Abstract
Background: Elevated circulating levels of albumin (ALB) are often associated with improved prognosis in patients with heart failure (HF). However, investigations of its association with hospital death and long-term death in HF patients in the intensive care unit (ICU) are limited. Aim: We examined whether increased blood ALB levels (first value at admission and maximum and minimum values in the ICU) were related to a greater risk of hospital death and long-term death in ICU patients with HF. Methods: For the first time, we analyzed 4084 ICU patients with HF admitted to the ICU in The Medical Information Mart for Intensive Care III (MIMIC-III) database. Results: Among 4084 HF patients, 774 (18.95%), 1056 (25.86%) and 1720 (42.12%) died in the hospital, within 30 days and 1 year, respectively. We conducted a logistic regression analysis and found significant inverse associations between blood ALB concentration and risk of hospital death, 30-day death and 1-year death when the covariates including age, sex, myocardial infarction (MI), hypertension, diabetes, valvular diseases, atrial fibrillation, stroke and chronic kidney disease (CKD) were adjusted. We additionally used a smooth curve for univariate analysis to establish an association between blood ALB concentration and death risk. Surprisingly, we observed U-shaped correlations between blood ALB concentration and hospital mortality, 30-day mortality and 1-year mortality. We found that the “inflection point” for the blood ALB concentration at the lowest risk of death was 3.5 g/dL. We further observed that a higher blood ALB concentration (albumin-max) did not contribute to a reduced risk of death (hospital death, 30-day death and 1-year death) in HF patients with an albumin concentration >3.5 g/dL. Conclusions: A lower blood ALB concentration contributed to a greater risk of hospital death and long-term death in HF patients admitted to the ICU, further suggesting that nutritional support in the ICU is highly important for improving the short-term and long-term mortality of HF patients. However, in HF patients without hypoproteinaemia (>3.5 g/dL), the impact of increased serum ALB on patient prognosis still needs to be demonstrated.
Keywords: Albumin, cardiovascular, hospital death, long-term death, heart failure
Introduction
Acute heart failure (HF) or worsening chronic HF is a heavy medical burden associated with short-term and long-term risk of death [1]. In the United States (US), approximately 10-51% of HF patients are hospitalized in the intensive care unit (ICU), with a high death rate of 10.6% [2,3]. The treatment and management of these HF patients is particularly important due to the high mortality risk in hospitals. Accurate risk stratification enables clinicians to perform appropriate medical decision-making [4].
Albumin (ALB) is a protective factor for HF patients. As a 69 kDa protein, blood ALB can maintain stable plasma colloid osmotic pressure and exhibit anti-inflammatory, antioxidant, anticoagulant, antiplatelet aggregation and colloidal permeation effects, contributing to key physiological functions [5,6]. Hypoalbuminemia (HAE, albumin level <3.5 g/dL), however, is highly prevalent in HF patients [7] and is caused by malnutrition, chronic inflammation, hemodilution, infection and other factors [8,9]. Existing evidence has shown that HAE is a predictor of all-cause mortality risk among HF patients. For example, Liu et al. reported that HAE is common in HF and preserved ejection fraction (HFPEF) patients and is associated with an increased risk of death [7]. Gotsman I et al. performed a cohort study involving a total of 5779 HF patients with a mean follow-up of 576 days, demonstrating that decreasing serum ALB was significantly associated with mortality after adjustment for significant confounding factors [10]. Uthamalingam S et al. conducted a cohort study including 438 consecutive patients with acute decompensation HF (ADHF) admitted to a large community hospital and reported that HAE is independently associated with increased one-year mortality in patients admitted with ADHF [11]. However, a series of prediction methods for in-hospital or long-term mortality are not currently available because these predictable models do not have good accuracy [12,13]. Among patients without HAE (albumin level >3.5 g/dL), there is relatively little discussion on the impact of serum ALB on hospital mortality and long-term mortality in ordinary ward or ICU-treated HF patients.
Considering the current research background, we obtained HF data from the Medical Information Mart for Intensive Care III (MIMIC-III) database to develop a predictive model for the associations between serum ALB levels (first value at admission and maximum and minimum values in the ICU) and hospital death and long-term death among HF patients in the ICU. We further confirmed that increased blood ALB levels independently contributed to reduced risks of hospital death and long-term death among patients without HAE.
