Neonatal sepsis is a common disease affecting several tissues through pro- and anti-inflammatory responses in the organism [1]. It is characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. The incidence of neonatal sepsis in the developing world is 10-30% and mortality is around 19% [2]. Neonates with sepsis may present in or progress to septic shock. Initially, it is characterized by cardiovascular dysfunction which eventually requires inotropic support [3]. Septic shock is a clinical syndrome with suspected infection with signs of decreased perfusion including patients with decreased mental status, prolonged capillary refill time >3 sec or flash capillary refill, diminished or bounding peripheral pulses, mottled, cool extremities, and decreased urine output of <1 mL/kg/h) in neonatal age [4-6].

Many neuroendocrine changes take place in our body during critical illness and one of these is the alteration of thyroid hormone activity during sepsis or septic shock. They help in the adaptation of metabolic function to stress and regulation of metabolic homeostasis. It has been hypothesized that the immune system cells can affect systemic thyroid hormone activity. This activity may be attributed to the complex pathophysiological interplay between Thyroid Stimulating Hormone (TSH) and the immune system [7,8]. A few previous literature have found the correlation between thyroid profile and septic shock among neonates [9,10].

Lodha R et al demonstrated that children with septic shock had a lower level of free triiodothyronine (fT3), triiodothyronine (T3), Thyroxine (T4), free Thyroxine (fT4), and TSH compared to those with sepsis [9]. Dutta S. et al. showed that low levels of T3, T4, and TSH are associated with fluid-resistant hypotensive shock among septic preterm neonates [10].

Since the majority of the previous studies related to septic shock deal with T3 or T4 hormone assay only and were conducted on a small sample size [9,10], there is a paucity of studies that have included all of TSH, T3, T4, fT3, and fT4 and correlated them to septic shock. Hence, the present study was conducted to evaluate the relationship between thyroid profile and septic shock in neonates and to compare the thyroid profile in survivor and non-survivor groups of septic shock.

The gestational age was assessed from the last menstrual period and the New Ballard Score. Neonates were also divided according to the presence of shock and the outcome. The demographic information and data on the use of vasoactive drugs, duration of shock, and blood investigation reports were also collected. Relevant investigations were sent for all the neonates including hemoglobin, TLC, ANC, CRP, blood culture, electrolytes, and random blood sugar. Other investigations like chest X-ray, lumbar puncture, urine routine and microscopy, urine for fungal hyphae, urine culture, and arterial blood gas analysis were done when required. In all the included neonates, the thyroid profile was done.

The blood samples collected in the test tube were centrifuged; serum thus obtained was used to estimate T3, T4, and TSH. They were estimated by the chemiluminescence method (using the Immulite1000 Immunoassay system-Siemens) [11]. Neonates who were found to be hypothyroid were excluded from the study and treated for hypothyroidism. Levels of T3, T4, TSH, fT3, and fT4 were compared in the newborn with septic shock with those without septic shock. They were also grouped and compared as survivors and non-survivors of septic shock. These levels were correlated with the requirement for vasoactive drugs and Vasoactive-Inotropic Score (VIS) was calculated, which is a useful surrogate outcome. We have divided neonatal septic shock cases into three groups based on the VIS. The first group includes<20 VIS, the second group between 20 to 50 VIS, and the third group was >50 VIS. All newborns were managed according to the standard treatment guidelines [1,12,13]. The approval was obtained from the institutional ethical committee of Gandhi Medical College, Bhopal, before the start of the study. After explaining the nature, procedure, and purpose of the study, written consent was obtained from the parents/ legal guardians of the neonates.

Statistical analysis

The data obtained was entered in the MS Excel spreadsheet. The results were expressed in mean ± standard deviation (SD) for continuous variables and as a percent (%) for categorical data. Observations were statistically analyzed using graph pad prism version 7.0. An independent sample t-test was used. The p-value of <0.05 was considered statistically significant. Microsoft Word and Excel were used to generate figures and tables.

The thyroid profile was performed in all 195 subjects. The mean value of TSH, T3, T4, fT3, and fT4 among neonates with septic shock were 5.27µg/ml, 59.47ng/dl, 5.16µg/dl, 1.21pg/ml, and 1.13µg/dl and in septic neonates without shock were 5.29 µg/ml, 136.10 ng/dl, 9.74 µg/dl, 2.59pg/ml, and 1.79 µg/dl respectively. A statistically significant (p<0.0001) difference was observed in the thyroid profile of the neonates with septic shock than those without septic shock except for TSH (p>0.05) (Table 2).

