Low T3 vs low T3T4 euthyroid sick syndrome in septic shock patients: A prospective observational cohort study

Abstract

BACKGROUND

Both phases of euthyroid sick syndrome (ESS) are associated with worse prognosis in septic shock patients. Although there are still no indications for supplementation therapy, there is no evidence that both phases (initial and prolonged) are adaptive or that only prolonged is maladaptive and requires supplementation.

AIM

To analyze clinical, hemodynamic and laboratory differences in two groups of septic shock patients with ESS.

METHODS

A total of 47 septic shock patients with ESS were divided according to values of their thyroid hormones into low T3 and low T3T4 groups. The analysis included demographic data, mortality scores, intensive care unit stay, mechanical ventilation length and 28-day survival and laboratory with hemodynamics.

RESULTS

The Simplified Acute Physiology Score II score (P = 0.029), dobutamine (P = 0.003) and epinephrine requirement (P = 0.000) and the incidence of renal failure and multiple organ failure (MOF) (P = 0.000) were significantly higher for the low T3T4. Hypoalbuminemia (P = 0.047), neutrophilia (P = 0.038), lymphopenia (P = 0.013) and lactatemia (P = 0.013) were more pronounced on T2 for the low T3T4 group compared to the low T3 group. Diastolic blood pressure at T0 (P = 0.017) and T1 (P = 0.007), as well as mean arterial pressure at T0 (P = 0.037) and T2 (P = 0.033) was higher for the low T3 group.

CONCLUSION

The low T3T4 population is associated with higher frequency of renal insufficiency and MOF, with worse laboratory and hemodynamic parameters. These findings suggest potentially maladaptive changes in the chronic phase of septic shock.

Key Words: Septic shock; Euthyroid sick syndrome; Low T3; Low T3T4; Intensive care unit

Core Tip: Euthyroid sick syndrome (ESS) is a significant clinical condition that greatly alters mortality in septic shock patients. Low values of T3 hormone levels have previously been associated with adaptation, while the condition with low T3 and T4 levels are still insufficiently known in terms of the impact on mortality and other pathophysiological mechanisms. This prospective study will give readers knowledge about the two types of ESS, and therefore new insight into hormonal disturbances in septic shock patients with possible thyroid hormone supplementation in the low T3T4 phase.

INTRODUCTION

A state of low T3 or low T3T4 hormones, also known as euthyroid sick syndrome (ESS), refers to characteristic changes in thyroid hormone levels that occur primarily in critically ill patients[1]. Mortality rates have been found to inversely correlate with serum T3 and T4 hormone levels, especially with a significant decrease in serum T4, where the probability of death reaches as high as 80%[2]. Significant abnormalities resulting from the development of ESS in a septic state include inhibition of thyrotropin-releasing hormone and thyroid-stimulating hormone (TSH) secretion, changes at the thyroid gland level, reduced binding of hormones to transport proteins, and changes in peripheral hormone metabolism[3]. Thyroid hormone changes in critically ill patients are time-dependent and occur in two phases: acute (likely adaptive) and chronic (most likely maladaptive). Initially, there is generally a fall in T3 levels, followed by a fall in T4 levels as critical illness progresses[4]. Carbohydrate deficiency in the initial phase inhibits the deiodination of T4 into T3, which inhibits T3 formation and increases reverse T3 levels. This process results in a decrease in T3 and an increase in reverse T3. Consequently, basal metabolism decreases with low T3 levels to conserve calories as a primary adaptive response[5]. Patients with only a low level of serum T3, a simpler form of ESS, do not exhibit clinical hypothyroidism. A decrease in serum T3 (without a corresponding decrease in T4) has no negative physiological effect associated with increased mortality. However, the prolonged phase is likely maladaptive owing to the unique circumstances of critical illness. This phase is characterized by the suppression of both thyroid and pituitary hormones[6]. As the severity of the disease progresses, a more complex syndrome associated with low T3 and low T4 gradually develops. Generally, TSH levels remain normal despite low serum hormone levels[7]. The main assumption is that ESS is a beneficial physiological response, particularly in the initial acute phase of critical illness; however, evidence supporting this view is still lacking[8]. Although there are still no indications for supplementation therapy, it is unclear whether both phases (initial and prolonged) are adaptive or if only the prolonged phase is maladaptive and requires supplementation.

