Prognostic Signicance of Thyroid Hormone For Prolonged Mechanical Ventilation In Critically Ill Patients With Cardiac Surgery

Background: This study aimed to examine the correlation between thyroid hormone and prolonged mechanical ventilation (MV) in the adult critically ill patients having undergone cardiac surgery. Methods: The present study refers to a retrospective, cohort study that was conducted at Cardiovascular Intensive Care Unit (CVICU) of Nanjing First Hospital from March 2019 to December 2020. Patients receiving cardiac surgery and admitted to the center of the authors in the study period were screen for a potential inclusion. Demographic information, thyroid hormone and other laboratory measurements and outcome variables were recorded for analyses. Prolonged MV was dened as the duration of MV after cardiac surgery longer than 5 days. Thyroid hormones were assessed for the prognostic signicance for prolonged MV. Results: On the whole, 118 patients having undergone cardiac surgery were included and analyzed in this study. Patients fell to the control (n=64) and the prolonged MV group (n=54) by complying with the duration of MV after cardiac surgery. The median total triiodothyronine (TT3) and free triiodothyronine (FT3) were 1.03 nmol/L and 3.52 pmol/L in the prolonged MV group before cardiac surgery, signicantly lower than 1.23 nmol/L (P=0.005) and 3.87 pmol/L, respectively in the control (P=0.038). multivariate logistic regression analysis indicated that TT3 before surgery (pre-op TT3) had a good prognostic signicance for prolonged MV (OR: 0.049, P=0.012). Conclusions: This study concluded that decreased triiodothyronine (T3) could be common in the cardiac patients with prolonged MV, and it would be further reduced after patients undergoing cardiac surgery. Besides, decreased T3 before surgery could act as an effective predictor for prolonged MV after cardiac surgery.


Introduction
Low triiodothyronine (T3) syndrome, i.e., non-thyroidal illness syndrome (NTIS), has been the most common abnormality of thyroid hormone in critically ill hospitalized patients [1]. Physiologically, reduced serum T3 levels refers to the initial response of the body to acute stress to ght against catabolism [2].
However, during prolonged critical illness, the normal response of the hypothalamus-pituitary-thyroid (HPT) axis can alter and contribute to low levels of T3 and thyroid-stimulating hormone (TSH), characterized as NTIS [3]. The correlation between NTIS and increased mortality in critically ill patients with sepsis and other diseases has been recently con rmed [4].
The NTIS has been demonstrated to occur in adult and pediatric patients having undergone cardiac surgery. Existing studies indicated that reductions in T3 was observed in patients undergoing cardiac surgery with or without cardiopulmonary bypass (CPB) [1]. Moreover, low T3 was indicated as a strong predictor for mortality in heart disease patients [5]. However, most studies were conducted in the population of pediatric patients. There have been rare studies in adult patients having undergone cardiac surgery.
Since thyroid hormone is critical to muscle function, this study aimed to explore the correlation between thyroid hormone and prolonged mechanical ventilation (MV) in the adult critically ill patients having undergone cardiac surgery.

Patients
The present study is a retrospective, cohort study that was conducted at an urban, tertiary care, Cardiovascular Intensive Care Unit (CVICU) of Nanjing First Hospital, a Teaching Medical College Hospital in China. Patients receiving cardiac surgery and admitted to the center of the authors from March 2019 to December 2020 were screened for a potential inclusion. The data of the patients were screened and collected from the electronic medical record (EMR) databases. All the study protocol was performed in accordance with the Declaration of Helsinki and was approved by Ethics Committee of Nanjing First Hospital, Nanjing Medical University (KY20170811-03).
The inclusion criteria of this study included: (1) adult patients with cardiac disease who had undergone cardiac surgery with CPB, (2) patients admitted to the center of the authors immediately after surgery, (3) available assessments of thyroid hormone before and 24h after cardiac surgery, and (4) patients receiving MV for over 48h after cardiac surgery. Patients who were pregnant, with known thyroid diseases and abnormal thyroid gland on palpation and other examinations (e.g., enlarged thyroid and thyroid nodules), or on hormonal therapy were excluded here.

Data collection
Demographic information was recorded for further analyses (e.g., gender, age, body mass index (BMI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, EuroSCORE and co-morbidities as well as thyroid hormone and other chemical data). In addition, types of operation and operation time were collected. Moreover, outcome variables (e.g., hospital mortality, time of MV, length of hospital stay and ICU stay) were recorded for further comparison. Prolonged MV was de ned as the duration of MV after cardiac surgery longer than 5 days.

