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
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Publication date:
2019
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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
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Chapter
Summary and
general discussion
133 Summary and general discussion
S
Summary
In this thesis we tried to elucidate the occurrence of myocardial damage and myocardial dysfunction in the critically ill and after cardiac surgery. In the first part of this thesis we focused on improving the use of the biomarker troponin (Tn) to identify myocardial damage after cardiac surgery. An important first step was to specify and quantify the drawback of the current recommended cut-off level for Tn to distinguish “normal” myocardial damage from excessive myocardial damage after coronary artery bypass surgery (CABG). After the general introduction, in chapter 2 we did this by conducting an survey study, which demonstrated that the recommended cut-off level for Tn has not been implemented in the majority of the European post-cardiac surgery intensive care units (ICU).1 Less than one third of the 302 surveyed cardiothoracic surgeons
actually agreed with this cut-off level.1 In this study we also found that there is a risk
of underdiagnoses of peri-operative myocardial infarction (PMI). Although its incidence is known to be about 10%2,3,4,the majority of the participants in our survey indicated a
PMI incidence of only 0-3% in their hospital1. We subsequently conducted a systematic
review (chapter 3) to evaluate whether the kinetics of Tn in a PMI are different from those in a spontaneously occurring myocardial infarction. We demonstrated in this review that the rise and fall of Tn in PMI after cardiac surgery is unique with a later peak level.5 After gaining a better understanding of the problems encountered in clinical
practice with Tn and the actual kinetics of Tn during a PMI, we focused in chapter 4 on improving the use of Tn as a prognostic masker for mortality after cardiac surgery. We compared four different methods by evaluating the pre-operative Tn, the delta Tn (difference from pre- to postoperative values), the peak level of Tn, and the timing of the peak level. We found that the peak level of Tn showed the strongest association to postoperative mortality.
In the second part of the thesis we focused on identifying an additional prognostic and/ or etiologic marker for myocardial dysfunction. In chapter 5 we demonstrated that post-operative serum albumin (SA) plasma level is linearly associated with the cumulative amount of myocardial damage in patients undergoing cardiac surgery.6 In chapter 6,
we also demonstrated that SA level upon ICU admission is associated with the dose requirement of noradrenaline, the amount of fluids administered, and the lactate level after 24 hours in the general ICU population.7 In chapter 7 we demonstrated that SA level
upon ICU admission is significantly associated with the occurrence of new-onset atrial fibrillation during the first 48 hours of ICU admission. These studies indicated that SA is at least a prognostic marker for myocardial damage and dysfunction in the ICU. Finally, in chapter 8, we conducted a validation study, which confirmed SA as a prognostic marker for arterial lactate level after 24 hours and for myocardial damage during the first 24 hours
134 Appendix
of ICU admission. In addition, we found an association between SA and all-cause mortality (one-day and 30-day). Considering the robustness of these associations after extensive correction for effect modifiers/potential confounders, the hypothesis of SA as a potential etiologic factor cannot be rejected.
Popular summary
In the first part of this thesis, the focus was on improving the use of Tn, which is a biomarker for damage to the heart to better identify the patients most at risk for cardiac dysfunction. First, in chapter 2, we found that Tn was not used in the recommended way.1 Subsequently, we found that in a heart attack after cardiac surgery, it takes longer
before Tn reaches its maximum value compared to a spontaneously occurring heart attack (chapter 3).5 The next step was to evaluate how to best use Tn following cardiac surgery
(chapter 4). We found that the maximum level of Tn had the highest association with dying within 30-days of surgery.
In the second part of this thesis we evaluated the prognostic value of the protein albumin. In chapter 5 we showed that low plasma levels of albumin immediately after cardiac surgery increased the total amount of cardiac damage.6 In chapter 6, we also demonstrated that
albumin levels in patients admitted to an intensive care is predictive for the amount of cardiac support medication that is needed during the first 24 hours.7 In chapter 7, we
demonstrated that albumin level is also related to new onset atrial fibrillation (a severe rhythm disturbance). Finally, we validated some of these results in chapter 8 in a separate cohort.
Nederlandse samenvatting | Dutch summary
De focus van het eerste deel van deze thesis was het optimaliseren van het gebruik van de biomarker troponine (Tn) om myocard schade na cardiochirurgie te diagnosticeren. Ten eerste hebben we laten zien dat in het merendeel van de cardio-chirurgische intensive care units (ICU) het huidige afkappunt voor Tn niet altijd en overal gehanteerd wordt (hoofdstuk 2).1 In hoofdstuk 3 hebben we laten zien dat bij een hartinfarct na cardiochirurgie de piek
van Tn later komt dan bij een spontaan ontstaan hartinfarct.5 Bij hoofdstuk 4 lag de focus
op het verbeteren van het gebruik van Tn als voorspeller voor korte termijn sterfte. We vonden dat de piekwaarde van Tn de sterkste associatie had met sterfte binnen 30 dagen na cardiochirurgie.