The aim of this study was to analyze the differences in clinical, laboratory, and hemodynamic parameters between two groups of patients in septic shock with ESS: Those with low T3 and those with low T3T4.

MATERIALS AND METHODS

This prospective observational cohort study was conducted between October 2022 and August 2023 after receiving approval from the institutional ethics committee (No. 00-03-35-38-14/22) and obtaining written consent from patients or their families. The study is registered at ClinTrials.gov (NCT06242626). The inclusion criteria encompassed all septic shock patients with ESS who had no prior history of pituitary or thyroid disease. The exclusion criteria comprised individuals below 18 years of age, those with a history of thyroid disease or thyroid enlargement, pregnant women, and those who declined to participate in the study. The patients' progress throughout the study is shown in Figure 1.

Figure 1 Flow diagram of the study design. ICU: Intensive care unit; MV: Mechanical ventilation; SI: Shock index; VDI: Vasoactive drug-dependent index.

Patients and the study protocol

Upon admission to the intensive care unit (ICU), patients who met the criteria for septic shock according to the surviving sepsis campaign and ESS criteria were divided into groups 1 (low T3) and 2 (low T3T4).

Definitions

Septic shock is defined as a consequence of sepsis, characterized by hypotension requiring vasopressors to sustain a mean arterial pressure (MAP) of ≥ 65 mmHg after crystalloid resuscitation and lactate levels > 2 mmol/L[9].

ESS is an abnormality in thyroid hormone levels without a previous hypothalamic–pituitary and thyroid function disorder. The most frequent changes include low T3 followed by low T3 and T4 with normal TSH[10]. All patients enrolled in the study received treatment in accordance with the 2016 Sepsis Survival Campaign guidelines[9].

Data collection

Demographic data and mortality scores [Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Sequential Organ Failure Assessment scores] were collected upon admission to the ICU.

Laboratory parameters were assessed on the day of admission (T0), the first day (T1), and the third day (T2) of the ICU stay. These parameters encompassed a complete blood count, C-reactive protein, procalcitonin, differential blood count, acid–base status with lactates, albumin levels, and thyroid hormones: TSH, free triiodothyronine, and free thyroxine. Hemodynamic monitoring involved hourly measurements of arterial blood pressure [systolic, MAP, and diastolic (DBP)] and heart rate during the first 4 days. Vasoactive drug requirements were quantified using the vasoactive drug-dependent index (VDI) and the shock index (SI), calculated as follows:

VDI: [(Dobutamine dose × 1) + (Norepinephrine dose × 100) + (Vasopressin dose × 100) + (Epinephrine dose × 100)) / MAP;

SI: Heart rate/systolic blood pressure.

The need for mechanical ventilation was categorized as Yes or No, and the length of ICU stay was expressed in days. The 28-day survival outcome was classified as either transfer or death.

Statistical analysis

Data analysis was performed using the statistical package for the social sciences version 23.0 (IBM Corp., Armonk, NY, United States). The sample size was determined using a power analysis with 95% confidence intervals. Categorical variables were assessed using Pearson's χ² test and presented as frequency and relative percentage. Parametric variables were reported as mean and standard deviation or median and range, as appropriate. Between-group comparisons were performed using the Student's t-test or the Mann–Whitney U test. Statistical significance was defined as P < 0.05.

