Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
Users Online: 697

 

Home  | About Us | Editors | Search | Ahead Of Print | Current Issue | Archives | Submit Article | Instructions | Subscribe | Contacts | Login 
     


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 61-66

Serum total triiodothyronine (T3) as a predictor of mortality and morbidity in critically ill patients and its correlation of predictability with acute physiology and chronic health evaluation II score: A prospective observational study


Department of Medicine, Melaka Manipal Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Submission24-Jun-2020
Date of Acceptance21-Sep-2020
Date of Web Publication29-Jun-2021

Correspondence Address:
Dr. Seema M Shetty
Department of Medicine, Melaka Manipal Medical College, Manipal Academy of Higher Education,Manipal-576104 Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCIIS.IJCIIS_88_20

Rights and Permissions
   Abstract 


Background: The aim is to assess the prognostic value of total T3, total T4, and thyroid-stimulating hormone among critically ill patients admitted to the medical intensive care unit (ICU) in association with mortality and its correlation with the acute physiology and chronic health evaluation II (APACHE II) score.
Methods: Our prospective observational study consists of 257 patients without known thyroid diseases admitted to the medical ICU. The baseline characteristics of the patients were recorded, including the APACHE II score and thyroid hormone levels at ICU admission. Based on the primary outcome of mortality, we analyzed the data by appropriate statistical methods. A P < 0.05 was considered significant.
Results: Of the 257 patients included in the study, 47 (18.28%) succumbed to their illnesses. A significant difference in T3 levels (P < 0.001), T4 levels (P < 0.001), and APACHE II score (P < 0.001) was found between the survivors and the nonsurvivors. There was negative correlation observed between T3 and APACHE II score (r = −0.448, P < 0.001) and T4 and APACHE II score (r = −0.221, P ≤ 0.001). Multivariate logistic regression analysis determined T3 to be the only independent predictor of ICU mortality among thyroid hormones. The area under the curve (AUC) for T3 (0.811 ± 0.04) was almost equal to that of the APACHE II score (0.858 ± 0.029). The duration of ICU stay and hospital stay in patients with low T3 was significantly higher compared to patients with normal T3.
Conclusion: Serum T3 is a good indicator for predicting mortality and morbidity among critically ill patients.

Keywords: Acute physiology and chronic health evaluation II, critical illness, intensive care unit, mortality, thyroid profile


How to cite this article:
Thilak M R, Shetty SM, Kotian CM, Mohammed AP, Dhunputh P, Umakanth S, Saraswat PP. Serum total triiodothyronine (T3) as a predictor of mortality and morbidity in critically ill patients and its correlation of predictability with acute physiology and chronic health evaluation II score: A prospective observational study. Int J Crit Illn Inj Sci 2021;11:61-6

How to cite this URL:
Thilak M R, Shetty SM, Kotian CM, Mohammed AP, Dhunputh P, Umakanth S, Saraswat PP. Serum total triiodothyronine (T3) as a predictor of mortality and morbidity in critically ill patients and its correlation of predictability with acute physiology and chronic health evaluation II score: A prospective observational study. Int J Crit Illn Inj Sci [serial online] 2021 [cited 2021 Aug 3];11:61-6. Available from: https://www.ijciis.org/text.asp?2021/11/2/61/319785




   Introduction Top


Critical illness is any disease process causing physiological instability that may lead to disability or death within minutes or hours.[1] Such illness is known to cause various hormonal disturbances, including abnormality in thyroid function. This alteration in thyroid function in critically ill patients with no previous thyroid disorder is called nonthyroidal illness syndrome (NTIS) (aka euthyroid sick syndrome or low T3 syndrome). NTIS has been shown to correlate with the severity of disease and increased mortality.

