Indications for Intravenous T3 and T4

Abstract

Therapy with thyroid hormones normally is restricted to substitution therapy of patients with primary or secondary hypothyroidism. Typically, thyroid hormones are given orally. There are few indications for intravenous use of thyroid hormones. Indications for parenteral application are insufficient resorption of oral medications due to alterations of the gastrointestinal tract, partial or total loss of consciousness, sedation in the intensive care unit or shock. In almost all cases, levothyroxine is the therapy of choice including congenital hypothyroidism. In preterm infants with an altered thyroid hormone status, studies with thyroid hormones including intravenous liothyronine showed a normalisation of T3 levels and in some cases an amelioration of parameters of ventilation. A benefit for mortality or later morbidity could not be seen. Effects on neurological improvements later in life are under discussion. Decreased thyroid hormone levels are often found after cardiac surgery in infants and adults. Intravenous therapy with thyroid hormones improves the cardiac index, but in all other parameters investigated, no substantial effect on morbidity and mortality could be demonstrated. Oral liothyronine therapy in these situations was equivalent to an intravenous route of application. In myxoedema coma, intravenous levothyroxine is given for 3 to 10 days until the patient can take oral medication and normal resorption in the gastrointestinal tract is achieved by restoring at least peripheral euthyroidism. Intravenous levothyroxine is the standard in treating patients with myxoedema coma. A protective effect on the heart of i.v. levothyroxine in brain-dead organ donors may be possible.

 

MissingLinkText

Keywords

thyroid - hypothyroidism - liothyronine - levothyroxine - triiodothyronine

Introduction

The indication for treatment with thyroid hormones is primarily substitution therapy for patients with primary or secondary hypothyroidism. At present, this is carried out almost exclusively in tablet form and more rarely in soluble form, for example, in the form of drops with a corresponding specification for babies and infants [1]. Parenteral substitution is only necessary in very rare cases.

There is always an indication for parenteral administration of medications if the patient cannot take these orally or if adequate resorption of the medication is not ensured by oral administration. This is always necessary if the patient is unconscious or is so heavily sedated or relaxed that oral intake of a tablet is not possible. Resorption disturbances can be due to disorders of the gastrointestinal tract such as inflammatory bowel disease, extensive resection of parts of the intestine or in a state of shock in an intensive care ward.

Specifications with levothyroxine and liothyronine (triiodothyronine) are available for treatment with intravenous thyroid hormone preparations. In clinical medicine, levothyroxine is used almost exclusively in the parenteral specification. In contrast, intravenous liothyronine is only used very rarely [2].

 

MissingLinkText

Materials and Methods

A systematic review was performed to investigate the indications and use of intravenous levothyroxine and intravenous liothyronine by searching the PubMed, Cochrane and EMBASE databases. We selected papers officially published in English. The major medical subject headings “intravenous levothyroxine”, “intravenous liothyronine”, “intravenous triiodothyronine”, “myxedema coma”, “cardiovascular surgery” were used as search terms.

 

MissingLinkText

Congenital hypothyroidism

Treatment with levothyroxine is the sole standard for the treatment of congenital hypothyroidism. This is usually administered orally, either in the form of crushed tablets with milk, soft gel capsules, or in a soluble form [3]. Intravenous administration is usually not necessary [4]. The indications and treatment options are dealt with in great detail in the current European guidelines (2014) for the treatment of congenital hypothyroidism [5] [6].

