Reichlin and Protnay et al. had found that the thyroid hormone levels dropped in some critical patients without thyroid diseases back in the 1970s. Then, in 1982, Leonard Wartofsky and Bunnan from Washington Hospital proposed the concept of low T3 syndrome12. The low T3 syndrome is a disorder in thyroid hormone metabolism under various stress states, most commonly with the reduction in triiodothyronine as early as 24 hours after onset13. The primary mechanism behind the change is the inhibition of 5'-deiodinase. Usually, the free T4 level is among the normal range but could slightly exceed the limits. We observed a decline in T3 in our cohort at an average of 10 days after neurocritical events, and half of the subjects showed normal T4 levels. 5'-deiodinase activation induces the conversion of T4 into serum reverse triiodothyronine (rT3), which usually elevates in non-thyroid disease. However, many studies confirmed that the increase of rT3 could not accurately distinguish non-thyroid disease from hypothyroidism14.
The low T3 state was regarded as an independent predictor of mortalities in critical patients, especially for critical events and heart failure caused by any incidences15. Low T3 level, cardiac risk factors and mortality are strictly related16. The abnormal thyroid hormone levels were in companion with the failure of other systems or organs. According to a study on hormones in patients with end-stage renal disease undergoing hemodialysis, 44.3% of all 167 subjects had low T3 syndrome, which is also associated with mortalities of 6 months and 12 months (P = 0.007)5. The liver is involved in the conversion of tetraiodothyronine (T4) into triiodothyronine (T3), and patients with liver cirrhosis often had thyroid hormone abnormalities. A study demonstrated that nearly 67% of liver cirrhosis patients in intensive care units (ICU) had low T3 syndrome, and fT3 and fT4 levels may be used as predictors of mortality in such critical patients17. Wehmann et al. found that the incidence of low T3 syndrome in hematological malignancies was 54%18. Wawrzyńskaet al. tested thyroid hormone concentration in severe respiratory failure patients in ICU and found that low T3 syndrome seems to be related to the decrease of PO2. Dying patients can have the lowest total T3 level, while the increase of TT3 serum concentration closely correlates with the improvement of the clinical state of patients12. Low fT3 levels have been interpreted as a physiological response aimed to reduce energy expenditure and minimize protein catabolism. Therefore, low T3 syndrome can be usually found in patients with malnutrition, fasting, and energy restrictions. A survival analysis of 669 hemodialysis patients with low T3 syndrome showed that nutritional status might serve as a “bridge” between low T3 levels and mortality. They also reported that age, cholesterol, and serum albumin concentration could be related to the extent of T3 level decline in different patients19. Therefore, low fT3 levels might also be an indicator of disease progression.
Neuroendocrine dysfunction (NED) is widespread in neurocritical patients. It has been reported that at least one NED was found in 35–50% of individuals with severe traumatic brain injury7, 20, 21, and this may be related to the disorder of the hypothalamic-pituitary-target organ axis during acute progression. Stress is a defensive mechanism of the body to cope with the stressor to maintain the homeostasis. When under stress, the body's three major regulatory systems, i.e., the nervous system, the endocrine system and the immune system, are fully activated to protect the body by responding to internal and external stress. However, when the stress is prolonged or the homeostatic response is inadequate, this mechanism could lead to worse clinical conditions22. Thyroid hormones play an essential role in driving development and maintaining functions of the central nervous system (CNS)23, 24. The CNS could be impaired in thyroid disorders such as myxedema coma and thyrotoxic crisis. Therefore, alterations in thyroid hormone levels are often used as an explanation for some CNS dysfunctions25, 26. Low T3 syndrome also affects the prognosis of neurological diseases such as acute stroke1, brain tumor9, 28. However, the CNS, as a complex functional network, interplays with multiple organs. Especially in neurocritical patients, multi-organ dysfunctions are prevalent. However, there are few clinical reports on patients with multi-system and multi-organ dysfunctions in companion with severe low T3 states.