Methods
Study population
We obtained data from an open ICU clinical database named MIMIC-III [14]. The MIMIC-III is a large, freely available database comprising deidentified health-related data associated with more than 40,000 patients who stayed in critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012 and is available on PhysioNet (physionet.org/content/mimiciii/1.4/) [15,16]. Before free access to certain resources on PhysioNet, we needed to complete training in human research and data privacy and then pass the test of human protection research participants. The project was approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA), and informed consent from each patient was exempted because all patient privacy information was deidentified before the data were obtained. All analyses in our study were consistent with relevant guidelines and regulations [17]. The author “Xin Wan” (ID 12340542) is responsible for collecting and analyzing data.
The MIMIC-III database contains information such as demographic information, vital sign measurements taken at the bedside, laboratory test results, medication use and mortality (including posthospital discharge). For the purpose of this study, we retrospectively analyzed all patients with HF in the database. According to the International Classification of Diseases, Ninth Revision (ICD-9) codes, we first extracted the data from all patients with HF (n=8648) admitted to the ICU for the first time. Among these individuals, only the first ICU admission data were included in the analysis when they underwent several ICU admissions. Then, we obtained clinical characteristic data, including demographic characteristics, comorbidities, laboratory indicators, medications and mortality data. Additionally, patients aged <18 years or with incomplete laboratory data were excluded. The present study aimed to investigate whether increased blood ALB levels independently contributed to reduced risks of hospital death and long-term death among patients with or without HAE. On the basis of the initial admission data, multiple biochemical test results were recorded; thus, we included the first (1st), maximum (max) and minimum (min) blood albumin levels for analysis. Subsequently, 4084 HF patients were enrolled in our analysis.
Exposure and death information
The main independent variables were blood ALB-1st, the serum ALB concentration (max) and the serum ALB concentration (min); these variables were measured in 4084 HF patients beginning at the first ICU admission. Hospital death, 30-day death and 1-year death were selected as the primary endpoints. Hospital death was defined only by the first admission to the ICU. Out-of-hospital death dates were obtained using the Social Security Administration death master file.
Covariates
The data were obtained from the database via the PostgreSQL Structured query language. Patient demographic data [age, sex (female and male)], blood-related biochemical data (creatinine, urea nitrogen and albumin), comorbidity information [myocardial infarction (MI), hypertension, diabetes, valvular disease, atrial fibrillation, stroke, chronic kidney disease (CKD) and malignant tumor] and medication information [albumin, beta-blockers (βRB), statins] were collected at the first admission to the ICU.
Statistical analysis
Continuous clinical variables are expressed as the mean (standard deviation) or median (quartile distance). The description of the frequency distribution is presented as N (%). The HF patients were divided into two subgroups according to the median blood ALB concentration (albumin <3 g/dL and albumin ≥ median 3 g/dL). The Kruskar-Wallis (K-W) test was used to determine the differences in continuous variables between the two subgroups, and the chi-square test was used to examine the differences in frequency distribution. Logistic regression analysis was used to evaluate the associations between blood ALB concentrations (albumin-1st, albumin-max and albumin-min) and the risk of hospital death, 30-day death and 1-year death, respectively, with a 95% confidence interval (CI). Logistic regression Model 1 to Model 2 were structured as follows: Model 1 was adjusted for age and sex; Model 2 was adjusted for age, sex, MI, hypertension, diabetes, valvular disease, atrial fibrillation, stroke and CKD. Malignant tumors have been confirmed to contribute to all-cause death risk [18]. Hence, we used sensitivity analysis to further evaluate the associations between blood ALB concentrations and death risk (hospital death, 30-day death and 1-year death) by using “malignant tumor” as a covariate in the above models. A smooth curve analysis was performed for univariate analysis to examine the nonlinear association between blood ALB concentrations (albumin-1st, albumin-max and albumin-min) and death risk (hospital death, 30-day death and 1-year death). Finally, according to the exact inflection point of the nonlinear relationship explored by the smoothed curve, further hierarchical analysis was performed to confirm the independence of the association. In this study, EmpowerStats 3.0 was used for all the statistical analyses, and a P value <0.05 was considered to indicate statistical significance.
