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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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
Albumin,
a marker for
post-operative
myocardial damage
in cardiac surgery
Abstract
Background: Low serum albumin (SA) is a prognostic factor for poor outcome after cardiac surgery. The aim of this study was to estimate the association between pre-operative SA, early post-operative SA and postoperative myocardial injury.
Methods: This single center cohort study included adult patients undergoing cardiac surgery during 4 consecutive years. Postoperative myocardial damage was defined by calculating the area under the curve (AUC) of troponin (Tn) values during the first 72 hours after surgery and its association with SA analyzed using linear regression and with multivariable linear regression to account for patient related and procedural confounders. The association between SA and the secondary outcomes (peri-operative myocardial infarction [PMI], requiring ventilation >24 hours, rhythm disturbances, 30-day mortality) was studied using (multivariable) log binomial regression analysis.
Results: In total 2757 patients were included. Post-operative SA levels (on average 26 minutes after surgery) were inversely associated with postoperative myocardial damage in both univariable analysis (regression coefficient -0.019, 95%CI -0.022/-0.015, p<0.005) and after adjustment for patient related and surgical confounders (regression coefficient -0.014 [95% CI -0.020 / -0.008], p <0.0005).
Conclusions: Post-operative albumin levels were significantly correlated with the amount of postoperative myocardial damage in patients undergoing cardiac surgery independent of typical confounders.
5
Introduction
An association between serum albumin (SA) and outcome in patients with and without cardiovascular diseases has been subject of investigation for decades. An average drop in the SA level of 30% following major surgery has been observed1, mainly because of
redistribution from the blood stream due to capillary leakage and increased losses. During cardiopulmonary bypass (CPB) in cardiac surgery the SA typically drops by 50-70%2,3,4,
mainly due to hemodilution as a consequence of the CPB priming volume.
We hypothesized that a low level of SA during cardiac surgery makes the heart more vulnerable to myocardial damage. Very recent findings indicate a potential pathway on how SA could have a cardio-protective effect by functioning as a natural inhibitor of the angiotensin-converting enzyme (ACE).5 ACE inhibitors are usually prescribed to treat
hypertension, are also known to have a cardio-protective effect and reduce mortality and morbidity in patients with cardiovascular disease.6,7 ACE normally enables the
transformation of angiotensin I (ATI) to angiotensin II (ATII). A sudden increase in ATII is shown in animal studies to immediately increase coronary resistance8 and decrease
coronary blood flow.9 ACE activity has also been associated with coronary vascular
resistance during CPB in humans10 In recent animal studies the cardio-protective effect
of ACE inhibition in cardiac surgery has been shown.11,12 Within the physiological range of
SA concentrations (35-52 mg/ml), almost all ACE is bound to albumin (and thus inactive).
5,13 Below the physiological range of SA concentrations there is a rapid increase in the
fraction of unbound (and thus active) ACE.5,13 The drop SA during cardiac surgery means
that a low (but still within the physiological range) pre-operative SA will drop below the physiological range intra-operatively. This would theoretically result in a tripling of the ACE level. 12 Research in the past demonstrated that ACE levels indeed doubled during
CPB.14 However, the underlying mechanism of this increase has not been studied yet. We
therefore speculate that this increase is due to a drop in SA level.
The aim of this study was to estimate the association between SA levels measured early postoperatively with postoperative myocardial damage in patients undergoing cardiac surgery.
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Chapter 5
Methods
This cohort study included all patients >18 years undergoing cardiothoracic surgery (either CABG and/or valve surgery), between January 2010 and December 2015 in the University Medical Center Groningen. Excluded were patient for whom no SA was available and patients with a critical pre-operative condition. A critical pre-operative condition was defined as either ventricular tachycardia, ventricular fibrillation, cardiopulmonary resuscitation, ventilator support, inotropic support, intra-aortic balloon pump, anuria, or oliguria before surgery. Priming of the cardiopulmonary circuit (when applicable) consisted of 1000 ml of crystalloid solution (Ringer’s lactate) and 500ml of colloid solution (hydroxyethyl starch [HES] 6%). In patients with contraindications to HES (e.g. severe kidney dysfunction) this colloid was replaced by 400 ml human albumin (HA) 20%. Data was collected from the Board Heart interventions Netherlands (BHN) registry, the hospital information system and from the electronic patient record system. Considering the nature of this study the local medical ethical review board waived the need for further approval (METc 2015/069). All SA levels measured from 72 hours before surgery up to 12 hours after the surgery were collected. The primary endpoint of this study was postoperative myocardial damage. Troponin (Tn) is the recommended cardiac biomarker to detect myocardial injury, because it is both highly sensitive and specific for myocardial damage.15 Postoperative myocardial
damage was defined by calculating the area under the curve (AUC) of troponin T (Tn) during the first 72 hours after surgery using the triangular method. For the sensitivity analysis, the AUC of Tn during the first 24 hours after surgery was calculated. The lab measurement of Tn changed in 2011 from µg/l to ng/l with the transition to high-sensitive Tn. For analysis purposes, all measurement in µg/l were converted to ng/l.