 

MissingLinkText

Use in pre-term infants

Reports on the clinical use of liothyronine include administration to premature infants. Some authors report increased morbidity and mortality with low thyroxine values (T4; L-3,5,3′,5′-tetraiodothyronine) in preterm infants and some studies show an association between low values of thyroxine, free T4 and low triiodothyronine (T3; 3,5,3′-triiodothyronine) and neonatal morbidity [7] [8] [9] [10] [11] [12]. Small for gestational age seems to be a risk factor for thyroid dysfunction in preterm born children [13] [14]. In preterm infants the umbilical cord values for T4, free T4, T3 and thyroxine-binding globulin are lower than in mature neonates. Postnatal increase in TSH is considerably less pronounced in preterm infants and in the first two weeks of life the circulating T4 and TSH values for preterm infants remain measurably lower [11] [15] [16] [17]. Whether the transient hypothroxinaemia in preterm infants and children with an extremely low birth weight is the cause or the result of the existing morbidity remains unclear. Parallels may be drawn with the euthyroid sick syndrome (non-thyroidal critical illness) in adult patients in intensive care wards. In euthyroid sick syndrome, TSH values for free T3 and free T4 are altered in the same direction. Several studies of the treatment of THOP syndrome (Transient Hypothyroxinaemia of Prematurity) with T3 and T4 preparations have been carried out [11] [18] [19] [20] [21] [22] [23] [24]. The inclusion criteria included various parameters such as insufficient postnatal TSH increase, persistently low T4 values or low T3 values. There are no prospective studies which include patient screening and inclusion according to predefined thresholds.

In the 1980s, it was observed that the T3 level in immature neonates was lower than in full term neonates. In immature neonates, respiratory distress syndrome may occur, which is essentially due to immaturity of the lungs and inadequate or qualitatively insufficient surfactant production [25]. The lower T3 values were attributed to inadequate T4 to T3 conversion in the liver. Type 2 deiodinase is responsible for this conversion. Cools et al. showed an increase in T3 values over the course of several days after a single intravenous dose of liothyronine in children born prior to the 30th week of pregnancy. However, this also resulted in increased suppression of TSH [26].

In an investigation of 50 preterm infants born prior to the 32nd week of pregnancy, treatment with 50 μg of liothyronine was initiated and this was compared with a control group without liothyronine treatment. No difference in mortality was seen between the two groups. Also, the maximum achievable oxygen concentration, the duration of artificial ventilation, and the complication rate were comparable. Only the FiO₂ concentrations required to maintain oxygen pressure between 50 and 60 mmHg changed significantly under liothyronine. The authors concluded that the data suggested that liothyronine treatment could have a relatively beneficial effect in immature neonates [18].

In a larger clinical study, 253 neonates with a gestational age of less than 30 weeks were treated with intravenous liothyronine plus hydrocortisone or administration of a placebo. The controlled and double-blind study was carried out in multiple centres. There was no difference between the two groups in the end points death and dependence on ventilation. Treatment with liothyronine plus hydrocortisone did not have any benefit for the children. Higher fT3 and fT4 values were linked to a better outcome, irrespective of the type of treatment [27].

Other studies used levothyroxine as well as liothyronine for the treatment of preterm infants. Overall, there were marked differences in study design. In some cases, there were clear differences in the dosages used and the route of administration also differed considerably. In addition to a single daily dose, in some cases medication was administered twice daily. In some cases, the medication was administered continuously and in others it was administered orally [18] [19] [20] [21] [24]. In summary, an analysis of the metadata in the context of a systematic Cochrane review could not find any clear evidence of an advantage for the treatment of preterm infants with thyroid hormones due to excessively low thyroid hormone values [28]. Prospective studies of the benefit of postnatal thyroid hormone treatment of preterm infants would be desirable [29].

 

MissingLinkText

Myxoedema coma

The term myxoedema coma is somewhat misleading, as not all patients are truly comatose. No definite criteria exist for the differentiation of severe hypothyroidism from myxoedema coma. Typical symptoms of severe hypothyroidism are restricted to intellectual capacity and concentration, hypothermia, hemodynamic instability, respiratory acidosis and, in some cases, varying degrees of loss of consciousness. Laboratory findings often show a very large increase in creatinine kinase, mild anaemia, and increased cholesterol values. Severe hypothyroidism is an extremely rare, life-threatening illness, which even today is associated with high mortality [30] [31]. The largest series of retrospective cases from 32 intensive care units (ICU) including 82 patients with severe hypothyroidism demonstrated an ICU mortality of 26%, with a six-month mortality of ICU survivors of 39% [32]. Over recent decades, the high mortality rate for myxoedema coma has fallen from 60–80% to 20–40% [32] [33] [34]. This is essentially attributable to greater attention by doctors, improved diagnostic possibilities and progress in intensive care treatment.

