University of Groningen The role of troponin and albumin to assess myocardial dysfunction after cardiac surgery and in the critically ill van Beek, Dianne E.C.

(1)

University of Groningen

The role of troponin and albumin to assess myocardial dysfunction after cardiac surgery and

in the critically ill

van Beek, Dianne E.C.

DOI:

10.33612/diss.101333600

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2019

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

van Beek, D. E. C. (2019). The role of troponin and albumin to assess myocardial dysfunction after cardiac

surgery and in the critically ill. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.101333600

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the

author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately

and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the

number of authors shown on this cover page is limited to 10 maximum.

(2)

Chapter

(3)

General

introduction

(4)

(5)

9

1

General introduction

Background

Worldwide approximately one million people require cardiac surgery each year, and this need

is only likely to increase further with the aging society in the following years.

1

_{Major adverse}

cardiac events (MACE) resulting from myocardial damage in general and postoperative

myocardial infarction (PMI) in particular, are major health concerns after cardiac surgery.

About 10% of all patients getting cardiac surgery suffer from PMI.

2,3,4

_{However, the}

proportion of patients actually diagnosed with PMI is substantially lower in clinical practice,

with a substantial percentage of PMIs remaining unrecognized. Underdiagnoses of PMI is a

major healthcare problem, because myocardial damage and subsequent MACE relates to an

increased mortality and an increased intensive care and hospital length of stay.

4,5,6

_{When PMI}

is detected, treatment options are readily available to prevent recurrence and/or ongoing

damage of the myocardium. However, false positive diagnoses could lead to both worse

prognostication and treatment of patients without PMI, who do not benefit from treatment

but are exposed to side-effects, therewith introducing harm.

The first challenge with diagnosing PMI is that, according to the Third Universal Definition,

there are five distinct types of MI

7

_:

▪ Type 1: spontaneous MI

▪ Type 2: MI due to ischemic imbalance

▪ Type 3: MI resulting in death with no biomarker available

▪ Type 4a: MI related to percutaneous coronary intervention (PCI)

▪ Type 4b: MI related to stent thrombosis

▪ Type 5: MI related to coronary artery bypass grafting (CABG)

The cornerstone for diagnosis of (P)MI is elevated biomarkers. The currently preferred

biomarker for detecting myocardial damage is troponin (Tn) subtype T or I, since they are

not only highly sensitive but also very specific for myocardial injury.

7

_{Although elevated Tn}

levels have been shown to be an excellent diagnostic marker for type 1 MI, interpreting

elevated Tn levels after cardiac surgery has proven to be more challenging. The reason for

this is that elevations of Tn are common after cardiac surgery

8

_{and regarded as inherent to}

cardiotomy, i.e. elevated levels can be present even in absence of PMI

2

_{. On the other hand,}

elevations of Tn levels have repeatedly been shown to be associated with MACE

8;9;10;11;12

and mortality

10;13

_{. How to distinguish between acceptable and unacceptable Tn elevation}

after cardiac surgery remains unclear. Currently, the recommended cut-off level for Tn

after coronary artery bypass surgery (CABG) to diagnose excessive myocardial damage is

10 times the 99

th

_percentile.

7

_{However, this cut-off level is expert based and there is not}

yet solid evidence whether this cut-off level results in a distinction between acceptable

and unacceptable Tn elevation.

(6)

10

Chapter 1

We hypothesize that: early identification of patients at risk after cardiac surgery allows

for pre-emptive measures to reduce morbidity and mortality and to redirect medical

resources to those who might benefit and away from those in which it might induce harm.

Adding an additional biomarker for myocardial damage and dysfunction will not only

allow to better identify the patients at risk but will provide a framework for designing

new preventive and therapeutic measures if a causal relationship can be established.

We hypothesized that serum albumin (SA) is a marker and potential causal factor for

myocardial damage and dysfunction. A low SA has been associated with an increase in

morbidity and mortality in cardiac patients (table 1).

Table 1. The association of low SA with morbidity and mortality in different cardiac populations.

Population Low SA

Patients with stable coronary artery disease ▪ ↑ MACE14;15;16

▪ ↑ Mortality16;17

Patients with acute coronary syndromes ▪ ↑ MACE16

▪ ↑ Heart failure18

▪ ↑ (Cardiac) mortality18;16;19;20

Patients undergoing cardiac surgery ▪ ↑ Blood transfusion21

▪ ↑ Infection21

▪ ↑ Acute kidney injury21;22

▪ ↑ Hospital and ICU stay23

▪ ↑ Mortality21;24;23

MACE: major adverse cardiac events, ICU: intensive care unit

Albumin infusion in patients undergoing cardiac surgery has shown to reduce the risk of

several adverse outcomes:

▪ ↓ Positive fluid balance

25

▪ ↓ Fluid boluses needed

25

▪ ↓ Norepinephrine dosage required

25

▪ ↓ Acute kidney injury

26

▪ ↓ Readmission rate

27

▪ ↓ In-hospital mortality

27

In patients admitted to the intensive care unit (ICU) a low SA is also associated with

mortality.