Results
Admission characteristics in patients with HF
We selected a total of 4084 patients with HF admitted to the ICU after strictly screening the first ICU admission in the database. Among these patients (shown in Table 1), the medians for the albumin-1st, albumin-max and albumin-min levels were 3.00 g/dL, 3.10 dL and 2.80 g/dL, respectively, and the numbers of hospital deaths, 30-day deaths and 1-year deaths were 774 (18.95%), 1056 (25.86%) and 1720 (42.12%), respectively. Based on the median blood ALB-1 level, these HF patients were classified into two subgroups (albumin <3 g/dL and albumin ≥3 g/dL). The HF patients with an albumin concentration <3 g/dL had a significantly greater rate of hospital death, 30-day death and 1-year death (all P<0.05) than did the HF patients with an albumin concentration ≥3 g/dL. However, the HF patients with an albumin concentration <3 g/dL tended to be female and had a significantly lower incidence of concomitant diseases, including MI, hypertension, valvular disease, CKD and malignant tumors, and a greater percentage of patients who used medications (albumin).
Table 1.
Admission characteristics in ICU patients with HF
| Variables | Albumin-1st < median (3.00 g/dL) (N=1843) | Albumin-1st ≥ median (3.00 g/dL) (N=2241) | P value |
|---|---|---|---|
| Age (year) | 73.46 (62.82-81.00) | 72.98 (61.92-80.65) | 0.255 |
| Gender (male), n (%) | 982 (53.28%) | 1284 (57.30%) | 0.010 |
| Hospital mortality, n (%) | 442 (23.98%) | 332 (14.81%) | <0.001 |
| 30-day mortality, n (%) | 600 (32.56%) | 456 (20.35%) | <0.001 |
| 1-year mortality, n (%) | 943 (51.17%) | 777 (34.67%) | <0.001 |
| Comorbidities | |||
| Hypertension, n (%) | 592 (32.12%) | 900 (40.16%) | <0.001 |
| Diabetes, n (%) | 63 (3.42%) | 84 (3.75%) | 0.573 |
| MI, n (%) | 119 (6.46%) | 214 (9.55%) | <0.001 |
| Stroke, n (%) | 64 (3.47%) | 96 (4.28%) | 0.184 |
| Atrial fibrillation, n (%) | 796 (43.19%) | 1001 (44.67%) | 0.344 |
| Valvular diseaser, n (%) | 358 (19.42%) | 572 (25.52%) | <0.001 |
| Malignant tumor, n (%) | 165 (8.95%) | 116 (5.18%) | <0.001 |
| CKD, n (%) | 221 (11.99%) | 389 (17.36%) | <0.001 |
| Blood parameters | |||
| Albumin-1st (g/dL) | 2.60 (2.30-2.70) | 3.40 (3.20-3.70) | <0.001 |
| Albumin-max (g/dL) | 2.70 (2.40-2.90) | 3.40 (3.20-3.70) | <0.001 |
| Albumin-min (g/dL) | 2.40 (2.10-2.70) | 3.20 (3.00-3.50) | <0.001 |
| Creatinine (mg/dL) | 1.20 (0.80-2.00) | 1.20 (0.90-1.90) | 0.312 |
| Urea nitrogen (mg/dL) | 29.00 (18.00-45.00) | 27.00 (18.00-44.00) | 0.109 |
| Medication | |||
| Albumin, n (%) | 289 (15.68%) | 210 (9.37%) | <0.001 |
| βRB, n (%) | 1076 (58.38%) | 1379 (61.54%) | 0.041 |
| Statins, n (%) | 362 (19.64%) | 565 (25.21%) | <0.001 |
-1st: the first laboratory value in ICU; -max: the maximum laboratory value in ICU; -min: the minimum laboratory value in ICU. ICU: intensive care unit; HF: heart failure; MI: myocardial infarction; CKD: chronic kidney disease; βRB: β receptor blocker.