Predicting mortality and morbidity among critically ill patients would enable risk stratification and more intensive care of these patients. While one such method of risk stratification is by using validated scoring systems such as the acute physiology and chronic health evaluation II (APACHE II) score that makes use of various clinical and biochemical parameters, another method is by studying the levels of certain serum markers as predictors. The role of thyroid hormones in predicting mortality among such patients is yet to be ascertained. Thus, we carried out a prospective observational study among critically ill patients admitted in the medical intensive care unit (ICU) to assess the prognostic value of total T3, total T4, and thyroid-stimulating hormone (TSH) in association with mortality and its correlation with the APACHE II score.


   Methods Top


Study setting and participants

We conducted our study in a secondary care hospital located in the Udupi district of Karnataka in South India. This study was a noninterventional, single-center, prospective observational study in critically ill patients admitted to the medical ICU between August 2016 to August 2017. Our study received ethical approval from the Manipal University Ethics Committee (IEC No. MUEC/008/2016-17). We obtained written informed consent from all the patients or their family members/surrogate. Our manuscript adheres to the STROBE guidelines. All patients >18 years and without prior thyroid disorder were included. Pregnant women and patients on amiodarone or dopamine that could potentially affect thyroid function were excluded.

Data collection

On admission to ICU, all the enrolled patients were subjected to baseline blood investigations including complete blood count, hemoglobin A1C, blood sugars, renal function tests, liver function tests, blood gas analysis, and other relevant tests. Thyroid function tests, i.e., total triiodothyronine (T3), total thyroxine (T4), TSH, were measured within 2 h of ICU admission. T3, T4, and TSH were measured using Elecsys electrochemiluminescence assay (Cobas e 411 analyzer; Roche Diagnostics; Mannheim, Germany). Testing was performed according to the manufacturer's instructions. The normal reference ranges of serum hormone concentrations in our laboratory are as follows: T3 (0.80–2.0 ng/ml); T4 (5.50–12.2 μg/dl); TSH, (0.3 μIU/ml to 4.5 μIU/ml). Based on history, clinical examination, and the worst parameters within the first 24 h of admission, acute physiology score, chronic health score, Glasgow Coma Scale score, and Age score were calculated to get the APACHE II score. Charlson Comorbidity Index (CCI) was calculated for each patient. The patients were followed up till discharge/death and duration of ICU stay, and the total duration of hospital stay was noted. The primary outcome was death in the ICU due to any cause. The association of thyroid hormones with mortality and morbidity and their correlation of predictability with the APACHE II score was assessed.

Sample size

Anticipating 15% of critically ill patients to succumb to their illness and at least 10% higher rate in low T3 group for the power of 80% and 95% confidence, a minimum of 250 critically ill patients were to be studied, considering the study by Harikumar et al.[2]

Data analysis

We used IBM SPSS, Version 20.0. (IBM Corp., Armonk, NY, USA) to perform the statistical data analysis. To assess the association of thyroid hormones with the outcome, T3, T4, and TSH were grouped as low, normal, and high according to our lab reference values (as described in the previous section). Mortality and morbidity between different groups were compared. Categorical data were expressed in absolute numbers and percentages. A Chi-square test was used to find the associations between categorical variables and outcomes. Mean and standard deviation was used to express normally distributed continuous data, and independent samples t-test was used to compare means between the two groups. For nonnormal distribution, the median and interquartile range was reported, and the Mann–Whitney U-test and Kruskal–Wallis analysis of variance were used to compare the median. Spearman's rho coefficient has been reported for the correlation between the APACHE II score and the levels of T3 and T4. Univariate and multivariate logistic regression analysis was carried out to identify independent variables predicting ICU mortality. Receiver operating curve (ROC) analysis was done to further assess the APACHE II score and T3 levels as predictors of mortality. A P < 0.05 was considered statistically significant.