The mean value of TSH, T3, T4, fT3, and fT4 among septic shock survivors and non-survivors were 5.27 µg/ml,80.01 ng/dl, 6.36 µg/dl, 1.40 pg/ml, 1.40 µg/dl and 2.40 µg/ml, 37.33 ng/dl, 3.86 µg/dl, 0.99 pg/ml, and 0.84 µg/dl, respectively. We found a significantly low level of TSH, T3, T4, fT3, and fT4 in survivors as compared to non-survivors neonates (P<0.0001) (Table 3). In our study, only T3 was found to be significantly co-related with VIS in septic shock in all the groups (p<0.001). The maximum mean value of T3 was observed with VIS less than 20 while minimum T3 was observed with VIS more than 50 (Table 4).

Table 2: Comparing mean thyroid indices between Septic shock patients and patients with sepsis without shock

Table 3: Comparing mean thyroid indices between septic shock survivor patients and non-survivors

In normal fetuses, concentrations of TSH, thyroxine-binding globulin (TBG), and thyroid hormones increase progressively during intrauterine life. A surge in the serum TSH is seen at 30 minutes after delivery (up to 60-70 μU/L). Within 1-7 days of the newborn, the concentration of TSH reaches 1-39 µU/ml which dropped to 0.5-6.5 µU/ml between 8-28 days. In the first postnatal week, the T4 serum levels reach concentrations (9-22 µg/dl) that are higher than at any other time of life as between 8-28 days, the concentration dropped to 8.2-17 µg/dl. The levels of T3 are in the range of 36-316 ng/dl within a week of delivery which can rise to 105-346 ng/dl in between 8-28 days. In between 1-7 days of newborn, the concentration of FT3 and FT4 are 1.3-6.1 pg/ml and 2.2-5.3 ng/dL which reaches to 2.2-8 pg/ml and 0.9-2.3 ng/dL at 8-28 days of newborn respectively [11,17-19].

In the present study, a maximum number of cases belonged to the category of low birth babies i.e., 1.5-2.5 Kg (67.69%). The higher prevalence of low birth babies in the study group can be explained as low birth weight is a known risk factor for the development of sepsis and shock. We found an increased number of institutional deliveries (67%) of neonates which can be correlated with the increased awareness and better health transport facilities in the community. The percentages of Institutional deliveries and home deliveries in Madhya Pradesh as per the National Family Health Survey (NFHS-4) were 80.8 and 2.3% respectively [20]. which is almost similar to the findings of our study. Out of total cases, 42.56% were on EBF, while a higher number of cases (57.5%) were either on top feed or mixed feed which are known risk factors for the development of sepsis, whereas, in Madhya Pradesh as per the NFHS-4, 58.2% infants were on EBF [20].

We found that the mean levels of TSH, T3, T4, fT3, and fT4 were lower in septic shock patients than that of without septic shock and the difference was statistically significant except for TSH which is quite similar to the findings of a study done by Yildizdas D et al [21]. where they found that the levels of T3, T4, fT3, fT4 levels of children with septic shock were significantly lower than those of sepsis without shock and control. They also observed low levels of TSH in children with septic shock and children with sepsis without shock, but the difference was not significant [21]. Dutta S et al [10]. compared thyroid hormone levels between septicemic preterm neonates with shock and without shock.

VIS is independently associated with important clinically relevant outcomes including ICU length of stay, ventilator days, and cardiac arrest /mortality [9,25]. We have tried our best to depict the relationship between thyroid hormone with septic shock among full-term neonates but despite our efforts, several limitations are present in our study. Firstly, we have not investigated the maternal thyroid profile. The maternal thyroid status was assessed based on history and drug intake, so we couldn’t assess the exact maternal thyroid status. Lastly, a larger sample size and serial TSH monitoring are required to establish the clear prognostic significance of the thyroid profile.

Our study suggested a significant decrease in TSH, T3, T4, fT3, and fT4 levels in patients with septic shock as that of patients without septic shock. We also found that there is a significant decrease in thyroid profile among septic shock survivors as compared to the non-survivors and only T3 was found to be significantly co-related with VIS in septic shock among all the patients.

The findings of this study regarding the association between thyroid hormone abnormalities and the outcome of patients with septic shock indicated that these abnormalities could be of prognostic value.

SD: Acquisition and interpretation of data, data analysis, drafting the article, and literature review; SJ: Concept, interpretation of data and data analysis, drafting the article, and literature review; AA: Data analysis, manuscript review, manuscript editing, revising the article critically for important intellectual content; JS will act as guarantor. All the authors approved the final manuscript.