135 Summary and general discussion
S
In het tweede deel van de thesis hebben we gekeken naar de prognostische waarde van het eiwit albumine. In hoofdstuk 5 hebben we laten zien dat albumine lineair geassocieerd is met de cumulatieve hoeveelheid myocard schade na cardiochirurgie.6 In hoofdstuk
6, hebben we laten zien dat albumine bij opname op de ICU geassocieerd is met de toegediende dosis noradrenaline, de hoeveelheid vocht toegediend en de hoogte van het lactaat na 24 uur.7 In hoofdstuk 7, laten we zien dat albumine ook geassocieerd is met
het krijgen van boezemfibrilleren op de ICU. In hoofdstuk 8 hebben we enkele resultaten gevalideerd in een onafhankelijk cohort.
General discussion
This thesis had two focus points. First, we aimed to identify and quantify the problem of identification of excessive myocardial damage in cardiac surgery using the biomarker troponin. Second, we aimed to evaluate the value of albumin plasma levels as marker for myocardial dysfunction in the intensive care unit. These two focus points will be discussed separately.
Excessive myocardial damage after cardiac surgery
Even in uncomplicated cardiac surgery myocardial damage can be an unavoidable consequence, due to direct manipulation of the heart and/or by the cardiopulmonary bypass (CPB)8;9. However, excessive myocardial damage after cardiac surgery has been
associated with major adverse cardiac events (MACE) and subsequently with an increased morbidity and mortality10,11,4 (figure 1). In case the excessive myocardial damage is
caused by early graft failure, early revascularization12,13 or even conservative treatment
could be beneficial6. Efforts should therefore be made to identify the patients at risk for
myocardial damage. On the contrary, it is not desirable to overutilize scarce resources and to expose patients to unnecessary (invasive) diagnostic procedures. Currently the lack of a scientifically proven and clinically applicable cut-off point to diagnose excessive myocardial damage can result in not identifying patients at risk and in lack of uniformity in diagnostic criteria hamper benchmarking (chapter 2). We found that different cardiac centers across western Europe use different criteria.
Determining where the exact tipping point is from ‘normal’ to ‘excessive’ myocardial damage is extremely difficult. For instance, Tn levels above the normal reference range after cardiac surgery are not necessarily considered as a sign of ongoing myocardial damage2,14. However, there is sufficient evidence linking Tn elevations in a prognostic
136 Appendix
In addition, the continuous development and improvement of high-sensitive Tn assays further complicate the distinction between normal and excessive levels. These new assays are so sensitive that for diagnosing spontaneous myocardial infarction the focus has been shifted on the changes in (delta) rather than absolute values of Tn.22,23 While, previously a change in Tn of 20% was already considered relevant24 to
diagnose spontaneous MI, it is now suggested that with the high sensitive Tn tests a change needs to be >100% to be considered relevant25. We could not find a linear
association between the delta of Tn (from pre-operative to post-operative values) and mortality (chapter 4). This lack of association may be due to the fact that the Tn level of patients with an already very high pre-operative Tn can probably not significantly increase further. In other words, if there is already extensive ongoing myocardial damage (with a corresponding high Tn), the procedure related myocardial damage will not dramatically affect the Tn level anymore. A different hypothesis regarding this phenomenon is that perhaps, with a focus on prognostication, the myocardial damage that occurs after cardiac surgery is more relevant than the myocardial damage that occurs during surgery, meaning that not the procedure itself, rather than its success in terms of revascularization and/or graft failure is most important. In that case, the focus of preventative care should be predominantly aimed at interventions during the early postoperative phase.
Another problem with cardiac surgery is that it consists of a mix of very different types of surgery; e.g. CABG performed with or without CPB, valve surgery or any combination of these. Even though it is known that the use of the CPB per se is related to Tn release8;9 and that different types of cardiac surgery result in different patterns
of postoperative Tn release26, we found that the general threshold of >10 times the
99th percentile was associated with mortality in both CABG surgery without CPB and
valve surgery (chapter 4). So even if the baseline Tn release (i.e. the ‘normal’ amount of myocardial damage) might differ across the types of cardiac surgery, the tipping point towards excessive myocardial damage remained similar. Our results thus indicate that it is potentially possible to have one common threshold for Tn that can be used for all types of cardiac surgery to identify myocardial injury. One single Tn threshold would be feasible for clinical practice. However, considering the low positive predictive value of Tn thresholds, any Tn threshold will need to be combined with additional (noninvasive) diagnostic criteria to identify the patients most at risk to prevent overtreatment of a large group of cardiac surgery patients. The interesting ethical dilemma that will arise with implementation of a Tn threshold (and supporting additional diagnostic criteria), but is beyond the scope of this thesis, is to set the optimal balance between overdiagnoses/overtreatment and the amount of resource utilization considered acceptable to prevent one death after cardiac surgery or another outcome important
137 Summary and general discussion
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to patients. All these factors need to be considered before successful implementation can occur. The focus of the first part of this thesis was to identify and quantify the problem of identification of excessive myocardial damage, and in addition to provide a first step in optimizing the use of Tn for this purpose.
Figure 1. Flowchart how cardiac surgery can result in excessive myocardial damage which is associated with
MACE. The occurrence of MACE increases morbidity and mortality.