RESULTS

Demographic data, mortality scores, vasopressor requirement, and complications

There were no statistically significant differences between the groups in demographic data and BMI, as well as in the duration of mechanical ventilation, outcome, and ICU stay. However, the SAPS II score was significantly higher in the low T3T4 group compared to the low T3 group (P = 0.029) (Table 1). The need for dobutamine (P = 0.003) and epinephrine (P = 0.000) was significantly greater in the low T3T4 group. Additionally, the incidence of renal failure and multiple organ failure (MOF) was significantly higher in the low T3T4 group (P = 0.000), as shown in Table 2.

Table 1 Demographic parameters, mortality scores, mechanical ventilation and outcome.

Parameters		Group		P value
		Low T3	Low T3T4
Age in years		64.8 ± 9.7	62.1 ± 15.9	0.483
Sex	Male	12 (50)	10 (43.5)	0.765
	Female	12 (50)	13 (56.5)
BMI		25.8 ± 5.4	26.6 ± 5.4	0.712
APACHE II		18.8 ± 6.9	20.8 ± 7.7	0.398
SAPS II		52.5 ± 13.1	59.0 ± 15.5	0.046
SOFA		10.6 ± 2.8	10.6 ± 4.6	0.857
Outcome
	Discharge	16 (66.6)	11 (47.8)	0.125
	Death	8 (33.3)	12 (52.1)
ICU stay in days		13.6 ± 25.0	22.0 ± 21.0	0.837
MV in days		9.5 ± 3.1	15.4 ± 19.3	0.906

Student’s t-test and χ² test were used for the analysis, and P < 0.05 was considered statistically significant between the groups. Mean ± standard deviation (SD) and n (%) values are found in the article by Kovacevic et al[29]. APACHE II: Acute physiology and chronic health evaluation II; BMI: Body mass index; ICU: Intensive care unit; MV: Mechanical ventilation; SAPS II: Simplified acute physiology score II; SOFA: Sequential organ failure assessment.

Table 2 Vasopressor requirement and complications according to the groups.

Parameters		Group		P value
		Low T3	Low T3T4
Vasopressors, No/Yes (%)
	Norepinephrine	0/24 (0.0/100.0)	0/23 (0.0/100.0)	Constant
	Vasopressin	9/15 (37.2/62.5)	12/11 (54.2/45.8)	0.311
	Dobutamine	14/10 (58.3/41.7)	4/19 (17.4/82.6)	0.003
	Epinephrine	18/6 (75.0/25.0)	4/19 (17.4/82.6)	0.000
Complications, No/Yes (%)
	Pneumonia	19/5 (79.2/20.8)	16/7 (69.6/30.4)	0.450
	ARDS	16/8 (66.7/33.3)	15/8 (65.2/34.8)	0.916
	Renal failure	20/4 (83.3/16.7)	7/16 (30.4/69.6)	0.000
	Liver failure	18/6 (75.0/25.0)	20/3 (87.0/13.0)	0.297
	MOF	19/5 (79.2/20.8)	6/17 (26.1/73.9)	0.000

Student’s t-test and χ² test were used for the analysis, and P < 0.05 was considered statistically significant between the groups. No/Yes (%) values are found in the article by Kovacevic et al[29]. ARDS: Acute respiratory distress syndrome; MOF: Multiple organ failure.

Laboratory parameters

The incidence of hypoalbuminemia on T2 (P = 0.047) was higher in the low T3T4 group compared to the low T3 group (Table 3). Similarly, lactatemia (P = 0.013) was also elevated in the low T3T4 group. In contrast, neutrophilia (P = 0.038) and lymphopenia (P = 0.013) were more pronounced on T2 in the low T3 group compared to the low T3T4 group (Table 4). Additionally, the neutrophil-lymphocyte ratio score was significantly lower in the low T3 group compared to the low T3T4 group (P = 0.037) (Table 5).

Table 3 Blood count, thyroid hormones and albumin values according to the groups.