28;29

_{SA supplementation studies in the ICU patients have mostly been focused}

on septic patients, in which a meta-analysis showed no clear effect on mortality

30

_{. However,}

in a study focusing on the entire ICU population, the patients with a low SA did benefit

from albumin infusion (as it was associated with an improved Sequential Organ Failure

Assessment score and a less positive fluid balance).

31

(7)

11

1 In addition to these associations, there are also signs that SA potentially has a direct effect

on the heart. For instance, when comparing 20% albumin administration intravenously to

crystalloid administration in healthy volunteers both the cardiac output and stroke volume

increased more (while the afterload decreased).

32

_{In patients after cardiac surgery 5%}

albumin infusion compared to saline infusion significantly increased the cardiac index

33

_,

and compared to Ringer’s lactate it prolonged the obtained hemodynamic stability after

infusion

34

_{. In endotoxemic rats albumin infusion has been shown to improve ventricular}

contractility and the myocardial oxygenation.

35

Even more so, in patients undergoing a percutaneous coronary intervention (PCI) a lower

SA was associated with a prolonged QTc interval (regardless whether the PCI was elective

or emergent).

36

_{A (consistently) prolonged QTc interval is associated with the development}

of atrial fibrillation (AF)

37

_{and sudden cardiac death}

36

_.

These direct effects on the heart of SA combined with the clinical association described

above (of a low SA and adverse outcomes and albumin infusion with improved outcome),

warrant to test the hypothesis that SA might be an important prognostic and/or causal

factor for myocardial dysfunction in the critically ill patients and those after cardiac surgery.

Objective of this thesis

The main objective of this thesis is to improve the identification of the patients most

at risk after cardiac surgery and in the ICU. To achieve this objective, we first wanted

to optimize the use of Tn to assess myocardial damage in patients undergoing cardiac

surgery. Second, we wanted to assess the role of SA, as merely a prognostic or potentially

a causal factor for myocardial damage and dysfunction in the intensive care in patients

undergoing both cardiac and non-cardiac surgery and in medical ICU patients. Finally,

our objective was to replicate some of our observations on SA in a distinct larger cohort.

Outline of this thesis

The first part of this thesis focuses on improving the use of Tn as a marker for excessive

myocardial damage after cardiac surgery. To do this, we first studied how different cardiac

surgery centers in Western Europe currently monitor (excessive) myocardial damage

and what their attitude towards the currently recommended criteria is (chapter 2). We

subsequently conducted a systematic review to study whether the kinetics of Tn in a PMI

(MI type 5) are different from the kinetics of Tn in MI type 1 and MI type 4 (chapter 3).

(8)

12

Chapter 1

Understanding the unique characteristics of the kinetics of Tn in type 5 MI, provides

the opportunity to form hypothesis about new and improved cut off points for the

diagnosis of type 5 MI. In chapter 4, we evaluated the prognostic value of four different

Tn measurements to determine which has the highest prognostic value for mortality after

cardiac surgery. The methods of Tn analysis that were tested were selected according to

the results of our systematic review (chapter 3) and the current available literature.

In the second part of this thesis we focused on the association of SA and various outcomes

after cardiac surgery and in critically ill patients (table 2). As a first step we evaluated

the possibility of an etiological association between low levels of SA and Tn release in

patients after cardiac surgery (chapter 5). Subsequently, we evaluated the association

between SA and myocardial dysfunction in non-cardiac surgical and medical ICU patients

in a prospective cohort (chapter 6). Myocardial dysfunction was defined by the need for

vasoactive agents, the need for fluids and elevated arterial lactate blood levels. In chapter

7, we focused on SA and the association with another symptom of myocardial dysfunction

in the ICU, namely new-onset atrial fibrillation (NOAF). Finally, we validated several of the

strongest associations we found in an independent prospective cohort (chapter 8). This

includes the associations between SA and myocardial damage (chapter 5), and SA and

symptoms of myocardial dysfunction (chapter 6).

The main results of these studies will be provided in a summary and subsequently a

reflection on these results will be given in the general discussion (chapter 9).

Table 2. the role of SA and myocardial damage and different symptoms of myocardial dysfunction.

