778 Current Drug Targets, 2009, 10, 778-787 1389-4501/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Treating Nonthyroidal Illness Syndrome in the Critically Ill Patient: Still a Matter of Controversy G. Bello * , G. Paliani, M.G. Annetta, A. Pontecorvi and M. Antonelli From the Department of Anesthesiology and Intensive Care (Drs. G. Bello, G. Paliani, M.G. Annetta, and M. Antonelli), and Institute of Endocrinology (Dr. A. Pontecorvi), Università Cattolica del Sacro Cuore, Policlinico Universitario A. Gemelli, Largo A. Gemelli, 8, 00168, Rome, Italy Abstract: The nonthyroidal illness syndrome (NTIS) is a clinical condition of abnormal thyroid function tests observed in patients with acute or chronic systemic illnesses. The laboratory parameters of NTIS usually include low serum levels of triiodothyronine, with normal or low levels of thyroxine and normal or low levels of thyroid-stimulating hormone. It is still a matter of controversy whether the NTIS represents a protective adaptation of the organism to a stressful event or a maladaptive response to illness that needs correction. Multiple studies have investigated the effect of thyroid hormone replacement therapy in certain clinical situations, such as caloric restriction, cardiac disease, acute renal failure, brain- dead potential donors, and burn patients. Treating patients with NTIS seems not to be harmful, but there is no persuasive evidence that it is beneficial. The administration of hypothalamic releasing factors in patients with NTIS appears to be safe and effective in improving metabolism and restoring the anterior pituitary pulsatile secretion in the chronic phase of critical illness. However, also this promising strategy needs to be explored further. Anyhow, an extremely prudent approach is needed if treatment is given. Much of the data appearing in the literature on the treatment of NTIS encourage further randomized controlled trials on large number of patients. At present, however, we believe that there is no indication for treating thyroid hormone abnormalities in critically ill patients until convincing proof of efficacy and safety is provided. Keywords: Critical illness; thyroid; triiodothyronine; hypothalamic hormones; intensive care units. INTRODUCTION Critical illness is defined as any life-threatening condition requiring the support of failing vital organ functions [1]. Critical illness induces multiple alterations in thyroid hormone profile in patients with no previously diagnosed intrinsic thyroid disease. Such alterations have been characterized as the the “euthyroid sick syndrome” [2- 4] and, more recently, the “nonthyroidal illness syndrome (NTIS)” [5]. The latter term will be used throughout this document. The laboratory parameters of NTIS usually include: low serum levels of triiodothyronine (T3) with normal or low levels of thyroxine (T4) and normal or low levels of thyroid- stimulating hormone (TSH) [1, 5]. Typical reference ranges for serum concentrations of thyroid hormones in normal adults are shown in Table 1. The NTIS is observed in about 70% of hospitalized patients with diseases of various etiologies [5-7]. The magnitude of either thyroid hormone decrease or TSH blunted response to thyrotropin-releasing hormone (TRH) during critical illness is proven to reflect the severity of illness and outcome [8-13]. The NTIS has been described in *Address correspondence to this author at the Istituto di Anestesiologia e Rianimazione, Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy; Tel.: +39-06- 30154386; Fax: +39-06-3013450; E-mail: gbello.gb@libero.it patients with a wide variety of clinical conditions, such as starvation [14], trauma [15], sepsis [16], myocardial infarction [17], cardiopulmonary bypass [18], and general surgery [19]. Many authors have considered the altered serum thyroid hormone levels in NTIS as a transient adaptive response of the organism to minimize metabolic demands during a stressful event. However, it is still a matter of controversy whether the NTIS represents a protective and appropriate adaptation to an acute insult or a maladaptive response to illness that needs correction [5, 20-22]. In the following sections, the pathophysiology of thyroid function and alterations occurring in critical illness will be firstly analysed. Then, the potential benefits and hazards of restoring the physiological serum thyroid hormone levels in critically ill patients will be discussed. Finally, the correlation between respiratory failure and the NTIS in patients undergoing mechanical ventilation will be reviewed. PATHOPHYSIOLOGY AND DIFFERENT STAGES OF THE NTIS The pathogenetic mechanisms that have been proposed to explain thyroid hormone abnormalities during critical illness include a decreased conversion of T4 to T3 in extrathyroidal tissues, and alterations in the binding of thyroid hormones to serum proteins [23, 24]. In the chronic phase of critical illness, also a decreased pulsatile frequency of TSH