Treatment and monitoring of patients with severe hypothyroidism should always be carried out in an intensive care ward, and at least in an intermediate care unit [35] [36]. In addition to substitution treatment with thyroid hormone, monitoring and treatment of the cardiovascular, respiratory and neurological systems are necessary [33] [37]. Concomitant infections often also require treatment. Sepsis is one of the most common fatal complications of myxoedema coma [38].

Treatment of severe hypothyroidism naturally focuses on thyroid hormone substitution. The following treatment regimens are used for the treatment of myxoedema coma: treatment with oral and intravenous levothyroxine or liothyronine and a combination of liothyronine and levothyroxine [34] [39] [40] [41] [42]. As myxoedema coma is an extremely rare disorder, there is an almost complete lack of comparative prospective studies of the various treatment regimens. Over the past three decades, mainly case descriptions have been published, as well as a few case studies with a small number of patients and a small number of studies of limited value [30] [34] [43]. In a retrospective analysis of 23 consecutive patients with myxoedema coma, Dutta et al. found no difference in clinical criteria and patient survival under oral or intravenous treatment with levothyroxine [38]. In Japan, a small retrospective series of treated patients showed a more unfavourable prognosis for older patients, for patients with concomitant cardiovascular disorders as well as with very high initial treatment doses of either more than 500 μg of levothyroxine or more than 75 μg triiodothyronine [34]. In a series of 14 patients with at least neurological signs of hypothyroidism oral administration of 300–500 μg levothyroxine could restore euthyroidism in all but one patient who died due to myxoedema coma [44]. Pereira et al. reported the use of nasogastric triiodothyronine alone in three patients with myxoedema coma. In one of them, a female patient with symptoms of atonal ileus, this did not result in an adequate increase in hormone levels, necessitating a switch to intravenous triiodothyronine treatment [45]. In more recent series, the patients were treated with levothyroxine alone. As soon as the patients were able to take oral medication, the switch was made from intravenous to oral administration [31].

In a survey of 800 German hospitals in 1997, 24 patients with hypothyroid coma were identified. All patients received treatment with levothyroxine; five patients received oral treatment and all others intravenous treatment [46].

In a study on primates (baboons) in 1983, Chernow et al. demonstrated that both triiodothyronine and levothyroxine were able to pass through the blood-brain barrier in both directions [47]. After intravenous administration, liothyronine could be detected in the cerebrospinal fluid more rapidly and at higher levels than levothyroxine.

The authors concluded that triiodothyronine may therefore be more suitable for the intensive care treatment of patients with myxoedema coma. Escobar-Morreale demonstrated that in functionally athyreotic rats (previous treatment with ¹³¹iodine), euthyreosis could not be achieved in all tissues by the administration of levothyroxine alone [48]. Euthyreosis was defined as the measured concentration of T3 and T4 in frozen tissue samples. Exceptions to this were the cerebral cortex, the cerebellum and brown adipose tissue. In these tissues there was no difference in the measured hormone values under intravenous administration of levothyroxine. Although from a present point of view these data remain important and interesting, these experiments do not allow the derivation of recommendations for the treatment of severe hypothyroidism, including myxoedema coma. In the meantime, it has been demonstrated that levothyroxine can also have direct effects in the target cell, which are independent of the receptor. Mere measurement of hormone levels in homogenised tissue does not allow any conclusive statement to be made regarding the biological effect of T3 and T4 in the target cell. It must also be considered that in rats, the production ratio of T3 in the thyroid is approximately 1:6 in comparison with the production of T4. However, in humans this ratio is much smaller at approx. 1:14.

