We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for articles published in English from inception to March 6, 2014, with the search terms “critically ill patients”, “intensive care”, or “sepsis” in combination with “thyroid dysfunction”, “euthyroid sick syndrome”, or “thyroid hormones”. References chosen were selected on the basis of their title.
SeriesThyroid function in critically ill patients
Introduction
The hypothalamic–pituitary–thyroid (HPT) axis is controlled by a classic endocrine feedback loop. Thyrotropin-releasing hormone (TRH) is released at the level of the hypothalamus, which stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). In turn, TSH drives the thyroid gland to release thyroid hormones. The prohormone thyroxine (T4) is converted in peripheral tissues to the active hormone tri-iodothyronine (T3). Hypothalamic TRH neurons were identified as determinants of thyroid hormone setpoint regulation more than three decades ago, and this discovery was followed by thyroid hormone receptor (TR) β being shown to have a key role in thyroid hormone negative feedback at the level of both the hypothalamus and anterior pituitary. Thus, the HPT axis was assumed to have a fixed setpoint, aiming at individually determined serum concentrations of thyroid hormones.1 However, studies2 have shown that these serum concentrations can be variable and adaptive in response to environmental factors, including nutrient availability and inflammatory stimuli.
Substantial changes in plasma concentrations of thyroid hormones have been noted in a range of diseases, characterised by clearly decreased plasma T3, low plasma T4, and increased plasma reverse T3 (rT3) concentrations. Despite low T3 and T4, TSH is typically maintained within its normal range or is slightly decreased. This ensemble of changes in thyroid function tests is collectively known as the non-thyroidal illness syndrome (NTIS).3 In this Series paper we focus on the presentation, pathogenesis, metabolic consequences, and clinical management of thyroid dysfunction in critically ill patients. The distinction between NTIS and primary thyroid disorders in patients in the intensive care unit (ICU) can sometimes be difficult, which will also be briefly discussed.
Section snippets
Non-thyroidal illness
In both human beings and rodents, illness decreases serum concentrations of thyroid hormones without a concomitant rise in serum TSH. This effect represents a deviation from normal negative feedback regulation in the HPT axis. If a similar drop in serum T3 and T4 happened in the context of primary hypothyroidism, serum TSH would be substantially increased and the patient would need thyroid hormone replacement therapy. The combination of low serum T3 and serum TSH within the reference range in
HPT axis feedback regulation and local thyroid hormone metabolism
Severe illness induces large changes in thyroid hormone economy, resulting in a downregulation of the HPT axis both at the hypothalamic and pituitary levels with an associated decrease in circulating thyroid hormone concentrations.3 This finding points to substantial changes to the negative feedback regulation in the HPT axis during NTIS.2 In people, central downregulation of the HPT axis during NTIS was supported by the observation in autopsy samples of decreased TRH gene expression in the
Diagnosis and management of severe primary thyroid disorders in patients in the ICU
The high prevalence of NTIS in patients in the ICU and the extent of HPT axis changes in these patients can make it difficult to distinguish NTIS from untreated primary hypothyroidism. Levothyroxine treatment should be continued during a patient's stay in the ICU in those who are known to have hypothyroidism. Although this practice seems trivial, prescription and continuation of chronic treatment is not always a main focus of care in the ICU setting. Findings from a retrospective chart review
Treatment and management of NTIS
Whether interventions aimed at normalising thyroid hormone concentrations in patients with extended critical illness are beneficial has so far not been satisfactorily answered. The table contains clinical studies reporting interventions in patients with NTIS. Only a few, rather small, RTCs have assessed the effects of treatment with thyroid hormones in patients with NTIS. These trials report results obtained in a large range of patient groups—eg, patients with acute renal failure,29 burn injury,
Conclusions
From a classic perspective, NTIS is a syndrome that occurs during various illnesses and is identified by decreased plasma concentrations of thyroid hormones with unclear resulting effects. Recent studies have shown that the changes in thyroid economy during NTIS suggest substantial and complex changes at the level of the HPT axis, in terms of setpoint regulation, and at the organ level, in terms of local metabolism of thyroid hormones (figure 5). Whether the noted changes in critically ill
Search strategy and selection criteria
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The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone
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Oral thyroid hormone pretreatment in left ventricular dysfunction
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Hypermetabolic low triiodothyronine syndrome of burn injury
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Effects of intravenous triiodothyronine during coronary artery bypass surgery
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Peri-operative oral triiodothyronine replacement therapy to prevent postoperative low triiodothyronine state following valvular heart surgery
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Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration
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