We assessed the prognostic implications of low triiodothyronine (T3) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in critically ill patients with acute heart failure. We acquired data for 144 critical care patients with acute decompensated heart failure, of which 106 were included in this study. Plasma thyroid hormones and NT-proBNP levels were determined within 48 hours of admission. We assessed these measures for predicting all-cause and cardiac mortalities. At a mean follow-up period of 25 ± 31 months, the all-cause mortality rate was 51% (54 of 106) and the cardiac mortality rate was 70% (38 of 54). A multivariate Cox regression model showed that log-transformed NT-proBNP levels (log NT-proBNP; hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38 to 6.08, p = 0.005) and T3 levels (HR 0.98, 95% CI 0.96 to 0.99, p = 0.008) were associated with all-cause mortality, and log NT-proBNP (HR 3.70, 95% CI 1.28 to 10.71, p = 0.02) and T3 (HR 0.98, 95% CI 0.96 to 0.99, p = 0.01) were associated with cardiac mortality. Based on cut-off values for NT-proBNP (10,685 pg/ml) and T3 (52.3 ng/dl), Kaplan-Meier analyses provided significant prognostic information with the highest risk for all-cause mortality in the low T3 (≤52.3 ng/dl)/high NT-proBNP (>10,685 pg/ml) group (HR 8.54, 95% CI 4.19 to 17.40, p <0.0001). In conclusion, T3 levels appear to be independent predictors for both all-cause and cardiac mortalities among critical ill patients with heart failure, and high NT-proBNP and low T3 levels predict a worse long-term outcome.
Thyroid hormones play a fundamental role in cardiovascular homeostasis under both physiological and pathologic conditions. In severe heart failure (HF), the main alteration in thyroid function is referred to as “low triiodothyronine (T3) syndrome,” which is characterized by decreased total serum T3 and free T3 levels with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) levels. Low T3 levels may possibly have negative effects by contributing to the progressive deterioration of cardiac function and myocardial remodeling in HF. Thus, low T3 levels may be a predictor of mortality for patients with severe HF. However, no studies have evaluated low T3 levels with regard to the long-term prognosis of critically ill patients with HF and a possible association with N-terminal pro-B-type natriuretic peptide (NT-proBNP). Thus, in this study, we sought to determine whether T3 and NT-proBNP levels could be useful prognostic predictors for critically ill patients with acute HF.
Methods
We studied 144 patients aged ≥18 years who had been admitted to the intensive care unit (ICU) of the Taoyuan General Hospital after acute decompensated HF or severe HF from October 2002 to October 2005. All patients had severe symptoms and signs of acute HF. We excluded 38 patients from this study for ≥1 of the following reasons: concomitant severe sepsis, pneumonia with severe respiratory failure, acute renal failure needing hemodialysis, primary or latent thyroid disorder, or amiodarone therapy. All patients had blood samples taken for plasma NT-proBNP levels and underwent thyroid function tests within 48 hours of their admission. Finally, 106 patients were enrolled in this study.
On admission to the ICU, we recorded information on demographics, co-morbidities, admission etiology, hemodynamics, left ventricular ejection fraction, and laboratory test results. Data on main interventions, concurrent medications, and lengths of stay in the ICU were obtained from medical records on discharge. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were recorded using the worst values for the first 24 hours after ICU admission. Written informed consent was obtained from study participants or their family members. The Institutional Review Committee on Human Research of Taoyuan General Hospital approved this study (TYGH99047).
All patients had blood samples taken within 48 hours of admission. Plasma NT-proBNP levels were determined using an Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany), as previously described. Thyroid function tests, including total T3, free T3, free T4, and TSH levels, were determined using Immulite 2000 (Bio DPC, Los Angeles, California). The reference ranges for our central laboratory were total T3, 84 to 172 ng/dl; free T3, 1.57 to 4.71 pg/ml; free T4, 0.89 to 1.76 ng/dl; and TSH, 0.4 to 4.0 μIU/ml.
All patients were appropriately treated with intravenous diuretics and vasodilators or inotropic agents during their ICU hospitalization. After discharge, patients were treated conservatively with individualized maximal doses of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and with or without β-blocker therapy. During follow-up, none of the patients received a heart transplant or cardiac resynchronization therapy.
Follow-up began when plasma NT-proBNP and thyroid hormones levels were first determined. All patients were monitored during hospital visits and by follow-up telephone conversations. We ascertained all-cause and cardiac mortalities from medical records or death certificates. Cardiac death required documentation of arrhythmias or cardiac arrest, death due to progressive HF, or myocardial infarction (MI) in the absence of a precipitating factor. Sudden unexpected death was classified as cardiac death when it occurred outside the hospital and was not followed up by autopsy.