Increased blood ALB concentrations contributed to reduced hospital death, 30-day death and 1-year death in HF patients
As previously reported, HF patients with lower serum ALB concentrations tend to have a significantly greater rate of death. Thus, we conducted a logistic regression analysis. After adjusting for the covariates of age and sex in Model 1 (Table 2), we observed that a high blood ALB concentration (for albumin-1st, OR=0.48, 95% CI=0.42, 0.55, P<0.001; for albumin-max, OR=0.52, 95% CI=0.45, 0.60, P<0.001; for albumin-min, OR=0.34, 95% CI=0.29, 0.39, P<0.001) was significantly associated with a decreased risk of hospital death. When the covariates MI, hypertension, diabetes, valvular disease, atrial fibrillation, stroke and CKD were included in Model 2, the associations of blood albumin (for albumin-1st, OR=0.50, 95% CI=0.44, 0.58, P<0.001; for albumin-max, OR=0.54, 95% CI=0.47, 0.63, P<0.001; for albumin-min, OR=0.35, 95% CI=0.30, 0.40, P<0.001) with the risk of hospital death changed little. Similarly, a high blood ALB concentration (for albumin-1st, OR=0.50, 95% CI=0.44, 0.58, P<0.001; for albumin-max, OR=0.54, 95% CI=0.47, 0.63, P<0.001; for albumin-min, OR=0.35, 95% CI=0.30, 0.40, P<0.001) was associated with a reduced risk of death at 30 days and 1 year (Table 2). Cancers have been recognized as a major factor in the death of elderly patients [18]. Therefore, we performed sensitivity analysis to further evaluate the association between blood ALB concentrations and death risk (hospital death, 30-day death and 1-year death) by using “malignant tumor” as a covariate in the above models. We still found that increased blood ALB levels were independently associated with hospital death, 30-day death and 1-year death, as shown in Table 3. Importantly, substantial evidence has confirmed that albumin therapy can reduce the incidence of complications and risk of death in patients with HEA in the ICU. However, our results showed that there were no significant differences in hospital death, 30-day death or 1-year death between patients who did and did not receive albumin therapy (all P values for interactions >0.05) (Table 4).
Table 2.
Logistic regression analysis of relationship between blood albumin level and mortality risk in ICU patients with HF
| Variables | Hospital death | 30-day death | 1-year death | |||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Model 1 | ||||||
| Albumin-1st | 0.48 (0.42, 0.55) | <0.001 | 0.49 (0.43, 0.55) | <0.001 | 0.47 (0.42, 0.52) | <0.001 |
| Albumin-max | 0.52 (0.45, 0.60) | <0.001 | 0.54 (0.47, 0.62) | <0.001 | 0.51 (0.45, 0.57) | <0.001 |
| Albumin-min | 0.34 (0.29, 0.39) | <0.001 | 0.36 (0.32, 0.41) | <0.001 | 0.39 (0.35, 0.44) | <0.001 |
| Model 2 | ||||||
| Albumin-1st | 0.50 (0.44, 0.58) | <0.001 | 0.51 (0.45, 0.58) | <0.001 | 0.49 (0.44, 0.55) | <0.001 |
| Albumin-max | 0.54 (0.47, 0.63) | <0.001 | 0.57 (0.50, 0.65) | <0.001 | 0.54 (0.48, 0.61) | <0.001 |
| Albumin-min | 0.35 (0.30, 0.40) | <0.001 | 0.38 (0.34, 0.43) | <0.001 | 0.41 (0.37, 0.46) | <0.001 |
Model 1: Adjusted for age and gender. Model 2: Adjusted for age, gender, MI, hypertension, diabetes, valvular diseaser, atrial fibrillation, stroke and CKD. -1st: the first laboratory value in ICU; -max: the maximum laboratory value in ICU; -min: the minimum laboratory value in ICU. ICU: intensive care unit; HF: heart failure; MI: myocardial infarction; CKD: chronic kidney disease.
Table 3.