   Results Top


Baseline characteristics

A total of 257 patients were included in the study, with female patients (52.1%) being marginally higher than males (47.9%). Th e age of patients ranged between 22 years to 93 years, with an average age of 66.99 ± 14.47 years. A large proportion of patients 152 (59.1%) were in the age group of 60–80 years. Among the 257 patients, 109 (42.41%) patients had low T3; 76 (29.57%) patients had low T4; 47 (18.28%) patients had high TSH. The median APACHE II score was significantly higher in males as compared to females [13 (9, 20) vs. 11(8, 17), P=0.017]. Infections (52.5%) followed by cardiovascular diseases (28.4%) were the most frequent cause for admission into the ICU [Supplementary Figure 1]. Among infections, respiratory tract infection and its complications (34.63%) were the most common. Some patients had multiple diagnoses at admission.

The baseline clinical and laboratory characteristics of the patients are listed in [Table 1]. Out of the 257 patients, 210 (81.71%) survived, and 47 (18.28%) expired. The mean age of the survivors was 66.39 ± 14.10 years, and nonsurvivors had a mean age of 69.38 ± 15.92 years. The difference between the mean age of the two groups was not statistically significant. The median CCI was 4 (2,5). A statistically significant difference in T3 levels (0.93 ± 0.30 vs. 0.59 ± 0.28, P < 0.001), T4 levels (6.89 ± 1.84 vs. 5.49 ± 2.16 < 0.001), median APACHE II score [11 (8, 15) vs. 21 (16, 29), P < 0.001], and median CCI [3 (2, 5) vs. 4 (3, 7) P = 0.006] was observed between the survivors and the nonsurvivors.
Table 1: Baseline characteristics and their association with outcome

Click here to view


Correlation of thyroid profile with acute physiology and chronic health evaluation II score

To identify predictors of mortality, Spearman's rank-order correlation analysis was done between the associated variables (T3, T4, APACHE II score). There was moderate, negative correlation found between T3 and APACHE II score (r = −0.448, P < 0.001), while a mild negative correlation between T4 and APACHE II score (r = −0.221, P < 0.001) was present. This indicates the presence of low T3 and low T4 are associated with increased severity of illness.

A univariate logistic regression analysis [Table 2] was performed to determine the predictors of ICU mortality. The logistic regression model was statistically significant χ2 (7) =102.616, P < 0.001. The model explained 53.6% (Nagelkerke R2) of the variance in ICU mortality and correctly classified 87.5% of cases. Among the thyroid hormones, only T3 was found to be a predictor for ICU mortality along with the APACHE II score. The logistic regression model, when adjusted for age, gender, and diabetes mellitus status of the patient, did not bring about significant changes in the results. A forward stepwise multivariate logistic regression analysis was performed with a criterion of 0.05 for entry and 0.10 for removal. It was observed that the probability of predicting ICU mortality by the APACHE II score increased with the addition of T3 (Cox and Snell R2 = 0.304, Nagelkerke R2 = 0.496) than by APACHE II Score alone (Cox and Snell R2 = 0.255, Nagelkerke R2 = 0.304).
Table 2: Univariate and multivariate logistic regression analysis for variables predicting intensive care unit mortality

Click here to view


To further assess T3 and APACHE II as predictors of mortality, the ROC curve was used [Figure 1]. Computation of the area under the ROC [Table 3] revealed that T3 levels (AUC: 0.811) are equally good predictors as compared to the APACHE II score (AUC: 0.858) for predicting mortality among critically ill patients. In conclusion, the APACHE II score and T3 level are predictive of mortality in patients.
Table 3: Receiver operating curve, area under the curve, sensitivity, and specificity for Acute Physiology and Chronic Health Evaluation II and total triiodothyronine

Click here to view
Figure 1: (a) Receiver operating curve for T3. (b) Receiver operating curve for acute physiology and chronic health evaluation II

Click here to view


Morbidity assessment

The duration of the ICU stay and the total duration of hospital stay was considered as indicators of morbidity for patients who survived and got discharged.On comparing patients in T3, T4, and TSH groups [Supplementary Table 1], the median (inter quartile range) duration of both ICU stay and hospital stay in patients with low T3 was significantly higher compared to that of patients with normal T3. Using the Kruskal–Wallis test, the association was found to be statistically significant (P < 0.001). However, there was no significant difference in the duration of ICU and hospital stay within the T4 and TSH groups.