Results for categorical variables are given as percentages, and results for continuous variables are given as means ± SDs for normally distributed variables or medians and interquartile ranges. Group comparisons were made by Student t test, Mann-Whitney U test, Fisher’s exact test, or chi-square test, as appropriate. Associations between continuous variables were assessed by Pearson product-moment analysis (Pearson r) or Spearman rank correlation analysis (Spearman r), as appropriate. Univariate and multivariate Cox regression analyses were used to determine the relative risks (hazard ratio [HR]) associated with NT-proBNP and thyroid hormones levels. NT-proBNP levels were log transformed (log NT-proBNP) because of the highly skewed distribution of NT-proBNP levels. All variables listed in Table 1 were assessed for significant univariate HR, and all significant variables from univariate analyses were included in a multivariate model. We also generated receiver operating characteristic curves to assess cut-off values for NT-proBNP and T3 levels that would prognostically discriminate between nonsurvivors (all-cause mortality) and survivors. These results are given as the area under the curve and its associated 95% confidence interval (CI). Based on the cut-off values for NT-proBNP and T3 levels, patient outcomes were assessed using Kaplan-Meier curves; a log-rank (Mantel-Cox) test was used to compare survival curves and estimate HR.
| Variable | All (n = 106) | Died During Follow-Up (n = 54) | Survived Throughout Follow-Up (n = 52) | p Value |
|---|---|---|---|---|
| Age (yrs) | 71 ± 13 | 76 ± 12 | 67 ± 14 | 0.001 |
| Men | 54 (51) | 28 (52) | 26 (50) | 0.85 |
| Body mass index (kg/m 2 ) | 22.9 (20.0−25.0) | 22.5 (19.7−24.6) | 23.4 (20.1−26.2) | 0.40 |
| Co-morbidities | ||||
| Diabetes mellitus | 56 (53) | 28 (52) | 28 (54) | 0.84 |
| Hypertension | 64 (60) | 31 (57) | 33 (63) | 0.53 |
| Coronary artery disease | 68 (63) | 38 (70) | 30 (58) | 0.18 |
| Cerebrovascular disease | 11 (10) | 5 (9) | 6 (12) | 0.70 |
| Chronic obstructive pulmonary disease | 15 (16) | 11 (20) | 4 (8) | 0.06 |
| Chronic kidney disease ∗ | 56 (53) | 33 (61) | 23 (44) | 0.08 |
| Atrial fibrillation | 26 (25) | 15 (28) | 11 (21) | 0.43 |
| Alcoholism | 2 (2) | 1 (2) | 1 (2) | 0.98 |
| Admission etiology | ||||
| Ischemic | 61 (58) | 27 (50) | 34 (65) | 0.11 |
| Hypertensive and/or hypertrophic cardiomyopathy | 20 (19) | 10 (19) | 10 (19) | 0.93 |
| Idiopathic dilated cardiomyopathy | 12 (11) | 5 (9) | 7 (13) | 0.50 |
| Valvular heart disease | 15 (14) | 9 (17) | 6 (12) | 0.45 |
| Other etiology | 18 (17) | 11 (20) | 7 (13) | 0.35 |
| Cardiogenic shock | 22 (21) | 11 (20) | 11 (21) | 0.92 |
| Mean arterial pressure (mm Hg) | 96 (82−110) | 92 (78−114) | 100 (89−110) | 0.11 |
| Left ventricular ejection fraction (%) | 42 (32−55) | 38 (30−50) | 46 (34−58) | 0.11 |
| Blood urea nitrogen (mg/dl) | 38.3 ± 24.6 | 42.3 ± 27.6 | 34.1 ± 20.4 | 0.09 |
| Estimated glomerular filtration rate † (ml/min) | 39 ± 31 | 34 ± 25 | 44 ± 35 | 0.09 |
| Troponin I (mg/dl) | 10.44 ± 28.39 | 11.29 ± 29.33 | 9.56 ± 27.63 | 0.76 |
| Free triiodithyronine (pg/ml) | 1.66 ± 0.61 | 1.62 ± 0.60 | 1.69 ± 0.62 | 0.56 |
| Free thyroxine (ng/dl) | 1.24 ± 0.38 | 1.20 ± 0.40 | 1.29 ± 0.36 | 0.22 |
| Triiodithyronine (ng/dl) | 57.7 ± 20.7 | 52.8 ± 17.2 | 62.7 ± 23.0 | 0.01 |
| Thyroid-stimulating hormone (μIU/ml) | 1.02 ± 1.15 | 1.10 ± 1.36 | 0.93 ± 0.89 | 0.44 |
| NT-proBNP (pg/ml) | 10,997 (5,283−25,443) | 17,297 (7,345−35,000) | 7,869 (4,016−16,948) | 0.001 |
| Mechanical ventilation | 39 (37) | 22 (41) | 17 (33) | 0.40 |
| Revascularization | 10 (9) | 6 (11) | 4 (8) | 0.55 |
| Valvular replacement surgery | 2 (2) | 1 (2) | 1 (2) | 0.98 |
| Implantable-cardioverter defibrillator | 1 (1) | 0 (0) | 1 (2) | 0.31 |
| Medications | ||||
| Diuretic | 102 (96) | 52 (96) | 50 (96) | 0.89 |
| Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker | 69 (65) | 32 (59) | 37 (71) | 0.20 |
| β Blocker | 29 (27) | 12 (22) | 17 (33) | 0.23 |
| Digoxin | 23 (22) | 14 (26) | 9 (17) | 0.29 |
| Aldactone | 17 (16) | 8 (15) | 9 (17) | 0.73 |
| Inotropic agents | 50 (47) | 29 (54) | 21 (40) | 0.17 |
| Length of stay in critical care unit (days) | 8 ± 7 | 10 ± 8 | 5 ± 4 | 0.001 |
| APACHE II score | 18 (12−23) | 20 (14−25) | 17 (11−21) | 0.03 |
| Follow-up (mo) | 25 ± 31 | 13 ± 18 | 37 ± 37 | — |
∗ Defined as baseline serum creatinine level of >2.0 mg/dl.