Parameter	Time	Group			P value
		Low T3	Low T3T4	95%CI
Leukocytes as × 109/L, median	T0	15.66	11.21	0.15 to 0.16	0.200
	T1	10.51	13.34	0.81 to 0.83	0.220
	T2	10.15	13.54	0.61 to 0.63	0.082
Erythrocytes as × 109/L, median	T0	4.21	4.01	0.46 to 0.48	0.231
	T1	3.96	3.81	0.61 to 0.63	0.216
	T2	3.78	2.85	0.53 to 0.51	0.335
Platelets as × 109/L, median	T0	227.00	147.00	0.08 to 0.10	0.206
	T1	209.00	142.00	0.24 to 0.26	0.180
	T2	180.00	180.50	0.36 to 0.38	0.160
TSH in mIU/L, median	T0	1.30	0.88	0.24 to 0.25	0.246
	T1	1.01	0.78	0.73 to 0.75	0.755
	T2	1.18	1.00	0.40 to 0.42	0.417
FT3 in pmol/L, median	T0	3.99	3.52	0.20 to 0.22	0.206
	T1	4.64	4.72	0.92 to 0.93	0.929
	T2	6.35	4.75	0.34 to 0.36	0.354
FT4 in pmol/L), median	T0	17.30	9.20	0.00 to 0.00	0.000
	T1	17.35	10.70	0.02 to 0.03	0.035
	T2	15.15	11.40	0.05 to 0.06	0.064
Albumin in g/L, mean ± SD	T0	27.29 ± 4.57	27.74 ± 4.64	-4.17 to 1.58	0.372
	T1	28.46 ± 3.29	27.39 ± 3.88	-4.40 to 0.15	0.131
	T2	29.75 ± 2.91	28.17 ± 6.41	-3.89 to -0.23	0.047

Student’s t-test and χ² test and Mann-Whitney U test were used for the analysis, and P < 0.05 was considered statistically significant between the groups. Median and mean ± standard deviation (SD) values are found in the article by Kovacevic et al[29]. CI: Confidence interval; FT3: Free triiodothyronine; FT4: Free thyroxine; T0: On the day of admission; T1: On the first day; T2: On the second day; TSH: Thyroid-stimulating hormone.

Table 4 Inflammatory parameters and blood gas analyzes.

Parameter	Time	Group			P value
		Low T3	Low T3T4	95%CI
Median
Neutrophils 1	T	0.88	0.86	0.29-0.31	0.300
	T1	0.88	0.85	0.19-0.21	0.391
	T2	0.86	0.82	0.03-0.04	0.038
Lymphocytes 1	T0	0.05	0.05	0.45-0.47	0.464
	T1	0.06	0.07	0.17-0.19	0.182
	T2	0.01	0.09	0.01-0.02	0.013
CRP in mg/dL	T0	89.00	106.00	0.92-0.93	0.923
	T1	145.50	153.00	0.54-0.56	0.559
	T2	119.00	77.60	0.08-0.09	0.436
PCT in ng/mL	T0	3.85	5.88	0.44-0.46	0.452
	T1	7.55	4.27	0.29-0.31	0.310
	T2	2.47	5.50	0.50-0.52	0.492
pH	T0	7.35	7.33	0.44-0.46	0.459
	T1	7.31	7.39	0.28-0.29	0.287
	T2	7.35	7.46	0.14-0.15	0.149
pCO2 in kPa	T0	5.52	5.06	0.18-0.19	0.198
	T1	5.19	5.59	0.30-0.32	0.318
	T2	5.82	5.10	0.85-0.86	0.864
pO2 in kPa	T0	11.73	12.10	0.44-0.46	0.448
	T1	10.39	13.59	0.82-0.84	0.829
	T2	9.59	12.10	0.92-0.93	0.929
HCO3 in mmol/L	T0	21.45	21.00	0.43-0.45	0.439
	T1	20.70	23.25	0.65-0.67	0.663
	T2	22.70	23.70	0.41-0.43	0.413
Lactate in mmol/L	T0	3.70	2.50	0.40-0.41	0.409
	T1	2.50	1.85	0.14-0.16	0.146
	T2	2.00	2.55	0.01-0.02	0.013

Mann-Whitney U tests were used for the analysis, P < 0.05 was considered statistically significant between the groups. Median values are found in the article by Kovacevic et al[29]. CI: Confidence interval; CRP: C-reactive protein; HCO₃: Bicarbonate; pCO₂: Partial pressure of carbon dioxide; pO₂: Partial pressure of oxygen; PCT: Procalcitonin; T0: On the day of admission; T1: On the first day; T2: On the second day.