Secondary outcomes included the occurrence of a peri-operative myocardial infarction (PMI), rhythm disturbances requiring treatment, requiring ventilation for more than 24 hours after surgery, and 30-day mortality.
The occurrence of a PMI was defined in the Board Heart interventions Netherlands (BHN) registry as two or more of the following four criteria: 1. typical chest pain, unresponsive to treatment 2. new echocardiography abnormalities 3. new typical electrocardiogram abnormalities 4. cardiac biomarker elevation.
5
Rhythm disturbances requiring treatment was defined as atrial fibrillation (AF), atrial flutter (AFl), asystole, and all other cardiac arrhythmias requiring treatment. Mortality was assessed as all-cause mortality within 30 days.
Statistical analysis
The baseline characteristics were subdivided into subgroups of patients based on their postoperative SA level. For binomial and categorical variables, the number and proportions were calculated, for continuous variables the mean and the standard deviation (SD) or the median with interquartile ranges (IQR) were calculated where appropriate. The association between pre- and postoperative SA level was evaluated using linear regression.
The AUC of Tn during the first 72 hours was first log transformed because the histogram indicated non-normal distribution of the data. The association between SA and the log of the AUC of Tn was assessed using linear regression. Subsequently the potential association between SA and the outcome was assessed with multivariable linear regression including patient related confounders and procedure related confounders (table 1).
We conducted a sensitivity analysis using the AUC of Tn during the first 24 hours’ post-surgery as the outcome, since Tn measurement(s) within the first 24 hours after post-surgery are done in all patients. In this sensitivity analysis, we repeated the univariable linear regression with the AUC of Tn after 24 hours as the outcome.
A subgroup analysis was conducted based on the pre-operative body mass index (BMI), the last-measured pre-operative creatinine level (maximum 72 hours before surgery), left ventricle ejection fraction, logistic EuroSCORE, and pre-operative Tn levels. The kidney function was determined using creatinine plasma levels.
The association between SA and the secondary endpoints (i.e. PMI, rhythm disturbances requiring treatment, requiring ventilation for more than 24 hours after surgery, and 30-day mortality) was evaluated using univariable log binomial regression. Multivariable log binomial (enter method) analysis was used to correct for the potential confounders mentioned in table 1.
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Chapter 5
Table 1. Potential confounders included in analysis.
Patient related variables ▪ ▪ Age ▪ ▪ Gender ▪ ▪ BMI ▪
▪ Last measured creatinine level before surgery (maximum 72 hours before surgery) ▪
▪ Diabetes mellitus ▪
▪ The last measured pre-operative level of Tn (maximum 72 hours before surgery) ▪
▪ LV function (categorical): unknown/ EF ≥ 50% / EF 31-50% / EF <30% ▪
▪ Recent MI (<90 days before surgery) ▪
▪ Logistic EuroSCORE Surgical variables
▪
▪ Surgery indication (categorical): elective/ urgent/ emergency ▪
▪ Type of procedure (categorical): CABG/ valve surgery / combination of CABG and valve surgery ▪
▪ AoX time ▪
▪ Anesthesia time
BMI: Body mass index, LV: left ventricle, EF: ejection fraction, MI: myocardial infarction, CABG: coronary artery bypass surgery, AoX: aortic cross clamp time
Results
A total of 2757 cardiac surgery patients were included in the study. The most common cardiac surgery was an isolated CABG (n=1785, 65%). Table 2 describes the baseline characteristics for four subpopulations; (a) patients with a normal SA after surgery (≥35g/L), (b) mild hypoalbuminemia (26-35 g/L), (c) severe hypoalbuminemia (18-26 g/L), (d) extreme hypoalbuminemia (≤18 g/L).
