Opposite Effect of Thyroid Hormones on Oxidative Stress and on Mitochondrial Respiration in COVID-19 Patients.

BACKGROUND: Thyroid hormones (TH)s are master regulators of mitochondrial activity and biogenesis. Nonthyroidal illness syndrome (NTIS) is generally considered an adaptative response to reduced energy that is secondary to critical illness, including COVID-19. COVID-19 has been associated with profound changes in the cell energy metabolism, especially in the cells of the immune system, with a central role played by the mitochondria, considered the power units of every cell. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects and alters mitochondrial functions, both to influence its intracellular survival and to evade host immunity. AIM OF THE STUDY: This study was undertaken to analyze the oxidative balance and mitochondrial respiration in COVID-19 patients with and without NTIS to elucidate the role that thyroid hormones (TH)s play in this context. METHODS: In our cohort of 54 COVID-19 patients, admitted to our University Hospital during the COVID-19 pandemic, we evaluated the generation of reactive oxygen species (ROS) by measuring the serum levels of derivatives of reactive oxygen metabolites (dROMs), and we analyzed the antioxidant capacity by measuring the serum biological antioxidant potential (BAP). We then analyzed the mitochondrial respiration in peripheral blood mononuclear cells (PBMC)s of 28 of our COVID-19 patients, using the seahorse instrument (Agilent). Results were correlated with the serum levels of THs and, in particular, of FT3. In addition, the role of T3 on bioelectrical impedance analysis (BIA) and mitochondrial respiration parameters was directly evaluated in two COVID-19 patients with NTIS, in which treatment with synthetic liothyronine (LT3) was given both in vivo and in vitro. RESULTS: In our COVID-19 patients with NTIS, the dROMs values were significantly lower and the BAP values were significantly higher. Consequently, the oxidative stress index (OSi), measured as BAP/dROMs ratio was reduced compared to that observed in COVID-19 patients without NTIS, indicating a protective role exerted by NTIS on oxidative stress. In our COVID-19 patients, the mitochondrial respiration, measured in PBMCs, was reduced compared to healthy controls. Those with NTIS showed a reduced maximal respiratory capacity and a reduced proton leak, compared to those with normal FT3 serum values. Such lowered mitochondrial respiratory capacity makes the cells more vulnerable to bioenergetic exhaustion. In a pilot study involving two COVID-19 patients with NTIS, we could reinforce our previous observation regarding the role of T3 in the maintenance of adequate peripheral hydroelectrolytic balance. In addition, in these two patients, we demonstrated that by treating their PBMCs with LT3, both in vitro and in vivo, all mitochondrial respiration parameters significantly increased. CONCLUSIONS: Our results regarding the reduction in the serum levels of the reactive oxygen species (ROS) of COVID-19 patients with NTIS support the hypothesis that NTIS could represent an adaptative response to severe COVID-19. However, beside this beneficial effect, we demonstrate that, in the presence of an acute reduction of FT3 serum levels, the mitochondrial respiration is greatly impaired, with a consequent establishment of a hypoenergetic state of the immune cells that may hamper their capacity to react to massive viral infection.

Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium.

BACKGROUND: Nonthyroidal Illness Syndrome (NTIS) can be detected in many critical illnesses. Recently, we demonstrated that this condition is frequently observed in COVID-19 patients too and it is correlated with the severity the disease. However, the exact mechanism through which thyroid hormones influence the course of COVID-19, as well as that of many other critical illnesses, is not clear yet and treatment with T4, T3 or a combination of both is still controversial. Aim of this study was to analyze body composition in COVID-19 patients in search of possible correlation with the thyroid function. METHODS AND FINDINGS: We report here our experience performed in 74 critically ill COVID-19 patients hospitalized in the intensive care unit (ICU) of our University Hospital in Rome. In these patients, we evaluated the thyroid hormone function and body composition by Bioelectrical Impedance Analysis (BIA) during the acute phase of the disease at admission in the ICU. To examine the effects of thyroid function on BIA parameters we analyzed also 96 outpatients, affected by thyroid diseases in different functional conditions. We demonstrated that COVID-19 patients with low FT3 serum values exhibited increased values of the Total Body Water/Free Fat Mass (TBW/FFM) ratio. Patients with the lowest FT3 serum values had also the highest level of TBW/FFM ratio. This ratio is an indicator of the fraction of FFM as water and represents one of the best-known body-composition constants in mammals. We found an inverse correlation between FT3 serum values and this constant. Reduced FT3 serum values in COVID-19 patients were correlated with the increase in the total body water (TBW), the extracellular water (ECW) and the sodium/potassium exchangeable ratio (Nae:Ke), and with the reduction of the intracellular water (ICW). No specific correlation was observed in thyroid patients at different functional conditions between any BIA parameters and FT3 serum values, except for the patient with myxedema, that showed a picture similar to that seen in COVID-19 patients with NTIS. Since the Na+/K+ pump is a well-known T3 target, we measured the mRNA expression levels of the two genes coding for the two major isoforms of this pump. We demonstrated that COVID-19 patients with NTIS had lower levels of mRNA of both genes in the peripheral blood mononuclear cells (PBMC)s obtained from our patients during the acute phase of the disease. In addition, we retrieved data from transcriptome analysis, performed on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)s treated with T3 and we demonstrated that in these cells T3 is able to stimulate the expression of these two genes in a dose-dependent manner. CONCLUSIONS: In conclusion, we demonstrated that measurement of BIA parameters is a useful method to analyze water and salt retention in COVID-19 patients hospitalized in ICU and, in particular, in those that develop NTIS. Our results indicate that NTIS has peculiar similarities with myxedema seen in severe hypothyroid patients, albeit it occurs more rapidly. The Na+/K+ pump is a possible target of T3 action, involved in the pathogenesis of the anasarcatic condition observed in our COVID-19 patients with NTIS. Finally, measurement of BIA parameters may represent good endpoints to evaluate the benefit of future clinical interventional trials, based on the administration of T3 in patients with NTIS.