Table 5 Vasoactive drug-dependent index, shock index and inflammatory prognostic scores.

Parameter	Time	Group			P value
		Low T3	Low T3T4	95%CI
VDI	T0	0.11	0.13	0.65-0.67	0.655
	T1	0.03	0.06	0.41-0.43	0.419
	T2	0.00	0.00	0.93-0.94	0.934
SI	T0	1.21	0.00	0.31-0.33	0.322
	T1	0.75	0.86	9.14-0.15	0.148
	T2	0.70	0.79	0.32-0.34	0.329
NLR	T0	15.00	12.00	0.29-0.31	0.298
	T1	15.00	13.00	0.21-0.23	0.218
	T2	12.00	7.00	0.03-0.04	0.037
PLR	T0	30.55	21.09	0.26-0.28	0.550
	T1	30.26	20.20	0.17-0.18	0.483
	T2	23.40	20.00	0.50-0.52	0.496
PI	T0	42.52	60.78	0.20-0.22	0.206
	T1	69.14	55.71	0.21-0.23	0.225
	T2	82.10	29.98	0.05-0.06	0.129

Mann-Whitney U test, Student’s t-test and χ² test were used for the analysis, P < 0.05 was considered statistically significant between the groups. Median values are found in the article by Kovacevic et al[29]. CI: Confidence interval; NLR: Neutrophil-lymphocyte ratio; PI: Prognostic index; PLR: Platelets-lymphocyte ratio; SI: Shock index; T0: On the day of admission; T1: On the first day; T2: On the second day; VDI: Vasoactive drug-dependent index.

Hemodynamic

DBP was significantly higher in the low T3 group compared to the low T3T4 group at T0 (P = 0.017) and T1 (P = 0.007). Similarly, MAP was higher in the low T3 group at T0 (P = 0.037) and T2 (P = 0.033) compared to the low T3T4 group (Figure 2). Heart rate values were significantly higher in the low T3T4 group compared to the low T3 group (P = 0.029) (Figure 3).

Figure 2 Systolic blood pressure, diastolic blood pressure and mean arterial blood pressure values according to groups. DBP: Diastolic blood pressure; MAP: Mean arterial blood pressure; SBP: Systolic blood pressure; T0: On the day of admission; T1: On the first day; T2: On the second day.

Figure 3 Heart rate values according to the groups. T0: On the day of admission; T1: On the first day; T2: On the second day.