Laboratory measurements
To conduct thyroid hormone analysis, total T3 (TT3), free T3 (FT3), total thyroxine (TT4), free thyronine (FT4) and TSH were determined from blood samples of the patients before and 24h after cardiac surgery.
Thyroid hormone was detected with Chemiluminescence immunoassay instrument (MAGLUMI 2000, Snibe Diagnostic, China). In addition, the reference values of the hospital of the authors included: TT3: 0.98-2.33nmol/L, TT4: 62.68-150.84nmol/L, FT3: 2.43-6.01pmol/L, FT4: 9.00-19.00pmol/L and TSH: 0.35-4.94mIU/L. Lactate was obtained from arterial blood gas with ICU blood-gas analyzer (NOVA CCX Blood Gas Analyzer, USA), and white blood cell (WBC) counts were determined from blood routine test performed in the central laboratory of the hospital of the authors with the use of automatic blood cell analyzer (COULTER LH 750, Beckman Coulter, USA). Biochemical analysis, involving total protein, albumin, aspartate aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and creatinine, was conducted in the central laboratory of the hospital of the authors by applying an Aeroset analyzer (Hitachi 7180 Automatic Biochemical Analyzer, Japan). The serum level of N-terminal pro brain natriuretic peptide (NT-proBNP) was identi ed with rapid diagnostic cassette and Immunoquantitative analyzer (FIA8000, Getein Biotech, China).
Statistical analysis SPSS 22.0 statistical software package (IBM Analytics, USA) was employed for the statistical analysis, and P<0.05 was considered with statistical signi cance. Continuous variables were expressed as median plus interquartile range (IQR), and categorical variables were expressed as frequency plus percentage. The differences between groups were assessed by performing student's t test for continuous variables with normality distribution and Mann-Whitney U test for continuous variables without normality distribution. The differences between groups for categorical variables were compared by performing Chisquare test.
Correlations between variables and prolonged MV were assessed by conducting logistic regression analysis. Variables with statistical signi cance in the univariate logistic regression were covered in the multivariate logistic regression. Moreover, receiver operating characteristic (ROC) curve was plotted to assess the prognostic ability of the variable for prolonged MV. Next, univariate and multivariate linear regression analysis were conducted to identify the correlations between variables and time of MV.
Likewise, in-depth multivariate linear regression only involved the variables showing statistical signi cance in the univariate analysis.

Results
On the whole, 1896 patients admitted to the center of the authors and having undergone cardiac surgery were screened, and 1778 patients were excluded (Fig. 1), leaving 118 patients included and analyzed in this study. Patients fell to the control (n=64) and the prolonged MV group (n=54) by complying with the duration of MV after cardiac surgery. Prolonged MV was de ned as time of MV longer than 5 days after cardiac surgery.  [4,10], P<0.001), as well as a prolonged duration of MV (8 days [5,10] vs. 3 days [3,4], P<0.001). No statistically signi cant difference was identi ed in the common clinical parameters (e.g., gender, age, BMI, APACHE II score and euroSCORE) between the control and the prolonged MV group. The main types of cardiac surgery consisted of aortic surgery, isolated valve surgery and combined surgery of coronary artery bypass grafting (CABG) and valve surgery in prolonged MV patients.
The proportion of patients having undergone aortic surgery in the prolonged MV group exceeded that in the control (28 [51.8%] vs. 22 [34.4%], P=0.056), though without statistically difference. The two groups had similar incidences of co-morbidities except chronic kidney disease, higher than that of the control (4 [6.2%] vs. 0 [0%], P=0.025). The left ventricular ejection fraction (LVEF) of the patients before cardiac surgery was comparable in the two groups, as well as the operation time.    Table 3 lists other laboratory parameters of the control and the prolonged MV group. NT-proBNP, total protein, albumin, AST, ALT, total bilirubin, creatinine, WBC as well as lactate before cardiac surgery were not different between the control and the prolonged MV group. No differences were identi ed in the mentioned laboratory parameters after cardiac surgery between the two groups either.  (Table 4). According to in-depth multiple stepwise logistic regression analysis by adopting the mentioned variables, signi cant correlations were found between prolonged MV and pre-op TT3 (OR: 0.049, 95% CI: 0.005-0.523, P=0.012, Table 5). The area under the ROC curve (AUROC) reached 0.73 (95% CI: 0.593-0.868, P=0.006) for pre-op TT3, indicating high prognostic signi cance for prolonged MV. The speci city and sensitivity of pre-op TT3 for prolonged MV reached 84.2% and 60.6%, respectively, with a cut-off value for of 1.255nmol/L.  CI: -1.029 to -0.640, P=0.012) still showed independent and signi cant correlation with the duration of MV.

