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
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
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.