Sensitivity analysis for relationship between blood albumin level and mortality risk in ICU patients with HF
| Variables | Hospital death | 30-day death | 1-year death | |||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Model 1 | ||||||
| Albumin-1st | 0.48 (0.42, 0.55) | <0.001 | 0.49 (0.43, 0.56) | <0.001 | 0.47 (0.42, 0.53) | <0.001 |
| Albumin-max | 0.52 (0.45, 0.60) | <0.001 | 0.55 (0.48, 0.62) | <0.001 | 0.52 (0.46, 0.58) | <0.001 |
| Albumin-min | 0.34 (0.30, 0.39) | <0.001 | 0.37 (0.32, 0.42) | <0.001 | 0.39 (0.35, 0.44) | <0.001 |
| Model 2 | ||||||
| Albumin-1st | 0.50 (0.44, 0.58) | <0.001 | 0.52 (0.46, 0.59) | <0.001 | 0.50 (0.45, 0.56) | <0.001 |
| Albumin-max | 0.54 (0.47, 0.63) | <0.001 | 0.58 (0.51, 0.66) | <0.001 | 0.55 (0.49, 0.62) | <0.001 |
| Albumin-min | 0.35 (0.30, 0.40) | <0.001 | 0.38 (0.34, 0.44) | <0.001 | 0.41 (0.37, 0.46) | <0.001 |
Model 1: Adjusted for age, gender and malignant tumor. Model 2: Adjusted for age, gender, MI, hypertension, diabetes, valvular diseaser, atrial fibrillation, stroke, CKD and malignant tumor. -1st: the first laboratory value in ICU; -max: the maximum laboratory value in ICU; -min: the minimum laboratory value in ICU. ICU: intensive care unit; HF: heart failure; MI: myocardial infarction; CKD: chronic kidney disease.
Table 4.
Medication-related subgroup analysis for association between blood albumin level with mortality risk in ICU patients with HF
| Variables | Hospital death | 30-day death | 1-year death | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
||||||||
| OR (95% CI) | P Value | P* | OR (95% CI) | P Value | P* | OR (95% CI) | P Value | P* | ||
| Albumin-1st | Albumin | 0.673 (0.487, 0.929) | 0.016 | 0.191 | 0.581 (0.425, 0.794) | 0.001 | 0.747 | 0.433 (0.316, 0.594) | <0.001 | 0.191 |
| NO Albumin | 0.496 (0.425, 0.579) | <0.001 | 0.524 (0.455, 0.603) | <0.001 | 0.519 (0.457, 0.588) | <0.001 | ||||
| Albumin-max | Albumin | 0.696 (0.500, 0.969) | 0.031 | 0.117 | 0.723 (0.536, 0.976) | 0.034 | 0.083 | 0.615 (0.453, 0.835) | 0.002 | 0.273 |
| NO Albumin | 0.501 (0.425, 0.591) | <0.001 | 0.526 (0.454, 0.611) | <0.001 | 0.522 (0.457, 0.597) | <0.001 | ||||
| Albumin-min | Albumin | 0.447 (0.315, 0.633) | <0.001 | 0.426 | 0.414 (0.296, 0.578) | <0.001 | 0.855 | 0.339 (0.243, 0.473) | <0.001 | 0.101 |
| NO Albumin | 0.352 (0.302, 0.411) | <0.001 | 0.395 (0.344, 0.453) | <0.001 | 0.430 (0.380, 0.485) | <0.001 | ||||
Adjusted for age, gender, MI, hypertension, diabetes, valvular diseaser, atrial fibrillation, stroke and CKD. P*: P value for interaction. -1st: the first laboratory value in ICU; -max: the maximum laboratory value in ICU; -min: the minimum laboratory value in ICU. ICU: intensive care unit; HF: heart failure; MI: myocardial infarction; CKD: chronic kidney disease.
Curvilinear relation analysis of blood ALB concentration with risk of hospital death, 30-day death and 1-year death in HF patients
Additionally, we used a smooth curve for univariate analysis to establish an association between blood ALB concentration and death risk. Surprisingly, we observed a curvilinear (U-shaped) correlation between blood ALB concentration and hospital death, 30-day death and 1-year death, as shown in Figure 1. We found that the “inflection point” at which patients had the lowest risk of death was 3.5 g/dL. According to the “inflection point” (albumin level =3.5 g/dL), HF patients were further divided into two subgroups (albumin level <3.5 g/dL and with albumin ≥3.5 g/dL), as shown in Table 5. We observed that an elevated serum ALB concentration did not contribute to a reduced risk of hospital death (OR=1.441, 95% CI=0.713, 2.913; P=0.309), 30-day death (OR=1.161, 95% CI=0.608, 2.218; P=0.652) or 1-year death (OR=0.695, 95% CI=0.397, 1.217; P=0.203), after all covariates, sex, hypertension, diabetes, valvular disease, atrial fibrillation, stroke and CKD, were controlled for in HF patients with an albumin concentration ≥3.5 g/dL (Table 5). Consistently, we still observed that higher albumin-min and albumin-max levels contributed to a reduced risk of (hospital death, 30-day death and 1-year death) in HF patients with an albumin level <3.5 g/dL.