 

MissingLinkText

Use in intensive care

Patients with myxoedema coma should always be treated in an intensive care unit. But in intensive care, there are more indications for the intravenous application of thyroid hormones. In all states of cardiovascular shock with insufficient blood supply of the gastrointestinal tract or a deficit in gastrointestinal function with consecutive malabsorption, patients who need a substitution of thyroid hormones should be treated via intravenous administration of levothyroxine. The non-thyroidal illness syndrome (also named euthyroid sick syndrome) with alterations in thyroid hormone metabolism in critically ill patients is still poorly understood. It is often associated with a poor outcome. Despite decreased levels of T3 in combination with normal or decreased levels of T4 and TSH, most studies showed no benefit to treat these patients with intravenous thyroid hormones [49] [50].

In neonates requiring extracorporal membrane oxygenisation (ECMO), laboratory values are often consistent with euthyroid sick syndrome. On ECMO, TSH, Total T3 and Total T4 show an initial decline, and this may be a consequence of dilution on therapy with ECMO. All three parameters show a spontaneous restoration without therapy with thyroid hormone [51]. In adults there are no studies available regarding changes of thyroid hormones on therapy with ECMO.

 

MissingLinkText

Use in cardiac surgery

After cardiopulmonary surgery in children, deviations in the measurable parameters of thyroid hormone metabolism are found, mostly with suppressed levels of free T3 and free T4 values [52]. In 2010, Portman et al. reported an age dependent effect of an intravenous T3 administration on the time to extubation after cardiopulmonary bypass surgery (TRICC Trial). In children under the age of 5 months a significant reduction in the time to extubation was found whereas this effect was not more visible in children older than 5 months [53]. In a subsequent randomized multicentre trial (n=220 children) these results could not be reproduced with no effect of intravenous T3 on time to extubation [54]. In both trials, treatment with T3 did not increase the risk of arrhythmias or sentinel adverse effects and seemed to be safe. In a study with a similar design to the TRICC trial, Marwali et al. treated children with oral T3 and demonstrated that with this form of administration T3 values normalised in children after cardiac surgery [55]. Choi similarly demonstrated that oral administration of T3 after surgery on the coronary arteries in children also resulted in a good increase in T3 values. Despite the fact, that T3 treated children needed less vasopressors on the first postoperative day, no improvement in the overall clinical condition was achieved with T3 treatment [56]. The administration of T3 to preterm infants and after cardiac surgery therefore remains controversial and is the subject of further discussion [57].

Cardiac surgery on adults also frequently results in a reduction in thyroid hormone values. In adults, intravenous administration of T3 after cardiac surgery has also been investigated in a series of studies [58] [59] [60] [61] [62] [63] [64]. Here, there was largely consistent evidence of an improvement in the cardiac index with considerably higher T3 values. The data for all the other parameters investigated varied considerably in the studies. The effects on systemic vascular resistance, pulse rate, pulmonary capillary wedge pressure, recurrence of atrial fibrillation, use of inotropic substances as well as on TSH and T4 values were ultimately inconclusive [65]. In three studies with oral administration of T3 after cardiac surgery in adults, the measured parameters were comparable with the investigations of intravenous T3 administration [65] [66] [67] [68].

Based on the currently available studies, there is therefore no secure evidence of benefit to patients in terms of morbidity and mortality after cardiac surgery. A recent meta-analysis confirmed this evaluation [69]. The form (T3 versus T4) and the type of administration of the thyroid hormone preparations (intravenous versus oral) is irrelevant.

 

MissingLinkText

Use in the management of brain-dead organ donors

Brain death precipitates heart failure in patients designated as heart donors if eligible. In large retrospective studies, treatment with intravenous T4 seemed to have a protective effect for the hearts to be transplanted [70] [71]. In a prospective randomized controlled trial intravenously administered T4 (n=14 T4 vs. n=11 placebo) could not improve cardiac function in brain dead organ donors with impaired heart function [72]. The same group compared the intravenous administration of T3 (n=16) versus T4 (n=21) over an 8-hour period in brain dead organ donors [73]. To clarify a possible benefit of intravenous T4 or T3 in heart donors, much bigger trials would be necessary, implying the collaboration of a great number of centres providing care for organ donors.