For 346 patients (13%) both a pre- and post-operative SA was available, for 5 (0.2%) only a pre-operative SA was available and for the 2406 remaining patients (87%) only a post-operative SA was available. The mean pre-post-operative SA (measured on average 10 hours before surgery) was with 29 ± 13 g/L higher than the mean post-operative SA of 26 ± 6 g/L (measured on average 26 minutes after surgery). Analysis showed that there was a linear association between the pre- and post-operative SA level (regression coefficient 0.061, 95% CI 0.011-0.112, p=0.018). However, when further evaluating this association it was noteworthy that for half of the patients (50%) with a severe or extreme hypoalbuminemia pre-operatively the post-operative SA was in a higher category, and only in 3.4% of the cases the post-operative SA was in a lower category (table 3).
5
Table 2. Baseline characteristics. Subgroups based on post-operative SA. Extreme hypo-albuminemia (≤18 g/L) (N=142) Severe hypo-albuminemia (18-26 g/L) (N=1105) Mild hypo-albuminemia (26-35 g/L) (N=1352) Normal SA (≥35g/L) (N=152) Women 57 (40.0%) 531 (48.1%) 648 (47.9%) 54 (35.5%) Age MD 69 (QR 59-78) MD 69 (QR 61-76) MD 66 (QR 57-73) MD 65 (QR 56-75) BMI (kg/m2) M 27.2 (SD 4.2) M 26.8 (SD 4.2) M 27.8 (SD 4.4) M 27.8 (SD 4.5) Diabetes 18 (12.7%) 192 (17.4%) 184 (13.6%) 27 (17.8%) Recent MI 51 (35.9%) 296 (26.8%) 304 (22.5%) 35 (23.0%) Pre-operative creatinine (umol/l) M 84 (SD 29) M 84 (SD 45) M 84 (SD 41) M 105 (SD 110) Logistic EuroSCORE M 6.69 (SD 8.24) M 6.16 (SD 7.20) M 4.76 (SD 5.37) M 5.56 (SD 6.31) Surgery ▪ Isolated CABG 104 (73.2%) 696 (63.0%) 884 (65.4%) 96 (63.2%) ▪ Isolated VS 17 (12.0%) 235 (21.3%) 371 (27.4%) 45 (29.6%)
▪ Combined CABG and VS 21 (14.8%) 174 (15.7%) 97 (7.2%) 11 (7.2%)
Anesthesia time in minutes
M 204 (SD 160) M 209 (SD 154) M 170 (SD 124) M 161 (SD 130)
Maximum Tn M 1183 (SD 2266) M 927 (SD 1968) M 781 (SD 2121) M 802 (SD 2787)
ICU LOS in days MD 1 (QR 1-4) MD 2 (QR 1-3) MD 1 (QR 1-2) MD 1 (QR 1-2)
M: mean, SD: standard deviation, MD: median, QR: interquartile ranges
SA: serum albumin, BMI: Body mass index, CABG: coronary artery bypass surgery, VS: valve surgery, LV: left ventricle, EF: ejection fraction, Tn: troponin ICU: intensive care unit, LOS: length of stay
Postoperative myocardial damage
On average, there were 5 ± 2 Tn measurements during the first 72 hours after surgery. The mean AUC of Tn during the first 72 hours after surgery for the four different subpopulations is presented in figure 1. The scatterplot of the post-operative SA level and the AUC of Tn indicated a linear association (figure 2).
Post-operative SA was significantly inversely related to the postoperative myocardial damage (regression coefficient -0.019, 95%CI -0.022/-0.015, p<0.005). This inverse association remained strong after adjustment for patient related and procedure related
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Table 3. Comparing the categories of SA pre-operatively and post-operatively. Pre-operative SA Post-operative SA N (%) ≤ 15 g/L Lower category NA Same category 24 (44.4%) Higher category 30 (55.6%) 15-25 g/L Lower category 5 (5.3%) Same category 45 (47.9%) Higher category 44 (46.8%) 25-35 g/L Lower category 35 (40.7%) Same category 46 (53.5%) Higher category 5 (5.8%) >35 g/L Lower category 93 (91.2%) Same category 9 (8.8%) Higher category NA
NA: not applicable
Figure 1. The AUC of Tn the first 72 hours after surgery. Error bars of the mean with the 95% confidence interval
of the AUC of Tn after the first 72 hours of surgery for the four different groups of postoperative SA levels; (a) extreme hypoalbuminemia (≤18 g/L), (b) severe hypoalbuminemia (18-26 g/L), (c) mild hypoalbuminemia (26-35 g/L), (d) patients with a normal SA (≥ 35g/L),
In univariable linear regression the pre-operative SA was significantly related to postoperative myocardial damage during the first 72 hours after surgery (regression coefficient 0.005 [95% CI [0.001 / 0.010], p=0.020). This association was no longer significant after adjustment for potential confounders.