Chapter Study population Focus Outcomes

5 Cardiac surgical ICU Retrospective cohort Myocardial damage ▪ Tn

6 Non-cardiac surgical and medical ICU

Prospective cohort Myocardial dysfunction ▪ Vasoactive agents ▪ Fluids

▪ Arterial lactate level ▪ Mortality

7 Non-cardiac surgical and medical ICU

Prospective cohort Myocardial dysfunction ▪ NOAF ▪ Mortality

8 Cardiac and non-cardiac surgical and medical ICU

Prospective cohort Myocardial damage and myocardial dysfunction

▪ Tn

▪ Arterial lactate level ▪ Mortality

(9)

13

1 References

1. Katlic MR, ed. Cardiothoracic Surgery in the Elderly.; 2011. ISBN: 978-1-4419-0892-6 2. Ramsay J, Shernan S, Fitch J, et al. Increased

creatine kinase MB level predicts postoperative mortality after cardiac surgery independent of new Q waves. J Thorac Cardiovasc Surg. 2005;129(2):300-306.

3. Chen JC, Kaul P, Levy JH, et al. Myocardial infarction following coronary artery bypass graft surgery increases healthcare resource utilization. Crit Care Med. 2007;35(5):1296-1301.

4. Croal BL, Hillis GS, Gibson PH, et al. Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery. Circulation. 2006;114(14):1468-1475.

5. Ramsay J, Shernan S, Fitch J, et al. Increased creatine kinase MB level predicts postoperative mortality after cardiac surgery independent of new Q waves. J Thorac Cardiovasc Surg. 2005;129(2):300-306.

6. Chen JC, Kaul P, Levy JH, et al. Myocardial infarction following coronary artery bypass graft surgery increases healthcare resource utilization. Crit Care Med. 2007;35(5):1296-1301.

7. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551-2567.

8. Nesher N, Alghamdi AA, Singh SK, et al. Troponin after cardiac surgery: a predictor or a phenomenon? Ann Thorac Surg. 2008;85(4):1348-1354. 9. Stearns JD, Dávila-Román VG, Barzilai B, et

al. Prognostic value of troponin I levels for predicting adverse cardiovascular outcomes in postmenopausal women undergoing cardiac surgery. Anesth Analg. 2009;108(3):719-726. 10. Eigel P, van Ingen G, Wagenpfeil S. Predictive value

of perioperative cardiac troponin I for adverse outcome in coronary artery bypass surgery. Eur J Cardiothorac Surg. 2001;20(3):544-549. 11. Peivandi AA, Dahm M, Opfermann UT, et al.

Comparison of cardiac troponin I versus T and creatine kinase MB after coronary artery bypass grafting in patients with and without perioperative

myocardial infarction. Herz. 2004;29(7):658-664. 12. Jacquet L, Noirhomme P, El Khoury G, et al. Cardiac troponin I as an early marker of myocardial damage after coronary bypass surgery. Eur J Cardiothorac Surg. 1998;13(4):378-384. 13. Paparella D, Cappabianca G, Visicchio G, et al.

Cardiac troponin I release after coronary artery bypass grafting operation: effects on operative and midterm survival. Ann Thorac Surg. 2005;80(5):1758-1764.

14. Suzuki S, Hashizume N, Kanzaki Y, Maruyama T, Kozuka A, Yahikozawa K. Prognostic significance of serum albumin in patients with stable coronary artery disease treated by percutaneous coronary intervention. Lazzeri C, ed. PLoS One. 2019;14(7):e0219044.

15. Wada H, Dohi T, Miyauchi K, et al. Long-term clinical impact of serum albumin in coronary artery disease patients with preserved renal function. Nutr Metab Cardiovasc Dis. 2018;28(3):285-290. 16. Wada H, Dohi T, Miyauchi K, et al. Impact of serum albumin levels on long-term outcomes in patients undergoing percutaneous coronary intervention. Heart Vessels. 2017;32(9):1085-1092.

17. Chien S-C, Chen C-Y, Leu H-B, et al. Association of low serum albumin concentration and adverse cardiovascular events in stable coronary heart disease. Int J Cardiol. 2017;241:1-5.

18. González-Pacheco H, Amezcua-Guerra LM, Sandoval J, et al. Prognostic Implications of Serum Albumin Levels in Patients With Acute Coronary Syndromes. Am J Cardiol. 2017;119(7):951-958. 19. Xia M, Zhang C, Gu J, et al. Impact of serum albumin

levels on long-term all-cause, cardiovascular, and cardiac mortality in patients with first-onset acute myocardial infarction. Clin Chim Acta. 2018;477:89-93.