 

MissingLinkText

Conclusion

Treatment with high dose intravenous administration of levothyroxine is the standard treatment for severe hypothyroidism and myxoedema coma [74] [75] [76]. A switch to oral treatment can be made for alert patients who are capable of swallowing and who do not have intestinal atony. Nasogastric administration is also possible if the function of the gastrointestinal tract is intact. Usually, the period for intravenous treatment is 3–10 days. Intravenous treatment with liothyronine is only carried out in extremely rare cases. A definite clinical advantage of intravenous T3 treatment compared to intravenous levothyroxine treatment cannot be identified, so that a possible planned T3 treatment can also be substituted with an intravenously administered levothyroxine preparation [77]. As long as primary adrenal failure cannot be ruled out in case of myxoedema coma, treatment must always be initiated with hydrocortisone prior to, or at least concomitant with the administration of thyroxine at a dose of 100 mg in order to prevent rapid deterioration in the patient’s condition [78] [79]. An additional summary of indications and clinical use of intravenous T4 and T3 is given in [Table 1].

Table 1 Indications and clinical use of i. v. levothyroxine (T4) and i. v. triiodothyronine (T3).

	i. v. Levothyroxine	i. v. Triiodothyronine
Congenital hypothyroidism1	x	–
Preterm infants	(x)2	(x)2
Myxoedema coma	x	(x)2
Oral medication impossible3	x	–
Insufficient enteral absorption3	x	–
Critical ill patients with disturbed gastrointestinal absorption3	x	–
Euthyroid sick syndrome	(–)2	(–)2
After cardiac surgery	(–)2	(–)2
Management of brain-dead organ donors	(–)2	(–)2