MACE: major adverse cardiac events
Albumin as prognostic factor for myocardial damage and dysfunction
Even after extensive correction for effect modifiers we demonstrated that SA is significantly associated with the entire spectrum from myocardial damage to myocardial dysfunction to even death (figure 2). Finally we conducted a validation study in a different cohort of patients, greatly increasing the robustness of our results and improving the usefulness of SA as a prognostic factor.27,28
The interesting question with SA is: is it merely a marker of severity of disease or does SA itself actually exert an impact on morbidity and mortality? This question has been answered for some clinicians, simply because albumin supplementation in general has not been proven to affect mortality29. However, albumin supplementation was associated
with a decrease in morbidity of ICU patients30,31. These somewhat opposing results can
be easily explained by the hypothesis that SA might impact morbidity, but only has a small (and thus hard to detect) effect on mortality. One could indeed argue that only interventions that reduce mortality are relevant. However, in my opinion, positively affecting the morbidity of ICU survivors is also very relevant. In addition, to truly test whether albumin supplementation has a positive effect on the outcome of ICU patients, it would be helpful to first identify the potential causal pathway that SA is involved, again to identify the patients who will most likely benefit from such supplementation. As discussed in chapter 5, there are indications that SA is a natural inhibitor of the angiotensin-converting enzyme (ACE) by binding the vast majority of ACE and thereby rendering it inactive.32,33
Cardiac surgery “Normal” myocardial damage Favourable outcome Excessive myocardial damage MACE Increased morbidity and mortality
138 Appendix
The S-shaped affinity of SA for ACE means that a sudden decrease in SA levels can result in a disproportional large release (and thus activation) of ACE.32,33 It has been shown that
during cardiopulmonary bypass (CPB) in cardiac surgery SA levels generally drop34,35,36,
and that at the same time ACE levels double37. However, whether the drop in SA levels is
correlated to the rise in ACE has not been studied yet.
A sudden increase in ACE renders the heart more vulnerable to myocardial damage by activating the angiotensin pathway resulting in an increase in coronary vascular resistance38,39 Drugs that inhibit ACE (ACE-inhibitors) have been shown to reduce both
the mortality and morbidity in patients at high cardiac risk40,41, and in animals they have
also been shown to be cardio-protective in cardiac surgery.42,43 However, simply applying
ACE-inhibitors to all cardiac surgery patients is likely not the answer to reduce the peri-operative cardiac risk When patients are started on ACE-inhibitors, the drug is titrated to inhibit the proportion of ACE that is normally present unbound in the body. Yet, because almost all ACE is normally bound to albumin, only an extremely small proportion of the total ACE present in the body is inhibited by ACE inhibitors. ACE inhibitors are therefore likely ineffective against the surge of ACE that becomes active upon a sudden drop in SA levels, such as occurring during cardiopulmonary bypass.
Not only cardiac surgical patients are more vulnerable to myocardial dysfunction, the same holds true for the general ICU population. SA is a negative acute phase protein in acute illness44, meaning the levels of SA decrease with the onset of acute illness. This drop in
SA levels in critical illness could therefore also cause a sudden increase in ACE and thus subsequent myocardial damage.
Conclusion
It is important to identify those patients who suffer from excessive myocardial damage after cardiac surgery to be able to prevent subsequent MACE and thus reduce morbidity and mortality in this setting. The currently recommended cut-off level for troponin, as the recommended biomarker for myocardial damage, is not widely adopted in clinical practice. We demonstrated that the postoperative peak Tn level has the strongest association with mortality and should preferably be used instead.
In addition, SA levels in ICU patients are associated with the amount of myocardial damage, noradrenaline requirements, fluid requirements, and arterial lactate levels. Routinely measuring SA levels upon ICU admission in both cardiac and non-cardiac ICU patients would be beneficial to identify those patients most at risk for myocardial damage and dysfunction.
139 Summary and general discussion
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Figure 2. A decrease in albumin is related to an increase in the mentioned outcomes.
Albumin
Mortality
Myocardial damage
Fluid resuscitation needed
Vasoactive support needed
Arterial lactate
Incidence of AF
Episodes of AF
AF: atrial fibrillation
Future perspectives
Ideally any new cut-off level for Tn level must show its clinical relevance as a prognostic marker before announced as standard. In my view, this is essential for its successful implementation into clinical practice. In this case, it would mean that, after validation, both the positive and negative effects of a new Tn cut-off level should be evaluated. This is especially true in the setting after cardiac surgery, where there is a gray zone of inconclusive Tn values not differentiating between normal and excessive myocardial damage.
140 Appendix
Future research should focus on further establishing the association between SA and outcome by evaluating the relationship between the SA and the ACE plasma levels. If sufficient support is found to maintain the hypothesis of this thesis, a randomized controlled trial (RCT) evaluating the effect on ACE levels and MACE when SA is maintained within the physiological range could ultimately establish this causal pathway. If indeed the MACE were related to SA, this would provide new treatment options to prevent major cardiovascular complications after cardiac surgery and in critically ill patients.
141 Summary and general discussion
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