DISCUSSION

In this prospective observational cohort study, we examined clinical, laboratory, and hemodynamic parameters in two groups of patients with ESS in septic shock. Our analysis included demographic data, mortality scores, length of ICU stay, and laboratory data with hemodynamics. The findings revealed a higher incidence of renal failure and MOF, along with more pronounced neutrophilia, lymphopenia, and hypoalbuminemia, alongside worse hemodynamics in the low T3T4 group. Previous studies have established an association between low thyroid hormones and mortality, yet the exact difference between low T3 and low T3T4 ESS remains uncertain. Earlier studies assumed that low T3 was an adaptive phenomenon. Low T3T4 ESS remains a subject of debate, particularly owing to the absence of an adaptive state in low T3T4, especially given higher concentrations of thyroid hormone receptors in patients with prolonged disease[11]. Therefore, low T3T4 could indicate the deteriorating process with significant changes in the pituitary–thyroid gland axis in septic shock, potentially requiring hormone supplementation. Our findings agree with other studies[12], which partially suggest that a prolonged phase of ESS characterized by low T3T4 challenges the commonly accepted notion of preservation associated with reduced thyroid hormone metabolism. Regarding demographic data, there is no evidence demonstrating an association of the epidemiological profile, except age, with a higher risk of developing ESS and, consequently, a higher mortality rate[13]. Previous studies have concluded that more significant fatal outcomes were observed in patients with lower levels of T3 and T4[14,15]. Our results also revealed higher values of the SAPS II score in the group with low T3T4, while the APACHE II score was more significant in the study by Praveen et al[16] in patients with ESS. In contrast to the findings of Ning et al[17] where mortality was higher in the low T3T4 group compared to the low T3 group, our results showed no difference in mortality between the groups. However, there was a significant difference in the incidence of renal failure and MOF and the requirement for vasoactive agents. In cases of low T4, successful effects of thyroid supplementation have been observed, as evidenced by a reduced need for vasopressors and successful weaning from mechanical ventilation[18]. Thyroid hormone replacement therapy did not show any benefit on neuromechanical efficiency in patients with low T3 ESS[19]. During critical illness with low T3, hypoalbuminemia arises from reduced albumin production and affinity for T3, while in the prolonged phase with low T3 and T4, it is primarily due to disrupted TSH pulsation[20]. Additionally, within the first 72 h after admission to the ICU with ESS, the phagocytic capacity of neutrophils decreases, influenced by the duration of critical illness[21]. The more pronounced neutrophilia and lymphopenia observed in the group with prolonged-stage disease or low T3T4 may indicate potential immune system depletion or bone marrow depression. This notion is supported by our observation of the increased lactatemia in the same patient group. The literature lacks data on differences in hemodynamic parameters between the two groups of septic shock patients with ESS: Low T3 and low T3T4. Most studies have primarily analyzed the effects of thyroid hormone replacement therapy in non-septic conditions[22-24]. Administration of triiodothyronine to animal models with septic shock resulted in supranormal hormone concentrations without significant hemodynamic effects or reduction in vasoactive drug requirement[25]. In relation to these findings, the preventive use of thyroid hormone in children undergoing cardiac surgery has been shown to reduce the severity of postoperative ESS and provide protection against myocardial reperfusion injury by increasing the expression of heat shock protein 70[26]. Septic shock frequently culminates in MOF owing to microvascular disruption and prolonged hypoxia, characterized by low T3T4 levels. Prolonged microvascular disorders stem from disturbances in angiogenesis attributed to prolonged low levels of thyroid hormones[27]. This assertion is supported by pretreatment with thyroid hormones, wherein pretreatment with T4 suppresses ischemia-reperfusion-induced activation and regulates heat shock proteins 27 and 70, which are involved in the fundamental mechanisms of ischemia[28]. Likewise, the acute administration of T3 during reperfusion enhances postischemic recovery of the myocardium by inhibiting the activation of mitogen-activated protein kinases. These findings indicate that the changes observed in the prolonged phase of the disease could potentially exert adverse effects on modulating microcirculatory events in conditions of prolonged septic shock, thereby requiring supplementation.

There are several limitations to this study. The most significant limitation is that we analyzed a small group of patients, and the analysis of certain data should have been extended, such as longer monitoring of laboratory data and hemodynamics. Additionally, patients with septic shock of various origins were included in the analysis, which may impact the generalizability of the findings. Future studies should focus solely on specific origins of septic shock (such as pneumonia or abdominal infection), considering the variations in therapy strategies, severity, and causative agents of infection.

CONCLUSION

ESS is prevalent in a significant proportion of critically ill patients, including those with septic shock. Higher neutrophilia, lymphopenia, and hypoalbuminemia, along with lower values of DBP and MAP and a higher heart rate, are more pronounced in the prolonged phase (low T3T4) compared to the initial phase (low T3) of septic shock. Therefore, the assessment of ESS should not be overlooked because our findings suggest a potentially maladaptive effect in the prolonged phase. However, further research involving a larger patient cohort is necessary to gain clearer insights into the overall outcomes in these patients.