x: Indicated; –: Not indicated. ¹ If oral substitution is not possible or not sufficient. ² No clear results in studies, individual decision or in studies. ³ If levothyroxine substitution is indicated.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 von Heppe JH, Krude H, L'Allemand D. et al. The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism. J Pediatr Endocrinol Metab 2004; 17: 967-974
• 2 Balhara B, Misra M, Levitsky LL. Clinical monitoring guidelines for congenital hypothyroidism: laboratory outcome data in the first year of life. J Pediatr 2011; 158: 532-537
• 3 Stagi S, Municchi G, Ferrari M. et al. An overview on different l-thyroxine (l-T(4)) formulations and factors potentially influencing the treatment of congenital hypothyroidism during the first 3 years of life. Front Endocrinol 2022; 13: 859487
• 4 Donaldson M, Jones J. Optimising outcome in congenital hypothyroidism; current opinions on best practice in initial assessment and subsequent management. J Clin Res Pediatr Endocrinol 2013; 5: 13-22
• 5 Léger J, Olivieri A, Donaldson M. et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr 2014; 81: 80-103
• 6 van Trotsenburg P, Stoupa A, Léger J. et al. Congenital hypothyroidism: a 2020-2021 consensus guidelines update – an ENDO-European reference network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid 2021; 31: 387-419
• 7 Meijer WJ, Verloove-Vanhorick SP, Brand R. et al. Transient hypothyroxinaemia associated with developmental delay in very preterm infants. Arch Dis Childhood 1992; 67: 944-947
• 8 Pop VJ, Brouwers EP, Vader HL. et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003; 59: 282-288
• 9 Reuss ML, Paneth N, Pinto-Martin JA. et al. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Eng J Med 1996; 334: 821-827
• 10 Simpson J, Williams FL, Delahunty C. et al. Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. J Clin Endocrinol Metab 2005; 90: 1271-1279
• 11 van Wassenaer AG, Kok JH, Dekker FW. et al. Thyroid function in very preterm infants: influences of gestational age and disease. Pediatr Res 1997; 42: 604-609
• 12 Williams FL, Ogston SA, van Toor H. et al. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab 2005; 90: 5954-5963
• 13 Liu C, Wang K, Guo J. et al. Small for gestational age is a risk factor for thyroid dysfunction in preterm newborns. BMC Pediatr 2020; 20: 179
• 14 Lin X, Chen X, Yang CY. An analysis of perinatal factors of low T3 syndrome in preterm neonates with a gestational age of 28-35 weeks. Ann Med 2021; 53: 1722-1726
• 15 Paneth N. Does transient hypothyroxinemia cause abnormal neurodevelopment in premature infants?. Clin Perinatol 1998; 25: 627-643
• 16 Fisher DA. Thyroid function in premature infants. The hypothyroxinemia of prematurity. Clin Perinatol 1998; 25: 999-1014 viii
• 17 Rabin CW, Hopper AO, Job L. et al. Incidence of low free T4 values in premature infants as determined by direct equilibrium dialysis. J Perinatol 2004; 24: 640-644
• 18 Amato M, Guggisberg C, Schneider H. Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Horm Res 1989; 32: 213-217
• 19 Amato M, Pasquier S, Carasso A. et al. Postnatal thyroxine administration for idiopathic respiratory distress syndrome in preterm infants. Horm Res 1988; 29: 27-30
• 20 Chowdhry P, Scanlon JW, Auerbach R. et al. Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia. Pediatrics 1984; 73: 301-305
• 21 Schönberger W, Grimm W, Emmrich P. et al. Reduction of mortality rate in premature infants by substitution of thyroid hormones. Eur J Pediatr 1981; 135: 245-253
• 22 Smith LM, Leake RD, Berman N. et al. Postnatal thyroxine supplementation in infants less than 32 weeks' gestation: effects on pulmonary morbidity. J Perinatol 2000; 20: 427-431
• 23 Valerio PG, van Wassenaer AG, de Vijlder JJ. et al. A randomized, masked study of triiodothyronine plus thyroxine administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects. Pediatr Res 2004; 55: 248-253
• 24 Vanhole C, Aerssens P, Naulaers G. et al. l-Thyroxine treatment of preterm newborns: clinical and endocrine effects. Pediatr Res 1997; 42: 87-92
• 25 Cuestas RA, Lindall A, Engel RR. Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood. N Eng J Med 1976; 295: 297-302
