Septic Shock: European View
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With increasing severity of illness, low total and free T 4 , and sometimes low TSH, can be observed 6. Decrease in plasma T 4 -binding globulin TBG or transthyretin as well as accumulation of substances that lower the plasma thyroid hormone-binding capacity appear also to be important for the above-mentioned alterations in thyroid hormone levels during critical illness 4.
For the vast majority of patients, thyroid function abnormalities observed during critical illness are transient and do not represent an underlying thyroid disease 7. Still, certain data suggest that the magnitude of thyroid hormone alterations in patients admitted to the intensive care unit ICU due to various causes is associated adversely with the patient outcome 8 , 9 , 10 , In this review, we sought to evaluate systematically the association between baseline thyroid function and the outcome of patients with, specifically, sepsis or septic shock.
The bibliographies of relevant articles were also hand searched. We performed an updated PubMed search on October 1, We selected for inclusion in our review, case—control or cohort studies either prospective or retrospective or clinical trials that provided data on the association between thyroid hormones at baseline and the outcome of patients of any age with sepsis or septic shock. We considered baseline thyroid function tests as those referring to the time of diagnosis of sepsis or the time of admission in the ICU.
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Data extracted from each of the included studies were those referring to the study design, the characteristics of the study population and the subgroups of patients compared, the baseline values of thyroid hormones, and their statistical association with the patient outcome through univariate or multivariate analysis, where reported. We also extracted data on the correlation of the thyroid hormones at baseline with sepsis prognostic scores.
From the literature searches that we performed in PubMed, we retrieved a total of articles. After first screening, based on the title and the abstract, we selected articles for further detailed evaluation, after which, we identified nine studies as eligible for inclusion in this review 12 , 13 , 14 , 15 , 16 , 17 , 18 , The process of selecting articles for inclusion in this review is depicted graphically in Fig.
Figure 1 Download Figure Download figure as PowerPoint slide Flow diagram of the detailed process of the selection of articles for inclusion in our review.
Citation: European Journal of Endocrinology , 2; All of the nine included studies had a prospective cohort design. Five of the studies involved children 1 , 13 , 14 , 15 , 17 , two additional studies involved exclusively neonates 12 , 16 , and the remaining two studies involved adults 18 , Mortality was the outcome evaluated in eight of the studies 1 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , while in the remaining study, the outcome evaluated was the length of stay in the pediatric ICU PICU In six of the included studies, it was specifically reported that the blood samples for thyroid hormone measurements were taken before administration of dopamine 1 , 12 , 13 , 14 , 15 , 16 , In Table 1 , we present data on the association between serum thyroid hormone levels at baseline and the outcome of patients with sepsis or septic shock.
Specifically, six of the nine studies included in this review showed, by univariate analysis, that among patients with sepsis or septic shock those with an unfavorable outcome had lower baseline serum levels of, either total or free, T 3 or T 4 , than those with a favorable outcome 12 , 13 , 14 , 15 , 16 , In two other studies that involved children and adults, who in both studies were admitted in the ICU due to septic shock, there was no difference in baseline T 3 or T 4 between non-survivors and survivors 1 , In the remaining study, which evaluated children with meningococcal sepsis admitted to the PICU, those who did not survive had higher baseline serum levels of T 3 than those who survived, while no difference was detected in the total and free T 4 levels In this study, non-survivors also had higher baseline levels of TSH.
Table 1 Association between baseline thyroid hormones and outcome of patients with sepsis or septic shock in different studies. Higher baseline TSH values in non-survivors were also observed in another study that evaluated children with septic shock admitted to the PICU. This study did not demonstrate differences in the levels of T 3 or T 4 between non-survivors and survivors 1.
On the contrary, lower baseline TSH was associated with higher mortality in a study that evaluated septic neonates admitted in the ICU 12 ; this was also accompanied with lower T 3 and T 4. The baseline TSH levels in the remaining six studies did not differ between patients with an unfavorable outcome compared with those with a favorable outcome.
