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.

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].

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.

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].

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].

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.

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.

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.

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.

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.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 12 March 2024

Accepted after revision: 02 May 2024

Accepted Manuscript online:
02 May 2024

Article published online:
05 June 2024