• 26 Cools F, van Wassenaer AG, Kok JH. et al. Changes in plasma thyroid hormone levels after a single dose of triiodothyronine in premature infants of less than 30 weeks gestational age. Eur J Endocrinol 2000; 143: 733-740
• 27 Biswas S, Buffery J, Enoch H. et al. Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants less than 30 weeks gestation: results of the THORN trial--thyroid hormone replacement in neonates. Pediatr Res 2003; 53: 48-56
• 28 Osborn DA, Hunt RW. Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants. Cochrane Database System Rev. 2007 1. Cd005948
• 29 La Gamma EF, van Wassenaer AG, Golombek SG. et al. Neonatal thyroxine supplementation for transient hypothyroxinemia of prematurity : beneficial or detrimental?. Treat Endocrinol 2006; 5: 335-346
• 30 Salomo LH, Laursen AH, Reiter N. et al. Myxoedema coma: an almost forgotten, yet still existing cause of multiorgan failure. BMJ Case Rep 2014; 2014: bcr2013203223
• 31 Roy N, Majumder A, Sanyal D. et al. Legions of presentations of myxedema coma: a case series from a tertiary hospital in India. J ASEAN Fed Endocr Soc 2020; 35: 233-237
• 32 Bourcier S, Coutrot M, Ferré A. et al. Critically ill severe hypothyroidism: a retrospective multicenter cohort study. Ann Intensive Care 2023; 13: 15
• 33 Wartofsky L. Myxedema coma. Endocrinol Metab Clin North America 2006; 35: 687-698 vii–viii
• 34 Yamamoto T, Fukuyama J, Fujiyoshi A. Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Thyroid 1999; 9: 1167-1174
• 35 Beynon J, Akhtar S, Kearney T. Predictors of outcome in myxoedema coma. Crit Care 2008; 12: 111
• 36 Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med 2007; 22: 224-231
• 37 Constant EL, de Volder AG, Ivanoiu A. et al. Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. J Clin Endocrinol Metab 2001; 86: 3864-3870
• 38 Dutta P, Bhansali A, Masoodi SR. et al. Predictors of outcome in myxoedema coma: a study from a tertiary care centre. Crit Care 2008; 12: R1
• 39 Arlot S, Debussche X, Lalau JD. et al. Myxoedema coma: response of thyroid hormones with oral and intravenous high-dose l-thyroxine treatment. Intensive Care Med 1991; 17: 16-18
• 40 McCulloch W, Price P, Hinds CJ. et al. Effects of low dose oral triiodothyronine in myxoedema coma. Intensive Care Med 1985; 11: 259-262
• 41 Mir SA, Wani AI, Masoodi SR. et al. Lithium toxicity and myxedema crisis in an elderly patient. Indian J Endocrinol Metab 2013; 17: S654-S656
• 42 Savage MW, Mah PM, Weetman AP. et al. Endocrine emergencies. Postgrad Med J 2004; 80: 506-515
• 43 Gupta KJ. Myxedema coma: a sleeping giant in clinical practice. Am J Med 2013; 126: e3-e4
• 44 Rajendran A, Bhavani N, Nair V. et al. Oral levothyroxine is an effective option for myxedema coma: a single-centre experience. Eur Thyroid J 2021; 10: 52-58
• 45 Pereira VG, Haron ES, Lima-Neto N. et al. Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. J Endocrinol Invest 1982; 5: 331-334
• 46 Reinhardt W, Mann K. [Incidence, clinical picture and treatment of hypothyroid coma. Results of a survey]. Med Klin (Munich) 1997; 92: 521-524
• 47 Chernow B, Burman KD, Johnson DL. et al. T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. Crit Care Med 1983; 11: 99-104
• 48 Escobar-Morreale HF, Obregón MJ, Escobar del Rey F. et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 1995; 96: 2828-2838
• 49 Fliers E, Boelen A. An update on non-thyroidal illness syndrome. J Endocrinol Invest 2021; 44: 1597-1607
• 50 Nistal-Nuno B. Euthyroid sick syndrome in paediatric and adult patients requiring extracorporeal circulatory support and the role of thyroid hormone supplementation: a review. Perfusion 2021; 36: 21-33
• 51 Leeuwen L, van Heijst AFJ, van Rosmalen J. et al. Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation. J Perinatol 2017; 37: 906-910
• 52 Talwar S, Khadgawat R, Sandeep JA. et al. Cardiopulmonary bypass and serum thyroid hormone profile in pediatric patients with congenital heart disease. Congenit Heart Dis 2012; 7: 433-440
• 53 Portman MA, Slee A, Olson AK. et al. Triiodothyronine supplementation in infants and children undergoing cardiopulmonary bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis. Circulation 2010; 122: S224-S233