Figure 1.
Smooth curve on association between blood albumin levels (first value on admission, maximum and minimum value during ICU) and hospital death and long-term death among HF patients from the ICU.
Table 5.
Subgroup analysis for relationship between blood albumin level and mortality risk in ICU patients with HF by “Albumin-1st =3.5 g/dL” as the classification variable
| Variables | Hospital death | 30-day death | 1-year death | ||||||
|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|||||||
| OR (95% CI) | P Value | P* | OR (95% CI) | P Value | P* | OR (95% CI) | P Value | P* | |
| Albumin-max | |||||||||
| <3.5 (g/dL) | 0.541 (0.444, 0.658) | <0.001 | 0.012 | 0.618 (0.516, 0.740) | <0.001 | 0.079 | 0.567 (0.479, 0.671) | <0.001 | 0.521 |
| ≥3.5 (g/dL) | 1.441 (0.713, 2.913) | 0.309 | 1.161 (0.608, 2.218) | 0.652 | 0.695 (0.397, 1.217) | 0.203 | |||
| Albumin-min | |||||||||
| <3.5 (g/dL) | 0.309 (0.258, 0.370) | <0.001 | 0.868 | 0.343 (0.291, 0.405) | <0.001 | 0.916 | 0.355 (0.303, 0.415) | <0.001 | 0.284 |
| ≥3.5 (g/dL) | 0.296 (0.205, 0.429) | <0.001 | 0.351 (0.249, 0.494) | <0.001 | 0.433 (0.319, 0.589) | <0.001 | |||
Adjusted for age, gender, MI, hypertension, diabetes, valvular diseaser, atrial fibrillation, stroke and CKD. P*: P value for interaction. -1st: the first laboratory value in ICU; -max: the maximum laboratory value in ICU; -min: the minimum laboratory value in ICU. ICU: intensive care unit; HF: heart failure; MI: myocardial infarction; CKD: chronic kidney disease.
Discussion
There were several important findings in this study: 1) There was a U-shaped correlation between blood ALB-max and hospital death, 30-day death and 1-year death risk in ICU-treated HF patients. In patients without HAE (albumin level >3.5 g/dL), an increased albumin level could increase hospital mortality and out-of-hospital death (hospital death, 30-day death and 1-year death). In particular, when the blood ALB concentration was above 3.5 g/dl, the risk of hospital death, 30-day death and 1-year death was significantly greater. 2) There were still negative associations between the serum ALB concentration and mortality risk in patients with HAE (albumin level <3.5 g/dL), which is consistent with the findings of previous studies.
There is already a large amount of evidence supporting HAE as a potentially modifiable risk factor for CVD and other chronic diseases. Clinical studies have indicated that reduced blood ALB levels are closely associated with HF, CHD, stroke and AF [9-13]. For example, the Health ABC Study demonstrated that lower serum ALB concentrations significantly contributed to new-onset HF [11]. The ARIC study indicated a significant association between reduced blood ALB and a high incidence of CHD [19]. The Framingham Offspring study included 4506 individuals with a follow-up of 22 years and suggested that the serum ALB concentration is a valuable risk factor for detecting the first MI [20]. The Northern Manhattan Study reported that reduced serum ALB levels can predict stroke events in 2986 patients [21]. The Copenhagen City Heart Study showed that a lower serum ALB concentration was associated with the development of AF in women after controlling for other known confounders [22]. Interestingly, we also found U-shaped correlations between blood ALB-max and in-hospital death, 30-day death and 1-year death risk in ICU-treated HF patients.