20. Plakht Y, Gilutz H, Shiyovich A. Decreased admission serum albumin level is an independent predictor of long-term mortality in hospital survivors of acute myocardial infarction. Soroka Acute Myocardial Infarction II (SAMI-II) project. Int J Cardiol. 2016;219:20-24.

(10)

14

Chapter 1

21. Gassa A, Borghardt JH, Maier J, et al. Effect of preoperative low serum albumin on postoperative complications and early mortality in patients undergoing transcatheter aortic valve replacement. J Thorac Dis. 2018;10(12):6763-6770.

22. Findik O, Aydin U, Baris O, et al. Preoperative Low Serum Albumin Levels Increase the Requirement of Renal Replacement Therapy after Cardiac Surgery. Heart Surg Forum. 2016;19(3):123. 23. Bhamidipati CM, LaPar DJ, Mehta GS, et al.

Albumin is a better predictor of outcomes than body mass index following coronary artery bypass grafting. Surgery. 2011;150(4):626-634. 24. Hebeler KR, Baumgarten H, Squiers JJ, et al.

Albumin Is Predictive of 1-Year Mortality After Transcatheter Aortic Valve Replacement. Ann Thorac Surg. 2018;106(5):1302-1307.

25. Wigmore GJ, Anstey JR, St. John A, et al. 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients After Cardiac Surgery (the HAS FLAIR Study). J Cardiothorac Vasc Anesth. March 2019.

26. Lee E-H, Kim W-J, Kim J-Y, et al. Effect of Exogenous Albumin on the Incidence of Postoperative Acute Kidney Injury in Patients Undergoing Off-pump Coronary Artery Bypass Surgery with a Preoperative Albumin Level of Less Than 4.0 g/ dl. Anesthesiology. 2016;124(5):1001-1011. 27. Kingeter AJ, Raghunathan K, Munson SH, et al.

Association between albumin administration and survival in cardiac surgery: a retrospective cohort study. Can J Anesth Can d’anesthésie. 2018;65(11):1218-1227.

28. Pan S-W, Kao H-K, Yu W-K, et al. Synergistic impact of low serum albumin on intensive care unit admission and high blood urea nitrogen during intensive care unit stay on post-intensive care unit mortality in critically ill elderly patients requiring mechanical ventilation. Geriatr Gerontol Int. 2013;13(1):107-115.

29. Yin M, Si L, Qin W, et al. Predictive Value of Serum Albumin Level for the Prognosis of Severe Sepsis Without Exogenous Human Albumin Administration: A Prospective Cohort Study. J Intensive Care Med. 2018;33(12):687-694. 30. Jiang L, Jiang S, Zhang M, Zheng Z, Ma Y. Albumin

versus Other Fluids for Fluid Resuscitation in Patients with Sepsis: A Meta-Analysis. Chalmers JD, ed. PLoS One. 2014;9(12):e114666. 31. Dubois M-J, Orellana-Jimenez C, Melot C, et al.

Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective, randomized, controlled, pilot study. Crit Care Med. 2006;34(10):2536-2540. 32. Bihari S, Wiersema UF, Perry R, et al. Efficacy and

safety of 20% albumin fluid loading in healthy subjects: a comparison of four resuscitation fluids. J Appl Physiol. 2019;126(6):1646-1660. 33. Ernest D, Belzberg AS, Dodek PM. Distribution

of normal saline and 5% albumin infusions in cardiac surgical patients. Crit Care Med. 2001;29(12):2299-2302.

34. Arya VK, Nagdeve NG, Kumar A, Thingnam SK, Dhaliwal RS. Comparison of Hemodynamic Changes After Acute Normovolemic Hemodilution Using Ringer’s Lactate Versus 5% Albumin in Patients on β-Blockers Undergoing Coronary Artery Bypass Surgery. J Cardiothorac Vasc Anesth. 2006;20(6):812-818.

35. Tokunaga C, Bateman RM, Boyd J, Wang Y, Russell JA, Walley KR. Albumin resuscitation improves ventricular contractility and myocardial tissue oxygenation in rat endotoxemia*. Crit Care Med. 2007;35(5):1341-1347.

36. Wu C-C, Lu Y-C, Yu T-H, et al. Serum albumin level and abnormal corrected QT interval in patients with coronary artery disease and chronic kidney disease. Intern Med J. 2018;48(10):1242-1251. 37. Zhang N, Gong M, Tse G, et al. Prolonged corrected

QT interval in predicting atrial fibrillation: A systematic review and meta-analysis. Pacing Clin Electrophysiol. 2018;41(3):321-327.