• 54 Portman MA, Slee AE, Roth SJ. et al. Triiodothyronine supplementation in infants undergoing cardiopulmonary bypass: a randomized controlled trial. Semin Thorac Cardiovasc Surg 2023; 35: 105-112
• 55 Marwali EM, Boom CE, Sakidjan I. et al. Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease. Pediatr Crit Care Med 2013; 14: 701-708
• 56 Choi YS, Shim JK, Song JW. et al. Efficacy of perioperative oral triiodothyronine replacement therapy in patients undergoing off-pump coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2013; 27: 1218-1223
• 57 Shih JL, Agus MS. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr 2009; 21: 536-540
• 58 Bennett-Guerrero E, Jimenez JL, White WD. et al. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. JAMA 1996; 275: 687-692
• 59 Güden M, Akpinar B, Sagğbaş E. et al. Effects of intravenous triiodothyronine during coronary artery bypass surgery. Asian Cardiovasc Thorac Ann 2002; 10: 219-222
• 60 Klemperer JD, Klein I, Gomez M. et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Eng J Med 1995; 333: 1522-1527
• 61 Klemperer JD, Klein IL, Ojamaa K. et al Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996; 61: 1323-1327 discussion 1328–1329
• 62 Mullis-Jansson SL, Argenziano M, Corwin S. et al. A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. J Thorac Cardiovasc Surg 1999; 117: 1128-1134
• 63 Novitzky D, Cooper DK, Barton CI. et al Triiodothyronine as an inotropic agent after open heart surgery. J Thorac Cardiovasc Surg 1989; 98: 972-977 discussion 977–978
• 64 Vavouranakis I, Sanoudos G, Manios A. et al. Triiodothyronine administration in coronary artery bypass surgery: effect on hemodynamics. J Cardiovasc Surg (Torino) 1994; 35: 383-389
• 65 Kaptein EM, Sanchez A, Beale E. et al. Clinical review: thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab 2010; 95: 4526-4534
• 66 Choi YS, Kwak YL, Kim JC. et al. Peri-operative oral triiodothyronine replacement therapy to prevent postoperative low triiodothyronine state following valvular heart surgery. Anaesthesia 2009; 64: 871-877
• 67 Magalhães AP, Gus M, Silva LB. et al. Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery. Braz J Med Biol Res 2006; 39: 969-978
• 68 Sirlak M, Yazicioglu L, Inan MB. et al. Oral thyroid hormone pretreatment in left ventricular dysfunction. Eur J Cardiothorac Surg 2004; 26: 720-725
• 69 Tharmapoopathy M, Thavarajah A, Kenny RPW. et al. Efficacy and safety of triiodothyronine treatment in cardiac surgery or cardiovascular diseases: a systematic review and meta-analysis of randomized controlled trials. Thyroid 2022; 32: 879-896
• 70 Rosendale JD, Kauffman HM, McBride MA. et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation 2003; 75: 1336-1341
• 71 Novitzky D, Mi Z, Sun Q. et al. Thyroid hormone therapy in the management of 63,593 brain-dead organ donors: a retrospective analysis. Transplantation 2014; 98: 1119-1127
• 72 Dhar R, Stahlschmidt E, Marklin G. A randomized trial of Intravenous thyroxine for brain-dead organ donors with impaired cardiac function. Prog Transplant 2020; 30: 48-55
• 73 Dhar R, Stahlschmidt E, Yan Y. et al. A randomized trial comparing triiodothyronine (T3) with thyroxine (T4) for hemodynamically unstable brain-dead organ donors. Clin Transplant 2019; 33: e13486
• 74 Bajwa SJ, Jindal R. Endocrine emergencies in critically ill patients: challenges in diagnosis and management. Indian J Endocrinol Metab 2012; 16: 722-727
• 75 Dubbs SB, Spangler R. Hypothyroidism: causes, killers, and life-saving treatments. Emerg Med Clin North Am 2014; 32: 303-317
• 76 Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am 2012; 96: 385-403
• 77 Mathew V, Misgar RA, Ghosh S. et al. Myxedema coma: a new look into an old crisis. J Thyroid Res 2011; 493462
• 78 Pimentel L, Hansen KN. Thyroid disease in the emergency department: a clinical and laboratory review. J Emerg Med 2005; 28: 201-209
• 79 Bürgi U, Perrig M. [Endocrine crises]. Ther Umsch 2005; 62: 369-373

Publication History

Received: 12 March 2024

Accepted after revision: 02 May 2024

Accepted Manuscript online:
02 May 2024

Article published online:
05 June 2024