A 2-sided p value of <0.05 was considered significant. Statistical analyses were done using SPSS, version 18.0 (SPSS Inc, Chicago, Illinois), and Prism 5 for Windows (GraphPad Software Inc., San Diego, California).
Results
During a mean follow-up of 25 ± 31 months, 54 (51%) of 106 patients died, which included 38 (70%) of 54 due to cardiac causes. The patients who died were older, had longer ICU stays, had higher APACHE II scores, higher NT-proBNP levels, and lower T3 levels than those who were still alive during follow-up ( Table 1 ).
There were significant correlations between free T3 and T3 levels (r 2 = 0.62, p <0.0001), free T3 and free T4 levels (r 2 = 0.23, p <0.0001), and free T4 and T3 levels (r 2 = 0.24, p <0.0001). Log NT-proBNP was positively correlated with TSH levels (r 2 = 0.05, p = 0.03) and inversely correlated with T3 levels (r 2 = 0.09, p = 0.002) but was not associated with free T3 or free T4 levels.
Univariate analyses showed that age, T3, log NT-proBNP, and APACHE II scores were associated with all-cause mortality ( Table 2 ). Multivariate analysis showed that age, T3, log NT-proBNP, and APACHE II scores were independent predictors of all-cause mortality.
| Variable | Univariate | p Value | Multivariate | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| Age | 1.04 (1.01−1.06) | 0.002 | 1.03 (1.00−1.06) | 0.048 |
| Sex | 1.10 (0.65−1.88) | 0.72 | 1.27 (0.74−2.18) | 0.39 |
| Free triiodithyronine | 0.65 (0.41−1.03) | 0.07 | ||
| Free thyroxine | 0.57 (0.30−1.09) | 0.09 | ||
| Triiodithyronine | 0.97 (0.96−0.99) | 0.001 | 0.98 (0.96−0.99) | 0.008 |
| Thyroid-stimulating hormone | 1.13 (0.90−1.42) | 0.28 | ||
| Log-transformed NT-proBNP | 4.16 (2.09−8.28) | <0.001 | 2.90 (1.38−6.08) | 0.005 |
| APACHE II score | 1.06 (1.02−1.10) | 0.006 | 1.05 (1.00−1.09) | 0.04 |
| Cardiac mortality | ||||
| Age | 1.02 (1.00−1.05) | 0.07 | 1.00 (0.98−1.04) | 0.74 |
| Sex | 1.54 (0.81−2.91) | 0.19 | 1.90 (0.97−3.72) | 0.06 |
| Coronary artery disease | 2.24 (1.18−4.97) | 0.03 | 1.48 (0.65−3.33) | 0.35 |
| Chronic kidney disease | 2.39 (1.21−4.73) | 0.01 | 0.94 (0.41−2.17) | 0.89 |
| Free triiodithyronine | 0.73 (0.43−1.23) | 0.24 | ||
| Free thyroxine | 0.56 (0.26−1.87) | 0.13 | ||
| Triiodithyronine | 0.98 (0.96−0.99) | 0.008 | 0.98 (0.96−0.99) | 0.01 |
| Thyroid-stimulating hormone | 1.24 (0.97−1.58) | 0.08 | ||
| Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker | 0.52 (0.30−0.98) | 0.04 | 0.64 (0.32−1.27) | 0.20 |
| Log-transformed NT-proBNP | 5.15 (2.19−12.11) | <0.001 | 3.70 (1.28−10.71) | 0.02 |
| APACHE II score | 1.06 (1.01−1.11) | 0.02 | 1.06 (1.00−1.11) | 0.04 |
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