As the acute progression comes to an end, the thyroid hormone levels may return to normal29. Maybe it implies that additional thyroid hormone supplements could improve the prognosis of low T3 patients. In our study, we evaluated the effects of the oral administration of levothyroxine sodium on survival outcomes and neurological outcomes in neurocritical patients with low-T3 syndrome. So far, several clinical studies on thyroid hormone replacement therapy for critical patients have been launched, focusing on topics including cardiac surgery30 − 32, malnutrition33, 34, heart failure35, 36, acute renal failure37, premature infants with acute respiratory distress syndrome38. Unfortunately, most of them did not find any significant positive effects of HRT on prognosis, and no apparent harmful effects have been found either. Some small studies still demonstrate prospects for HRT, such as T3 supplementation in patients undergoing cardiac surgery, leading to less needs of inotropic support and better hemodynamic parameters39. There are scarcely any reports of thyroid hormone replacement therapy improving the prognosis of neurocritical patients with low T3 syndrome.
We divided 32 patients into 2 groups based on whether they received HRT (oral levothyroxine tablets, 100 µg). Then we performed Kaplan-Meier analysis and Cox regression analysis with 3 to 72 months follow-up and used mortality as indicators. From the results of Kaplan-Meier analysis, overall survival was significantly inferior in non-HRT patients than in HRT patients (P = 0.034, 16.445 vs. 47.470 months). The univariate regression analysis showed that the mortality risk in the non-HRT group was 3.322 times higher than the HRT group (P = 0.043, HR = 0.301 95%CI 0.094–0.964). We incorporated the clinically significant variables (age and GCS) into multivariate analysis and the results showed no statistical difference in mortality risk between HRT and non-HRT group (P = 0.087, HR = 0.340 95%CI 0.099–1.172). Although the P-value of the multivariate regression analysis was 0.087, we still obtained a low-risk ratio (0.340, HRT vs. non-HRT group). Thus, we believe that oral hormone supplementation played a decisive role in improving prognosis and survival.
We sought to find evidence supporting that oral hormone supplementation could improve neurological outcomes in neurocritical patients with low serum T3. Descriptive analysis of short and long-term GCS or GOS showed that HRT patients have superior long-term GCS and GOS than non-HRT (GCS: 9.33 ± 1.28 vs. 7.57 ± 1.49; GOS: 3.00 ± 0.41 vs. 2.43 ± 0.47). However, the t-test showed no significant difference in short or long-term improvement in neurological functions between the two groups. Thyroid hormones enhanced the biological response to catecholamines40, which played a vital role in maintaining the stability of vascular volume and the function of endothelial cells. The velocity of cerebral arterial blood flow is often positively correlated with thyroid hormone levels in vivo41. We believe that the normal thyroid hormone level is essential for maintaining craniocerebral hemodynamics stability. We observed an improvement of survival in patients who received hormone supplementation. Our study, however, did not obtain a positive result in neurological outcomes and that may result from the abysmal neurological prognosis in neurocritical patients. Besides, neurological assessments that are more precise than GCS or GOS could help achieve a more accurate result.
In our study, it seems that the oral hormone supplementation did not rapidly restore fT3 levels to a normal range. Among 15 patients who were re-tested for thyroid function in the HRT group, 5 (33.3%) had been corrected, and the other 10 (66.7%) had not. In spite of the result, we still believe that hormone supplementation makes its contribution to correcting the low T3 state. A prospective study treated patients with low T3 syndrome and ischemic or non-ischemic dilated cardiomyopathy with intravenous infusion of synthetic l-T3 for 3 days (initial dose: 20 µg/m2/d) and found a rapid increase in free T3 level as well as a significant improvement in neuroendocrine profile and ventricular performance36. Therefore, proper hormone administration and dosage and a dynamic fT3 concentration monitoring were considered beneficial for the correction of low serum T3 in critical patients. Indeed, for critical patients, or more specifically, neurocritical patients, the exact relationship between the improvement of prognosis and complete correction of low T3 states requires more research and more support from evidence-based medicine.