Especially for protein foods, the serum or plasma ALB concentration has been considered an important nutritional marker for several decades, and a circulating level <3.5 g/dL is defined as HAE. The levels of plasma and urine ALB can also reflect protein synthesis in the liver and the functional state of the vascular endothelium. Indeed, some previous clinical and basic studies have noted that the serum ALB concentration has a significant impact on circulating blood parameters and the incidence of many diseases, such as CVD [19-22], cancer [23] and infections [24]. Research has also suggested that the serum ALB concentration has an important influence on survival time [25]. In a previous meta-analysis, Peng et al. reported that HAE was related to increased mortality in HF patients [26]. Mahmoud et al. showed that a higher risk of in-hospital mortality in HF patients was related to lower serum ALB concentrations [27]. Jabbour et al. observed that reduced serum ALB at baseline contributed to an increased mortality risk after a follow-up of more than 2 years in 212 HF patients [28]. However, although multiple prognostic scores or risk grading models for HF patients have been proposed and validated, the accuracy and applicability of these models are not reliable. In-depth risk stratification may help clinicians make more appropriate clinical decisions. Recently, low albumin levels have been increasingly regarded as a predictor of morbidity and mortality risk, independent of age, sex, comorbidities and other confounding factors [29-31]. Consistent with these findings, our findings showed that a lower serum ALB concentration contributed to higher hospital mortality and out-of-hospital death in patients with HAE (albumin level <3.5 g/dL). Surprisingly, we additionally observed U-shaped correlations between blood ALB-max levels during the ICU and hospital death, 30-day death and 1-year death risk in ICU-treated HF patients. In patients without HAE (albumin level >3.5 g/dL), an increased serum ALB concentration (blood albumin maximum in the ICU) could inversely increase hospital mortality and out-of-hospital death, especially when the blood albumin concentration was above 4.0 g/dL. The U-shaped correlation may partially explain why some previous prediction models were not accurate. Furthermore, in a previous study, our team members also found that in 925 CKD patients with an albumin level >3.4 g/dL, increased albumin (blood albumin-max levels arriving in the ICU) contributed to an increased risk of CVD complications and 1-year mortality [32]. However, one study from the same database (MIMIC database) showed an almost linear negative correlation between blood ALB concentration and all-cause mortality by restricted cubic spline curve analysis [33]. The differences in the results might originate from the use of the average serum ALB concentration to represent the correlation between the serum ALB concentration and short-term mortality. Moreover, there were also significant differences in the population included and in the variables extracted in our study, which may be an important reason for the different results [33].
The advantages of this retrospective study were that we first selected ICU patients with HF from the MIMIC-III database with a large sample size (n=4084) and evaluated the relationships between blood ALB concentrations (albumin-1st, albumin-max and albumin-min) and the risk of hospital death, 30-day death and 1-year death. We were surprised to observe an important point of interest in our research: among ICU patients with HF, HAE patients had significantly increased hospital mortality and long-term mortality in the later stage. However, in patients without HAE, continuing to supplement patients with albumin may actually increase their mortality risk, which is also the first phenomenon we have reported. Certainly, the reliability of this research conclusion also needs to be confirmed by additional meta-analyses or clinical trials. Several shortcomings also need to be noted. First, even if multivariable adjustment was made, the major limitation of this study was that it was still a retrospective and observational study, making it impossible to confirm the causal association between blood ALB concentration and hospital mortality and out-of-hospital death. Additionally, known or unknown confounding factors were still not fully controlled. For example, blood ALB levels can be affected by malnutrition, chronic inflammatory states, hepatic congestion and other factors. The severity of HF and its accompanying conditions, such as acute decompensated HF, acute pulmonary edema and cardiogenic shock, were not included in the study. Second, the HF stage and exact cause of death could not be assessed due to the inherent limitations of the MIMIC database. Third, the influence of drugs on blood ALB concentrations in the ICU was not taken into account. Fourth, there were multiple measurements of blood ALB, so we included only the first, maximum and minimum blood ALB concentrations after admission to the ICU. Finally, it is currently unclear whether there are racial differences in the associations between blood ALB concentrations and hospital mortality and out-of-hospital death.
Conclusion
Our findings suggested that increased albumin levels were independently associated with reduced in-hospital death and out-of-hospital death risk in HF patients without HAE (blood albumin <3.5 g/dL). However, we additionally found that increasing albumin levels were inversely associated with increased in-hospital death and out-of-hospital death risk in HF patients without HAE.
Disclosure of conflict of interest
None.
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