   Discussion Top


The state of abnormal thyroid function seen in critical illness is known as NTIS. This alteration of the normal thyroid homeostasis in the critically ill occurs due to dysregulations in the hypothalamus-pituitary-thyroid axis and altered metabolism of thyroid hormones.[3] The changes seen in NTIS are dynamic. In the acute phase of critical illness, often, triiodothyronine (T3) levels are low with elevated rT3 and normal/low thyroxine (T4) and normal TSH. In prolonged critical illness; however, levels of TSH, T3, and T4 are all low.[4],[5],[6]

Considerable controversy exists on whether the thyroid hormone level alterations in NTIS are a physiological adaptation during illness to conserve energy, or whether they are maladaptive and require treatment.[6],[7] Clinical studies show conflicting results with both advocates for and against the treatment of NTIS with thyroid supplementation.[8],[9],[10],[11],[12],[13],[14],[15] At present, however, no evidence-based consensus or guideline advocates treatment of NTIS in the critically ill; treatment and management of underlying critical illness is the focus.

Some studies that were done among ICU patients, as well as subsets of critically ill patients with sepsis, acute coronary syndrome, neurological patients, multi-trauma patients, and surgical ICU patients, have shown that NTIS, particularly low levels of T3, correlate with disease severity and predict a poor prognosis.[2],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] Conversely, a few studies show no association between NTIS and prognosis.[27],[28],[29]

In our study of 257 patients, most patients were geriatric, with ages between 60-80 years (59.1%) and a mean age of 66.99 ± 14.47 years. This is consistent with other similar studies among adult ICU patients.[2],[16] The major cause of the critical illness was infectious diseases (52.52%), with respiratory tract infection and its complications being preponderant (34.63%). Cardiovascular diseases were found to be a major cause of critical illness leading to ICU admission in previous studies.[2],[16],[17] The mortality in our study group was 18.28%, and it was found to be significantly higher among males as compared to females (26.01% vs. 11.1%, P = 0.002), which can be attributed to the greater severity of illness noted in males as described by median APACHE II score [13 (9, 20) vs. 11 (8, 17), P = 0.017]. A statistically significant difference in T3 levels was found between the survivors and the nonsurvivors (P < 0.001). This association of low thyroid hormones with increased severity of illness and mortality was confirmed by a moderate negative correlation of T3 with the APACHE II score (r = −0.448, P < 0.001). A comparison of our study with other similar studies among patients admitted in ICU is shown in [Table 4].
Table 4: Comparison with similar studies

Click here to view


A significant association of low T3 with mortality was also seen in the other studies on general ICU patients.[2],[16],[17] However, conflicting results were observed in the association of low T4 and low TSH with mortality compared to our study. Whereas in our study, low T4 showed a similar association with mortality in the study by Erick Chinga-Alayo et al. and Harikumar et al., there was no significant difference in serum T4 levels between survivors and nonsurvivors.[2],[17] In the study by Feilong Wang et al., T3, T4, TSH, fT3, fT4, and APACHE II score were all found to be associated with mortality in ICU.[16] Of these, only fT3 and APACHE II scores were determined as independent predictors of mortality. In our study, we found the T3 and APACHE II score as independent predictors of mortality in ICU patients. Among the survived patients in this study, the patients with low T3 also had increased duration of ICU and hospital stay and higher APACHE II scores, indicating a possible association of NTIS with increased morbidity as well.

There is scarce published evidence available from the Indian subcontinent that assesses the prognostic value of total T3 among critically ill adult patients admitted to the medical ICU. A literature search among the studies in India showed only two such studies, both conducted in North India, with one large study of 270 patients and another of a smaller sample size of 100 patients.[2],[30] In the study by Gutch et al., the mean total T3 levels were found to be lower among survivors as compared to nonsurvivors (P = 0.007).[30] However, the fT3 and fT4 levels were lower in nonsurvivors as compared to survivors.

