journal of the Japanese Circulation Society. 2015;79(9):1963-9. 67.

Estep JD, Cordero-Reyes AM, Bhimaraj A, Trachtenberg B, Khalil N, Loebe M, et al.

RI PT

Percutaneous placement of an intra-aortic balloon pump in the left axillary/subclavian position provides safe, ambulatory long-term support as bridge to heart transplantation. JACC Heart failure. 2013;1(5):382-8.

Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Guyton RA, et al.

SC

68.

2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report

M AN U

of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. The Journal of thoracic and cardiovascular surgery. 2014;148(1):e1-e132. 69.

Shah P, Smith S, Haft JW, Desai SS, Burton NA, Romano MA, et al. Clinical Outcomes

of Advanced Heart Failure Patients with Cardiogenic Shock Treated with Temporary Circulatory

TE D

Support Before Durable LVAD Implant. ASAIO journal (American Society for Artificial Internal Organs : 1992). 2016;62(1):20-7. 70.

Lima B, Kale P, Gonzalez-Stawinski GV, Kuiper JJ, Carey S, Hall SA. Effectiveness and

EP

Safety of the Impella 5.0 as a Bridge to Cardiac Transplantation or Durable Left Ventricular Assist Device. The American journal of cardiology. 2016;117(10):1622-8. Riebandt J, Haberl T, Mahr S, Laufer G, Rajek A, Steinlechner B, et al. Preoperative

AC C

71.

patient optimization using extracorporeal life support improves outcomes of INTERMACS Level I patients receiving a permanent ventricular assist device. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2014;46(3):486-92; discussion 92.

32

ACCEPTED MANUSCRIPT

72.

Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al. The 2016

International Society for Heart Lung Transplantation listing criteria for heart transplantation: A

International Society for Heart Transplantation. 2016;35(1):1-23. 73.

RI PT

10-year update. The Journal of heart and lung transplantation : the official publication of the

Zangrillo A, Biondi-Zoccai G, Ponschab M, Greco M, Corno L, Covello RD, et al.

Milrinone and mortality in adult cardiac surgery: a meta-analysis. Journal of cardiothoracic and

74.

SC

vascular anesthesia. 2012;26(1):70-7.

Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan

M AN U

decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Experimental and clinical cardiology. 2012;17(3):125-30. 75.

Greco T, Calabro MG, Covello RD, Greco M, Pasin L, Morelli A, et al. A Bayesian

TE D

network meta-analysis on the effect of inodilatory agents on mortality. British journal of anaesthesia. 2015;114(5):746-56. 76.

Toller W, Heringlake M, Guarracino F, Algotsson L, Alvarez J, Argyriadou H, et al.

EP

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion.

AC C

International journal of cardiology. 2015;184:323-36.

33