Anesthetic Management of an Adult Patient With Down Syndrome for Thoracic Surgery.

The anesthetic management of adult patient with Down syndrome (DS) can be challenging due to poor patient cooperation, age-related comorbidities, and a possible difficult airway. Thoracic anesthesia requires an advanced airway management; thus, treatment of DS patients can be particularly demanding. An accurate preoperative assessment is paramount in order to plan a well-designed perioperative strategy in advance. This report describes the anesthetic management of an adult patient affected by DS who underwent pleural decortication for pleural empyema.

The impact of different gas mixtures on inflammatory responses in advanced recreational divers.

INTRODUCTION: Decompression sickness (DCS) is considered a 'bubble disease'. Intravascular bubbles activate inflammatory responses associated with endothelial dysfunction. Breathing gas has been proposed as a potential risk factor but this is inadequately studied. Different gases are used in scuba diving. Helium-containing 'trimix' could theoretically mitigate inflammation and therefore reduce DCS risk. This study determined the effect of air and trimix on the inflammatory response following dives to 50 metres of sea water, and evaluated the differences between them in advanced recreational divers. METHODS: Thirty-three divers were enrolled in this observational study and were divided in two groups: 17 subjects were included in the air group, and 16 different subjects were included in the trimix (21% oxygen, 35% helium, 44% nitrogen) group. Each subject conducted a single dive, and both groups used a similar diving profile of identical duration. A venous blood sample was taken 30 min before diving and 2 h after surfacing to evaluate changes in interleukins (IL) IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor α (TNFα), vascular endothelial growth factor (VEGF), Interferon γ (IFN-γ), monocyte chemoattractant protein 1 (MCP-1) and epithelial growth factor (EGF) after diving. RESULTS: No differences were observed between groups in demographic data or diving experience. Following the dive, IL-6 values showed a slight increase, while IL-8 and EGF decreased in both groups, without significant variation between the groups. CONCLUSIONS: In physically fit divers, trimix and air gas mixture during deep diving did not cause relevant changes in the inflammatory markers tested.

Opioid-free anesthesia versus opioid-inclusive anesthesia for breast cancer surgery: a retrospective study.

BACKGROUND: Breast cancer surgery is usually managed using opioid-inclusive anesthesia (OIA), although opioids are associated with several adverse events, including nausea, vomiting, and constipation. Multimodal opioid-free anesthesia (OFA) has been introduced to reduce the incidence of these side effects. In this single-center retrospective study, we investigated whether ketamine, combined with magnesium and clonidine, could effectively control postoperative pain in patients undergoing quadrantectomy, while reducing postoperative nausea and vomiting (PONV). RESULTS: A total of 89 patients submitted to quadrantectomy were included and divided into an OFA group (38 patients) and an OIA group (51 patients) according to the received anesthetic technique. Analgesia in the OIA group was based on an intraoperative infusion of remifentanil, and analgesia in the OFA consisted of an intraoperative infusion of ketamine and magnesium sulfate. Postoperative pain in both groups was managed with nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol. Postoperative pain, assessed with the numeric rating scale (NRS), requirements for additional analgesics, the incidence of PONV, and patient satisfaction evaluated using a QoR-40 questionnaire were compared between the two groups. Levels of pain at 30 min and 6, 12, and 24 h after surgery; number of paracetamol rescue doses; and the incidence of PONV were lower in the OFA group (p <0.05). Patient satisfaction was comparable in the two groups. CONCLUSIONS: A combination of ketamine, magnesium, and clonidine could be more effective than opioid-based analgesia in reducing postoperative pain and lowering PONV occurrence after quadrantectomy for breast cancer.