Discussion
Key ndings A retrospective, cohort study was conducted to assess the prognostic signi cance of thyroid hormone for prolonged MV in critically ill patients having undergone cardiac surgery. As revealed from the results of this study, serum levels of thyroid hormone were down-regulated signi cantly in the cardiac patients having undergone cardiac surgery. Besides, prolonged MV patients after cardiac surgery had markedly lower level of TT3 before surgery. Furthermore, TT3 before surgery, signi cantly correlated with the duration of MV, acted as an effective predictor for prolonged MV in patients having undergone cardiac surgery.
Relationship to previous studies NTIS refers to a common endocrine disorder in critically ill patients, which has been correlated with various manifestations in the ICU. Hypothyroidism might be critical to the persistent spectrum of symptoms identi ed in the critically ill patients. Considerable studies con rmed the prognostic signi cance of NTIS for mortality in the critically ill patients [4,[6][7][8], whereas the studies largely concentrated on the critically ill patients with internal medical disease (e.g., sepsis and septic shock). The prognostic signi cance of NTIS or T3 in surgical critically ill patients remains not known. In this study, a correlation was not identi ed between T3 and the mortality in the patients having undergone cardiac surgery, primarily attributed to the heterogeneity of study population.
The critical primary condition, severe surgical trauma and short-term postoperative adverse events of the patients after cardiac surgery seriously limited the surgical e cacy and prognosis of patients, i.e., the major problems to be urgently solved by the clinical physicians at present. Patients with cardiac disease suffer from long-term heart disease, resulting in long-term stress state attributed to the disease, often complicated with NTIS even before cardiac surgery. Furthermore, the level of thyroid hormone would further decrease after cardiac, thereby seriously affecting the prognosis of patients.
NTIS is traditionally recognized as a self-protection mechanism that down-regulates the overall metabolism to conserve energy under stress. With the gradual recovery of body injury, the symptoms of NTIS will be mitigated, so intervention will not be required. However, when the stress state or critical illness persists, NTIS will adversely affect the recovery of the body, thereby resulting in overcorrection.
Thus, positive intervention may improve the prognosis.
Several studies demonstrated the bene cial effect of thyroid hormone replacement in the patients having undergone cardiac surgery. A prospective study performed by Zhang et al. [9] revealed that the incidence of postoperative NTIS could be reduced and the myocardial ischemia-reperfusion injury in pediatric patients could be protected by taking oral thyroid hormone 0.4 mg/kg for 4 consecutive days before cardiac surgery. The study by Marwali et al. [10] also con rmed the promoting effect of thyroid hormone replacement in pediatric patients having undergone cardiac surgery. They indicated that the incidence of postoperative low cardiac output syndrome could be down-regulated through the administration of 1 mg/kg thyroid hormone every 6 h after surgery for patients undergoing cardiopulmonary bypass. In a prospective, multicenter, randomized, double-blind controlled study by Portman et al. [11], intravenously administered T3 effectively could up-regulate serum levels of FT3 in patients having undergone coronary artery bypass grafting for congenital heart disease without signi cant adverse effects and improve the cardiac function signi cantly. However, as suggested from a meta-analysis by Flores et al. [12], T3 treatment after cardiopulmonary bypass could not reduce mortality and duration of MV and ICU stay, as well as improving cardiac function. Likewise, two studies in patients with CABG [13,14]

Study implications
As impacted by the characteristics of the primary diseases and surgical intervention, complications after surgery are commonly the primary concerns for the patients having undergone cardiac surgery. Though numerous studies con rmed the prognostic signi cance of NTIS in medical critically ill patients, existing studies on adult patients having undergone cardiac surgery have been rare. Also, the exact effect of postoperative thyroid hormone supplementation remains controversial. This study demonstrated the prognostic signi cance of T3 before surgery for prolonged MV after cardiac surgery, which might help prove the necessity of thyroid hormone therapy in the patients having undergone cardiac surgery.
However, the exact population requiring thyroid hormone therapy and the time of intervention may still be veri ed by large-scale, multi-center and high-quality clinical studies.

Limitations
This study has several limitations. First, the patients with MV for over 48 h after cardiac surgery were only included, and considerable patients having undergone cardiac surgery were excluded. In this way, the result in this study may not be applicable to all the patients having undergone cardiac surgery. Second, since this study is a retrospective study, it might cause selection biases. Third, as impacted by the restriction of this retrospective study, the effect of thyroid hormone supplementation on the prognosis and prolonged MV was not assessed here.

Conclusions
This study investigated the prognostic signi cance of T3 for prolonged MV in patients having undergone cardiac surgery. As revealed from this study, decreased T3 could be common in the cardiac patients with prolonged MV before surgery, and it would be further reduced after patients undergoing cardiac surgery.
Decreased T3 before surgery was an effective predictor for prolonged MV after cardiac surgery, thereby demonstrating that thyroid hormone therapy might be pro  Screening of the study patients.