5
Figure 2. Post-operative SA level and the AUC of Tn. Scatter plot of the post-operative SA level and the AUC of
Tn during the first 72 hours after surgery for the 2757 included patients. One data point per patient. The linear association is estimated by the equation y=7,85-0,02*x.
The subsequently conducted sensitivity analysis for the association between post-operative SA and myocardial damage during the first 24 hours after surgery showed consistency of the results. The linear regression was significant for myocardial damage during the first 24 hours (regression coefficient -0.016 [95% CI [-0.020 / -0.011], p<0.0005). The association between pre-operative SA and myocardial damage during the first 24 hours could not be reproduced.
Table 4. Linear regression albumin and postoperative myocardial damage during the first 72 hours. Regression coefficient (95% CI) p Univariable -0.019 (-0.022 / -0.015) <0.0005
Patient confounders* -0.015 (-0.021 / -0.009) <0.0005
Patient + surgical confounders** -0.014 (-0.020 / -0.008) <0.0005
CI: confidence interval. * Age, Gender, BMI, last measured creatinine before surgery, diabetes mellitus, the last measured pre-operative level of Tn, LV function, Recent MI, EuroSCORE
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Chapter 5
Subgroup analyses
To determine whether there is a true association between SA and post-operative myocardial damage, or whether SA is merely a marker of poor patient`s condition, we conducted several subgroup analyses (table 5). We addressed the nutritional status using the BMI. For the subgroups of patients with a normal weight and the overweight patients the association remained significant (p<0.0005). For patients with a normal (-0.02, 95%CI -0.02 / -0.02, p<0.0005) or slightly elevated creatinine (-0.01, 95%CI -0.02 / -0.01, p=0.002) the association was significant. For the 133 patients with a LV ejection fraction <30% the association was not significant, but for those with an ejection fraction between 30-50% (-0.02, 95%CI -0.02 / -0.01, p<0.0005) and >50% (-0.02, 95%CI -0.02 / -0.02, p<0.0005) it was. For all subgroups of the EuroSCORE the association remained significant (p=<0.0005 to 0.010), as well for an elevated or normal pre-operative Tn level (p=<0.0005 to 0.023), and for all types of surgery (p=<0.0005 to 0.001).
Secondary outcomes
In total 575 patients experienced at least one MACE (21%); 26 experienced a PMI, 535 had rhythm disturbances and 31 died within 28 days of surgery. Post-operative SA was significantly associated to PMI (OR 0.93, 95% CI 0.88-1.00, p=0.040), and for requiring mechanical ventilation more than 24 hours (0.96, 95%CI 0.93-0.98, p=0.001), but not for 30-day mortality (OR 0.94, 95% CI 0.87-1.02, p=0.114) after correction for both patient related and surgical confounders (table 6).
5
Table 5. Linear regression analysis between post-operative SA and the AUC of Tn after 72 hours for different
subgroups.
N Regression coefficient (95% CI) p BMI Underweight (<20 kg/m2) 53 -0.00 (-0.02 / 0.02) 0.790 Normal weight (20-25 kg/m2) 728 -0.02 (-0.02 / - 0.01) <0.0005* Overweight (>25 kg/m2) 1638 -0.02 (-0.02 / - 0.02) <0.0005* Missing 338 -0.02 (-0.03 / - 0.01) 0.003* Creatinine Normal (<100 umol/l) 2283 -0.02 (-0.02 / -0.02) <0.0005*
Mildly elevated (100-150 umol/l) 378 -0.01 (-0.02 / -0.01) 0.002*
Elevated (≥150 umol/l) 85 -0.01 (-0.03 / 0.01) 0.339 Missing 11 -0.09 (-0.18 / 0.01) 0.077 Euroscore (n) Lowest 25% (≤ 2.03) 700 -0.02 (-0.03 / -0.02) <0.0005* Middle 25% (2.03-6.83) 1303 -0.02 (-0.02 / -0.01) <0.0005* Highest 25% (≥6.83) 611 -0.02 (-0.02 / -0.01) <0.0005* Missing 143 -0.02 (-0.04 / -0.01) 0.010* LV ejection fraction ≤30% 133 -0.01 (-0.03 / 0.01) 0.200 31-50% 882 -0.02 (-0.02 / -0.01) <0.0005* >50% 1737 -0.02 (-0.02 / -0.02) <0.0005* Missing 5 -0.01 (-0.12 / 0.09) 0.717 Pre-operative Tn elevated (>50ng/L) Yes 221 -0.01 (-0.02 / -0.00) 0.023* No 212 -0.02 (-0.03 / -0.01) 0.002* Missing 961 -0.01 (-0.01 / -0.00) <0.0005* Type of surgery CABG 1785 -0.02 (-0.02 / - 0.02) <0.0005* Valve 669 -0.01 (-0.02 / -0.00) 0.001* Combined 303 -0.02 (-0.03 / - 0.01) <0.0005*
LV: left ventricle, CABG: coronary artery bypass grafting, Tn: troponin, CI: confidence interval, *indicates significant result
Table 6. Univariable binary logistic regression results for adverse events after cardiac surgery. Post-operative SA
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Chapter 5
Discussion
The main finding of our study is that post-operative SA and the AUC of Tn as a marker of myocardial damage were significantly correlated during the first 72 hours. This correlation was maintained after adjustment for both patient-related and surgical confounders: the higher the post-operative SA the lower was cumulative myocardial damage. In addition, post-operative SA was significantly associated to PMI, requiring mechanical ventilation more than 24 hours, and to 30-day mortality.