Our study has certain limitations. (1) Although we have excluded patients of known thyroid illness prior to admission from history and clinical examination, the inclusion of some patients with intrinsic thyroid illness cannot be ruled out as we did not follow-up the patients after discharge. (2) Although we excluded patients who were taking amiodarone and those treated with dopamine, many other drugs such as corticosteroids, propranolol, barbiturates, benzodiazepines, phenytoin, lithium, octreotide, and furosemide may have interfered with thyroid function tests. However, it is difficult to adjust for all these potential confounders in clinical practice because so many drugs are involved, and many of them essential for management in critical patients. (3) Other thyroid parameters such as fT3 and fT4, rT3 were not analyzed due to financial constraints.


   Conclusion Top


NTIS is common in patients with a critical illness. The presence of low T3 and low T4 are associated with increased severity of illness. Low T3 is a good independent predictor of mortality, almost comparable to APACHE II SCORE. The addition of T3 to the APACHE II score increased the predictability of the APACHE II score. In the developing countries, where financial constraints considerably influence management decisions, serum T3 can be utilized as a cheap and useful independent predictor of prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require the Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is 1212092-1. We also certify that we have not plagiarized the contents in this submission and have done a Plagiarism Check.



 
   References Top

1.
Frost P, Wise MP. Recognition and early management of the critically ill ward patient. Br J Hosp Med (Lond) 2007;68:M180-3.  Back to cited text no. 1
    
2.
Kumar KV, Kapoor U, Kalia R, Chandra NS, Singh P, Nangia R. Low triiodothyronine predicts mortality in critica lly ill patients. Indian J Endocrinol Metab 2013;17:285.  Back to cited text no. 2
    
3.
Mebis L, van den Berghe G. The hypothalamus-pituitary-thyroid axis in critical illness. Neth J Med 2009;67:332-40.  Back to cited text no. 3
    
4.
Van den Berghe G. Non-thyroidal illness in the ICU: A syndrome with different faces. Thyroid 2014;24:1456-65.  Back to cited text no. 4
    
5.
Chopra IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82:329-34.  Back to cited text no. 5
    
6.
Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Obes 2013;20:478-84.  Back to cited text no. 6
    
7.
Stathatos N, Levetan C, Burman KD, Wartofsky L. The controversy of the treatment of critically ill patients with thyroid hormone. Best Pract Res Clin Endocrinol Metab 2001;15:465-78.  Back to cited text no. 7
    
8.
Bennett-Guerrero E, Jimenez JL, White WD, D'Amico EB, Baldwin BI, Schwinn DA. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. JAMA 1996;275:687-92.  Back to cited text no. 8
    
9.
Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE. Tri-iodothyronine treatment in children after cardiac surgery: A double-blind, randomised, placebo-controlled study. Lancet 2000;356:529-34.  Back to cited text no. 9
    
10.
Malik FS, Mehra MR, Uber PA, Park MH, Scott RL, Van Meter CH. Intravenous thyroid hormone supplementation in heart failure with cardiogenic shock. J Card Fail 1999;5:31-7.  Back to cited text no. 10
    
11.
Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: A randomized, placebo-controlled study. J Clin Endocrinol Metab 2008;93:1351-8.  Back to cited text no. 11
    
12.
Acker CG, Flick R, Shapiro R, Scantlebury VP, Jordan ML, Vivas C, et al. Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am J Trans 2002;2:57-61.  Back to cited text no. 12
    
13.
Acker CG, Singh AR, Flick RP, Bernardini J, Greenberg A, Johnson JP. Trial of thyroxine in acute renal failure. Kidney Int 2000;57:293-8.  Back to cited text no. 13
    
14.
Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J ClinEndocrinol Metab 1986;63:1-8.  Back to cited text no. 14
    
15.
Kumar E, McCurdy MT, Koch CA, Hamadah A, Fülöp T, Gharaibeh KA. Impairment of thyroid function in critically Ill patients in the intensive care units. Am J Med Sci 2018;355:281-5.  Back to cited text no. 15
    