Three of the included studies further evaluated the above-described associations in multivariate analysis. One of these studies showed that in pediatric patients who survived meningococcal septic shock, lower baseline serum T 4 was an independent predictor of an unfavorable outcome, specifically prolonged ICU stay The baseline interleukin 6 IL6 level was also independently associated with this outcome. The second study that included pediatric ICU patients with meningococcal sepsis or septic shock showed that the effect of the thyroid function tests on mortality lost significance in the multivariate analysis, and that IL6 was the only independent predictor of this outcome In the remaining study, which was performed on newborns admitted to the ICU with bacterial sepsis, the presence of euthyroid sick syndrome was independently associated with mortality In Table 2 , we present data on the correlation of thyroid function tests at baseline with various sepsis prognostic scores.
Such associations were reported in three of the nine included studies, which all evaluated children with meningococcal sepsis or septic shock admitted to the PICU 13 , 14 , In one of these studies, both the pediatric risk of mortality PRISM score and the sequential organ failure assessment score had a moderate negative correlation with the baseline T 4 value In the remaining study, no significant relevant associations were observed Table 2 Correlation between baseline thyroid hormones and sepsis prognostic scores in patients with sepsis or septic shock included in different studies.
The majority six out of nine of the evaluated relevant studies showed that lower baseline thyroid hormone values, either T 3 or T 4 , are associated with worse outcome for patients with sepsis or septic shock. The above observations apply mainly to children rather than to adults, as the latter group was evaluated in only two of the included studies. Still, definite conclusions on the above issue cannot be drawn on the basis of the data available herein, as the associations observed were not always consistent between the included studies, or within each study with regard to different thyroid function tests evaluated.
Moreover, the association of thyroid hormones at baseline and the outcome of patients with sepsis or septic shock was not commonly evaluated in appropriate multivariate models to adjust for the effect of potential confounders.
It is interesting that one of the included studies showed that, among the 26 children with meningococcal sepsis studied, the 18 who survived had lower T 3 levels at PICU admission than the 8 who did not survive This finding stands in contrast to the rest of the included studies, which either showed the opposite or no relevant association.
One potential explanation for the discordant findings of the study in this regard is that ten of the survivors received treatment with dopamine, whereas the non-survivors received norepinephrine or dobutamine. Dopamine can suppress the pituitary release of TSH and thus potentially the production of T 3 20 , while norepinephrine is believed to stimulate the secretion of TSH Notably, the non-survivors in this study also had higher TSH levels Yet, it was not specifically stated whether dopamine administration preceded the collection of blood samples for the thyroid hormone measurements.
Introduction
However, in the great majority of the remaining studies, thyroid hormone measurements were performed prior to dopamine use 1 , 12 , 13 , 14 , 15 , In addition, in the study, in which higher T 3 levels were observed in non-survivors of meningococcal septic shock, the age of the non-survivors was significantly lower than that of the survivors 10 vs 29 months respectively The changes that occur in thyroid hormone levels during the first month of life could, at least in part, account for the differences in the T 3 levels observed in this study.
Specifically in neonates, the plasma thyroid hormone levels are typically elevated compared with those in older children This is related to the TSH surge that occurs in the immediate postnatal period and to the elevated TBG levels secondary to maternal estrogen In normal term neonates, the total and free T 4 levels fall gradually over the next 4—6 weeks but remain higher than in older children and adults for a few months.
The T 3 levels gradually reach those of infancy, between 2 and 12 weeks of life 22 , In early neonatal life, there has also been observed an increased activity of type III deiodinase D3 enzyme with secondary increase in rT 3 levels and increase in the degradation of T 3 to T 2 , which reaches the adult range during the fourth postnatal month 22 , It is questionable whether the findings of our review can be applicable to adult patients with sepsis or septic shock, who were evaluated in only two of the included studies.