The results of our study are in line with other research. In a long-term population cohort study in participants without cardiovascular disease (CVD) hypoalbuminemia has been associated with an increased incidence of myocardial infarction (MI) 16, while in a different
cohort every gram per liter decrease of SA between two samples increased the risk of cardiovascular disease17. In patients with acute coronary syndrome (ACS) admission SA
levels <35 g/l were associated with the occurrence of in-hospital adverse events (e.g. death, heart failure, myocardial re-infarction). 18 Patients undergoing percutaneous coronary
intervention (PCI) for MI with a serum albumin <35 g/l compared to patient with a normal serum albumin had significantly increased short term (9.4% vs. 2%) and long-term mortality (23% vs. 8%), as well as more recurrent-infarctions (12% vs. 8%).19 In patients undergoing
cardiac surgery, the association of a low pre-operative albumin and a poor outcome has also been described: even mild preoperative hypoalbuminemia was associated with an increase in mortality20, prolonged postoperative ventilator dependency20,21, more acute
kidney injury22,23, and a longer intensive care and hospital length of stay20.
It is known that SA contributes to maintaining the intravascular volume, partially by contributing to the integrity of the vascular wall7;8. A lower SA could therefore result in more
tissue edema and reduce the circulating volume by extravasation. We hypothesized that a low level of SA during cardiac surgery makes the heart more vulnerable to myocardial damage by increasing the level of free ACE. This possible cardio-protective effect of SA has to be studied further in humans. Another possible hypothesis is the positive effect of SA on the contractility of the heart, which has been demonstrated in an animal study24. This study
supports the association between SA levels and cardiac outcome after cardiac surgery, especially because the subgroup analysis showed stability across the different subgroups. Although we have hypothesized that low levels of SA during cardiac surgery would make the heart more vulnerable to myocardial damage, this was not an etiological study and no intraoperative SA measurements were available. We believe that due to the changes of SA during surgery, early post-operative SA levels better reflect the SA levels during surgery than pre-operative SA levels. The results of our study support our hypothesis,
5
since we found that patients with a low pre-operative SA had a higher post-operative SA. This increase in SA is likely due to albumin infusions, because our pre-operative SA measurement is too short before surgery (10 hours on average) to improve SA in any other way. If the patients with a low pre-operative SA received transfusion and therefore had a higher per-operative SA, they are potentially more protected from myocardial damage. A limitation of this study is that we used the AUC of Tn to quantify myocardial damage. This method has not been validated to quantify myocardial damage. However, it is a common mathematical method to extrapolate a continuous variable over time. Tn is part of the myocardial contractile apparatus and is both highly sensitive and specific for myocardial damage. 15 Elevated Tn has been shown to be associated with mortality24, and future
cardiac events25.
We believe that using the AUC gives a more accurate representation of the actual myocardial damage than for instance one single peak level of Tn, because the AUC also allows to identify patients with prolonged ongoing less severe myocardial damage. In addition, although we included all potentially relevant patient related- and operative factors to address the presence of common confounders, we cannot exclude the possibility of residual confounding in unmeasured and unknown factors.
This study is a first step in better understanding the potential cardio-protective effects of SA by indicating an association between post-operative SA and myocardial damage independent of confounders. However, this causal pathway needs to be further explored in future studies, ideally not only by measuring the SA levels during surgery, but by combining it with ACE measurements during surgery. After acquiring a better understanding of this potential natural pathway, intervention studies using albumin supplementation can be optimized.
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