16.
Wang F, Pan W, Wang H, Wang S, Pan S, Ge J. Relationship between thyroid function and ICU mortality: A prospective observation study. Crit Care 2012;16:R11.  Back to cited text no. 16
    
17.
Chinga-Alayo E, Villena J, Evans AT, Zimic M. Thyroid hormone levels improve the prediction of mortality among patients admitted to the intensive care unit. Intensive Care Med 2005;31:1356-61.  Back to cited text no. 17
    
18.
Hosny M, Rashad R, Atef D, Abed N. Predictive value of thyroid hormone assessment in septic patients in comparison with C-reactive protein. Egypt J Crit Care Med 2015;3:55-61.  Back to cited text no. 18
    
19.
Padhi R, Kabi S, Panda BN, Jagati S. Prognostic significance of nonthyroidal illness syndrome in critically ill adult patients with sepsis. Int J Crit Illn Inj Sci 2018;8:165-72.  Back to cited text no. 19
[PUBMED]  [Full text]  
20.
Lamprou V, Varvarousis D, Polytarchou K, Varvarousi G, Xanthos T. The role of thyroid hormones in acute coronary syndromes: Prognostic value of alterations in thyroid hormones. Clin Cardiol 2017;40:528-33.  Back to cited text no. 20
    
21.
Brozaitiene J, Mickuviene N, Podlipskyte A, Burkauskas J, Bunevicius R. Relationship and prognostic importance of thyroid hormone and N-terminal pro-B-Type natriuretic peptide for patients after acute coronary syndromes: A longitudinal observational study. BMC Cardiovasc Disord 2016;16:45.  Back to cited text no. 21
    
22.
Jiang X, Xing H, Wu J, Du R, Liu H, Chen J, et al. Prognostic value of thyroid hormones in acute ischemic stroke-A meta analysis. Sci Rep 2017;7:16256.  Back to cited text no. 22
    
23.
Pande A, Goel VK, Rastogi A, Gupta A. Thyroid dysfunction in patients of ischemic cerebrovascular accidents. Thyroid Res Pract 2017;14:32-7.  Back to cited text no. 23
  [Full text]  
24.
Malekpour B, Mehrafshan A, Saki F, Malekmohammadi Z, Saki N. Effect of posttraumatic serum thyroid hormone levels on severity and mortality of patients with severe traumatic brain injury. Acta Med Iran 2012;50:113-6.  Back to cited text no. 24
    
25.
Bouras P, Rogdakis A, Giannakakis P, Damaskos D, Mavrodakou V, Tsalavoutas S, et al. Thyroid axis disturbances in adult multi-trauma patients without traumatic brain injury. Hell J Surg 2013;85:144-52.  Back to cited text no. 25
    
26.
Azhough R, Movassaghi R, Farbod A. Thyroid function as a predictive tool for the prognosis of traumatic patients admitted in surgery ICUs. Adv Biosci Clin Med 2017;5:14.  Back to cited text no. 26
    
27.
Ray DC, Drummond GB, Wilkinson E, Beckett GJ. Relationship of admission thyroid function tests to outcome in critical illness. Anaesthesia 1995;50:1022-5.  Back to cited text no. 27
    
28.
Quispe E Á, Li XM, Yi H. Comparison and relationship of thyroid hormones, IL-6, IL-10 and albumin as mortality predictors in case-mix critically ill patients. Cytokine 2016;81:94-100.  Back to cited text no. 28
    
29.
Meyer S, Schuetz P, Wieland M, Nusbaumer C, Mueller B, Christ-Crain M. Low triiodothyronine syndrome: A prognostic marker for outcome in sepsis? Endocrine 2011;39:167-74.  Back to cited text no. 29
    
30.
Gutch M, Kumar S, Gupta K. Prognostic value of thyroid profile in critical care condition. Indian J. Endocrinol. Metab 2018;22:387.  Back to cited text no. 30
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Methods
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed334    
    Printed10    
    Emailed0    
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal