Full text of DOI:10.1592/phco.21.17.1368.34425

Triiodothyronine Supplementation in Patients Undergoing
Cardiopulmonary Bypass
Marc G. Reichert, Pharm.D., and Kelly C. Verzino, Pharm.D.
Patients undergoing cardiopulmonary bypass may develop clinically
significant physiologic alterations in the perioperative period, including
alteration of thyroid hormone concentrations. Alterations in the
concentration of thyroid hormones are of concern due to the effects of these
hormones on cardiac function. Hypothyroidism is associated with a decrease
in cardiac performance; therefore, supplementation with the active thyroid
hormone triiodothyronine (T ) in patients undergoing cardiopulmonary
3
bypass has been investigated to improve outcomes. In addition, T has been
3
studied as an agent to reduce the frequency of atrial fibrillation after
cardiopulmonary bypass.
(
Pharmacotherapy 2001;21(11):1368–1374)
OUTLINE
in myocardial contractility, decrease in heart rate,
decrease in cardiac output and stroke volume,
Physiology
and an increase in systemic vascular resistance
Cardiopulmonary Bypass and Thyroid Hormones
Studies for Cardiac Inotropy
Animal Studies
Human Studies
Clinical Studies in Atrial Fibrillation Prophylaxis
Acquisition Cost
3
(
SVR). The effect of this decline in cardiac
performance may result in difficulty weaning the
patient from cardiopulmonary bypass at the end
of the procedure. Therefore, investigations were
undertaken to determine if supplementation with
T3 could improve cardiac function and improve
patient outcomes. Subsequently, the utility of T3
Conclusion
Clinically significant physiologic alterations
result when a patient undergoes cardiopulmonary
bypass. These alterations may include neurologic,
hematologic, renal, and endocrine sequelae.
Among the endocrine alterations, attention has
been placed on the effect of cardiopulmonary
bypass on thyroid hormones because of the
effects of these hormones on cardiac function.
Specifically, cardiopulmonary bypass has been
shown to decrease concentrations of triiodothyronine
in preventing atrial fibrillation after cardiopulmonary
bypass was assessed.
4
, 5
Physiology
The thyroid gland secretes thyroxine (T ) and
4
T in response to stimulation by thyrotropin
3
6
(
thyroid-stimulating hormone). Once in the
circulation, T and T are transported primarily
4
3
by thyroid-binding globulin and to a lesser extent
6
by albumin and prealbumin. The free or
(
T ), the physiologically active thyroid hormone,
3
1
–3
unbound hormone is responsible for the biologic
activity. Normally, approximately 0.03% of the
total T (TT ) concentration is unbound (free T
thus inducing a hypothyroid state.
Hypothyroidism is associated with a decrease
4
4
4
3
[
FT ]) as compared with 0.2–0.5% of T (free T
From the Department of Pharmacy, Wake Forest
University Baptist Medical Center, Winston-Salem, North
Carolina (both authors).
Address reprint requests to Marc Reichert, Pharm.D.,
Department of Pharmacy, Wake Forest University Baptist
Medical Center, Medical Center Boulevard, Winston-Salem,
NC 27157.
4
3
3
[FT ]). After reaching the periphery, approximately
3
3, 6
3
0% of T is converted to T . This is facilitated
4 3
by the enzyme 5′-monodeiodinase, which also
may act on T to create reverse T (rT ), a
4
3
3
6
biologically inactive product.

TRIIODOTHYRONINE SUPPLEMENTATION IN CARDIAC SURGERY Reichert and Verzino
1369
Alterations in cardiac function seen with
thyroid hormones result from direct action of
these hormones on the heart and indirect
Table 1. Summary of Effects of Cardiopulmonary Bypass
1,
on Thyroid Hormone Concentrations Intraoperatively
2
0–26
7
, 8
Thyroid Hormone
Effect
activities in the periphery.
The mechanism by
Total T4
Total T3
Free T4
↓/↔
↓/↔
↑ /↔
which thyroid hormones have a direct effect on
the heart is unknown; however, animal studies
have demonstrated several physiologic
a
Free T3
Reverse T3
Thyrotropin
↑/↔
↑/↔
↓/↔
9
–19
alterations.
These alterations include a
variation of calcium and potassium transport, a
change of adenosine triphosphatase activity, a
reduction in adrenergic (␣ and ␤) receptor
number, and an involvement in regulating
↓
= decreased concentration; ↑ = increased concentration; /↔ = or
no change in concentration.
a
May be caused by heparin displacement.
9
–19
myosin synthesis.
Cardiac output also may be indirectly altered
by the effect of thyroid hormones on SVR.
Thyrotoxicosis is associated with a decline in
SVR, and hypothyroidism is associated with an
2
2, 24
This result may be due to heparin’s
2
2
displacement of T4 from proteins. According to
most of the investigations, concentrations of total
T3 (TT3) decrease with bypass even more
profoundly than do TT4 concentrations.
However, data on FT3 have shown a mixed
picture, with results indicating an increase, a
7
, 8
increase in SVR.
Therefore, in the hypothyroid
2
0, 21, 23
state, an increase in SVR could correlate with an
increase in diastolic blood pressure, which would
7
, 8
translate into lower cardiac output.
Until
1
, 20–22, 25,
further research is conducted, the exact
mechanism by which thyroid hormones affect
cardiac performance will remain theoretical.
decrease, or no change in concentrations.
2
6
Interestingly, thyrotropin concentrations do
not show much change despite the variations in
1
, 20–25
With regard to T supplementation in the
other thyroid hormones.
rT have been shown to increase or remain
unaltered during bypass.
Most of these changes in thyroid parameters
are consistent with what has been termed the
euthyroid sick syndrome, or nonthyroidal
Concentrations of
3
prevention of atrial fibrillation, the mechanism
by which supplementation may prevent the
occurrence is unknown. This is complicated by
the fact that to our knowledge the cause of atrial
fibrillation after cardiopulmonary bypass has not
3
2
0–22
2
2–25, 27–29
4
illness.
This syndrome has been
been elucidated.
observed in patients undergoing stress and is
characterized by decreases in TT and FT and by
insignificant decreases in TT , FT , and
3
3
Cardiopulmonary Bypass and Thyroid
Hormones
4
4
thyrotropin. Physiologically, conversion of T to
4
Cardiopulmonary bypass results in a different
physiologic state. Patients are exposed to
nonpulsatile blood flow, hypothermia, hemo-
dilution, and many pharmacologic interventions.
The resultant physiologic state has been the
target of a tremendous amount of research.
T decreases, and rT production increases
3
3
2
8
without an increase in thyrotropin. According
to these data, the response of the thyroid
hormones to cardiopulmonary bypass may be
characterized as a stress response.
Several investigators have studied thyroid
2
1–26
The effects of cardiopulmonary bypass on
thyroid hormones intraoperatively in both adults
hormone concentrations after bypass.
The
results indicate a pattern similar to that of
1
, 20–26
21–26
and children are summarized in Table 1.
intraoperative concentrations.
Concentrations
These effects have varied among studies. The
variations may be due to differences in anesthetic
technique, surgical technique, cardiopulmonary
priming fluid, degree of hypothermia, pharmaco-
logic agents, and whether thyroid concentrations
were corrected for hemodilution.
of T are typically decreased and may take several
4
2
1, 23, 25, 26
days to return to normal.
Concentrations
of T and FT are decreased postoperatively and
3
3
2
1–26
may reach a nadir 24–48 hours after bypass.
Decreased concentrations have been demonstrated
as long as 7–8 days after bypass.
2
3, 25
Interestingly,
Overall the TT concentrations decrease or are
thyrotropin concentrations may remain normal
4
2
1–26
unaltered with the institution of bypass, and FT
or decreased in the postoperative period.
4
1
, 20–26
concentrations increase during bypass.
Of
Again, this is opposite to what one would expect
if thyroid hormone concentrations are depressed.
In contrast to the elevated concentrations of FT4
interest, concentrations of FT were found to
4
1
,
increase profoundly with heparin administration.

1
370
PHARMACOTHERAPY Volume 21, Number 11, 2001
rate of rise of left ventricular pressure (dP/dtmax
seen intraoperatively, FT has been shown to
normalize after bypass.
Study results suggest that certain cytokines
may be involved in the pathogenesis of
nonthyroidal illness.
investigators have studied the effects of tumor
necrosis factor (TNF) and interleukin-6 (IL-6) on
thyroid hormones.
study discovered that a bolus injection of TNF
into six healthy volunteers produced the
characteristic changes seen with nonthyroidal
illness. In contrast, the authors of another
study found that lower doses of TNF infused
continuously into rats did not alter thyroid
activity. Other investigators also found a
correlation between IL-6 concentrations and
nonthyroidal illness.
trations of IL-6 correlated with decreased concen-
trations of T , FT , T , and FT and increased
concentrations of rT .
studies, however, IL-6 had no effect on 1-5′-
deiodinase activity. With the mixed results
demonstrated for TNF and the inability to fully
explain nonthyroidal illness with increasing
concentrations of IL-6, one wonders if TNF and
IL-6 are markers of thyroid illness instead of a
cause, or part of a larger cause. We are hopeful
that this will be explained through future
research.
)
4
2
2, 24–26
as compared with that of controls. In addition,
the overall survival in treated pigs was 100% (11
of 11) versus 45% (5 of 11) in the control group.
Of note, inotropes were not administered in this
study.
2
7, 29–33
Particularly,
In a subsequent investigation, baboons were
exposed to 3 hours of ischemia during cardio-
pulmonary bypass. When myocardial function
2
7, 29–33
The authors of one
3
0
35
was considered, no significant differences were
noted between T -treated animals and control
3
animals. The difference between this study and
the previous investigation may have been an
2
9
insufficient dose of T (6 µg) to overcome the
3
damage from the 3 hours of ischemia.
Another group of investigators studied the
2
7, 31–33
Increased concen-
effects of T on ischemic and normal hearts in
3
3
6, 37
animals.
The primary outcome measures of
3
3
4
4
contractility were load independent and included
left ventricular peak pressure and left ventricular
end-diastolic pressure. Thus, the function of the
left ventricle was the primary focus. In an
isolated rabbit heart model, the investigators
2
7, 31–33
In one of these
3
3
1
demonstrated that the administration of T to
3
normal rabbit hearts had no effect on left
ventricular function as compared with that of
36
controls. Conversely, in the hearts that were
subjected to a period of ischemia, T -treated
3
hearts had a significant improvement in left
ventricular function as compared with that of
controls. The favorable recovery of the left
ventricle after ischemia was confirmed in a
The question then remains, if patients who
undergo cardiopulmonary bypass experience
nonthyroidal illness, should thyroid hormone,
particularly the active hormone T , be
37
3
subsequent investigation. This same group of
administered to these patients to improve cardiac
function? Furthermore, whether supplementation
facilitates weaning from bypass and decreases
recovery time and mortality need to be
determined.
investigators randomly assigned 14 pigs to
treatment with T or to a control group after
3
37
cardiopulmonary bypass and ischemia. In both
the treatment group and the control group, left
ventricular function was significantly depressed
after ischemia and 30 minutes of reperfusion.
However, at 90 and 120 minutes after reperfusion,
Studies for Cardiac Inotropy
pigs treated with T had a significantly improved
recovery of left ventricular function as compared
with that of controls.
Animal Studies
3
With the data demonstrating a decrease in T3
as the result of bypass, one group of investigators
set out to observe the effects of T replacement in
animals exposed to ischemia during cardio-
pulmonary bypass.
bypass model, 22 pigs experienced either 2 or 3
hours of ischemia. Half of the pigs in each of
these groups received 6 µg of T , and the other
half served as controls. The most important
results were seen 10 minutes after bypass in the
group undergoing 2 hours of ischemia. Treated
pigs had a significant increase in mean arterial
pressure, cardiac output, heart rate, and maximum
From these animal studies, it appeared that
3
supplementation with T improved cardiac
3
function most notably after ischemia. In
3
4, 35
In a cardiopulmonary
addition, a dramatic improvement in survival of
34
the pigs was demonstrated.
Therefore,
3
4
investigation of the effects of T in humans was
3
3
performed to evaluate whether improved cardiac
function and patient outcomes would result.
Human Studies
In two studies published in 1989 by the same

TRIIODOTHYRONINE SUPPLEMENTATION IN CARDIAC SURGERY Reichert and Verzino
1371
group of investigators, T was given to patients surgery. Two such studies were subsequently
3
3
8, 39
41, 42
41
undergoing cardiopulmonary bypass.
The
published.
The first investigation included
results showed promise, but the series were
patients undergoing coronary artery bypass graft
who had an LVEF less than 40%. One hundred
forty-two patients were randomly assigned to
3
8, 39
limited to a small number of patients.
In the
3
8
observational investigation, five patients who
could not be weaned from bypass and five
patients who had impaired myocardial function
postoperatively despite aggressive inotropic
receive T (0.8-µg/kg intravenous bolus followed
3
by a 0.113-µg/kg/hr continuous infusion for 6
hrs) or placebo after the aortic cross clamp was
removed. The investigators found no difference
between the groups in terms of frequency of
arrhythmias, need to return to bypass, inotropic
support, administration of amrinone or
vasopressor agent, placement of an intraaortic
balloon pump, or need for pacing. An increase in
cardiac index 2 hours after the cross clamp was
removed in patients receiving T3 was
documented; however, inotropes were titrated to
achieve a cardiac index above 2.1, so the
difference may have been due to inotrope dosing.
support were given T 4–10 µg intravenously.
3
Within 1 hour, all five patients dependent on
cardiopulmonary bypass were able to be
separated from bypass, and all 10 patients had a
significant decrease in inotropic support
requirements.
3
9
In the follow-up study, 48 patients were
stratified by left ventricular ejection fraction
(
LVEF). Twenty-four patients had an LVEF less
than 30% (part 1), and 24 patients had an LVEF
greater than 40% (part 2). Approximately half
the patients in each part received T at various
In addition, the patients who received T had a
3
3
intervals (T treatment group), and the other half
lower SVR than that of patients receiving
placebo. With regard to outcomes, no differences
were noted between the groups in terms of
duration of mechanical ventilation, length of stay
in the intensive care unit or hospital, or
perioperative mortality. A sample size calculation
was not included in the article; therefore,
whether the study had enough patients to
achieve adequate power is uncertain. Thus, T3
may improve cardiac performance but does not
appear to improve clinical outcomes.
In the subsequent investigation, 211 patients
were randomly assigned to receive one of three
interventions. The interventions groups were a
T3 treatment group (0.8 µg/kg-intravenous bolus
followed by a 0.12-µg/kg/hr continuous infusion
for 6 hrs), a positive control group (normal saline
intravenous bolus followed by a dopamine
infusion at 5 µg/kg/min for 6 hrs), and a placebo
group (normal saline intravenous bolus and
infusion). After randomization, 6 patients had to
be excluded with 205 remaining for investigation.
3
received placebo (placebo group). Of note, the
dosing regimen was altered between part 1 and
part 2 due to the discovery that FT3
concentrations did not remain within the normal
range for the entire period in part 1. All patient
caregivers were blinded to the treatment group.
In part 1, no difference in hemodynamic
parameters was seen between the treatment
group and the placebo group; however, T -treated
3
patients had a significant decrease in inotropic
4
2
and diuretic requirements. In part 2, T -treated
3
patients had a significant increase in cardiac
output due to an increase in stroke volume, and a
significant decrease in systemic vascular and
pulmonary vascular resistance. No differences
were noted in inotropic or diuretic needs
between the T treatment group and the placebo
3
-
group. The authors did not comment on how
well the groups were matched within each part. 4
0
In 1993, another group of investigators
published a study in which 20 patients were
treated with T or placebo by using the dosing
The results demonstrated that T did not have
3
3
3
9
regimen in part 2 of the study discussed above.
any significant effect on hemodynamic parameters,
need for inotropic support, or use of an intra-
aortic balloon pump. Dopamine, in contrast,
significantly increased heart rate and trended
toward a reduced need for inotropes. In
addition, a significant difference was not
demonstrated between the groups in terms of
dysrhythmias, death, stroke, myocardial
infarction, or need for an intervention due to
continued bleeding. The study, however, was
powered to detect a difference in the duration of
inotropic support; therefore, the study may not
Included were patients undergoing elective open-
heart surgery, and no differences were found
between T or placebo administration on heart
3
rate, pulmonary capillary wedge pressure, mean
arterial pressure, and left ventricular stroke work
index. Of note, inotropic agent usage was not
analyzed.
The conflicting results in the previous
investigations led to an increased need for a large,
randomized, double-blind, placebo-controlled
trial to help define the role of T in cardiac
3

1
372
PHARMACOTHERAPY Volume 21, Number 11, 2001
have had sufficient power to detect a difference
in the secondary end points. Of note, length of
stay in the intensive care unit, length of stay in
the hospital, and duration of mechanical
ventilation were not studied. As indicated by the
authors, this study does not rule out any effect of
T on cardiac function; however, T supplemen-
Definitive therapy for preventing this
complication is unknown, but administration of
perioperative thyroid hormones for preventing
postoperative atrial fibrillation has been
4
, 5
reported.
Perioperative T3 supplementation was
evaluated in a placebo-controlled, randomized
trial for the prevention of postoperative atrial
fibrillation in patients undergoing coronary
3
3
tation cannot be recommended in all patients.
More recently, an investigation was published
that included 40 children (aged 2 days–10.4
4
artery bypass graft (CABG) surgery. Enrolled
4
3
yrs). Patients were randomly assigned to the T3
treatment group (2 µg/kg-bolus on postoperative
day 1 and 1-µg/kg bolus subsequently up to 12
days) or to the placebo group (normal saline).
All patients received dopamine infusions that
patients had an ejection fraction less than 40%
and no known history of thyroid dysfunction.
Patients received either dextrose 5% as a placebo
(65 patients) or intravenous T3 (66 patients) as a
0.8 µg/kg-bolus given at removal of the aortic
cross clamp and a continuous infusion of 0.113
µg/kg/hour for 6 hours followed by a 50%
reduction in dose every hour for 3 hours, at
which time the infusion was discontinued.
Standardized protocols for anesthesia and
postsurgical care were used, including
supraventricular arrhythmia prophylaxis with
digoxin 0.25 mg/day and metoprolol 25 mg
twice/day in most patients beginning on
postoperative day 1.
were discontinued simultaneously with T or
3
placebo. Thyroid hormone concentrations were
tested only postoperatively; thus, the preoperative
and intraoperative thyroid status of the patients
is unknown. Of note, none of the patients died
during the study. Cardiac index in all patients
and overall cardiac function in patients with
longer procedures were significantly improved in
the T3 treatment group. There were no
significant differences between the T and
3
Duration of bypass did not differ between the
groups. Mean serum T3 concentrations
decreased within 30 minutes of bypass in the
control group and remained low up to 24 hours
after placebo administration; however, in the T3
group, concentrations were elevated during the
infusion and returned to normal at 24 hours.
Initially, postoperative occurrence of arrhythmias
including atrial fibrillation did not differ between
the groups during the first 24 hours after surgery.
The incidence did differ during the subsequent
placebo groups in terms of length of stay in the
intensive care unit, total dose of catecholamines
administered, duration of mechanical ventilation,
need for oxygen supplementation, or
intervention scores in the early postoperative
period. The intervention score was determined
by applying a number (1–4) to 76 interventions
in the intensive care unit. The score was assessed
to determine a patient ’s postoperative course. A
significant difference was demonstrated between
T3 and placebo at day 4 and total score assessed.
An improved postoperative course was
9
6 hours. Atrial fibrillation occurred in 24% of
3
T -treated patients and in 46% of patients
experienced by the T -treated group. However,
3
receiving placebo (p≤0.009), with most episodes
occurring between postoperative days 2 and 4.
Prophylactic administration of digoxin and
metoprolol postoperatively were similar in both
groups.
the total scores did not appear to represent a
large clinically significant difference between the
T group and the placebo group (23.2 ± 18.1
3
[
SD] and 26 ± 18.5). Again, T improved cardiac
3
function but did not appear to alter patient
outcomes.
One study described differences in outcomes
on the basis of age (< 70 yrs and ≥ 70 yrs) in 319
4
5
patients who underwent CABG. A dose of 10
Clinical Studies in Atrial Fibrillation
Prophylaxis
µg of intravenous T was given at the beginning
3
of bypass. A second dose was administered after
removal of the aortic cross clamp, followed by
Patients who undergo cardiopulmonary bypass
surgery are at risk of developing postoperative
tachyarrhythmias. Specifically, the development
of postoperative atrial fibrillation is estimated to
postoperative intravenous T 200 µg once/day for
4
2 days. Postoperative atrial fibrillation was
reported in 9.4% of patients. Whether thyroid
hormone resulted in a lower than expected
frequency of postoperative atrial fibrillation is
unknown due to the absence of a placebo group.
4
4
occur in 20–30% of patients.
Potential
complications include hemodynamic instability,
4
4
stroke, and prolonged hospitalization.

TRIIODOTHYRONINE SUPPLEMENTATION IN CARDIAC SURGERY Reichert and Verzino
1373
The same authors performed a follow-up case
series study to evaluate multiple drug
concentration that was demonstrated may be a
marker of an underlying disorder but not the
administration including T for prevention of
cause of the disorder. Therefore, T supplemen-
3
3
postoperative atrial fibrillation in 517 patients
tation may improve hemodynamics but does not
appear to change patient outcomes. Data on T3
supplementation for prevention of postoperative
atrial fibrillation are limited and do not support
routine use for this purpose. Thus, until further
research or pharmacoeconomics proves a benefit
undergoing CABG with use of cardiopulmonary
5
bypass. Patients received intravenous T 10 µg
3
administered by means of the bypass circuit
when the aortic cross clamp was removed. On
postoperative days 1 and 2, intravenous T was
4
administered once/day. Other agents adminis-
tered to patients postoperatively included a one
time dose of intravenous magnesium sulfate 2 g
with subsequent doses given for a serum
magnesium concentration less than 2.2 mEq/dl,
metoprolol 25–100 mg/day, digitalis,
corticosteroids, and loop diuretics. In addition, if
patients experienced any unstable atrial rhythm,
intravenous procainamide was begun. The
overall incidence of atrial fibrillation was 10.3%
in 53 patients. A comparison of patients who
developed atrial fibrillation with those who did
not revealed higher rates of preoperative
myocardial infarction (37% vs 22%, p<0.05), left
main stenosis (27% vs 11%, p<0.01), and older
age (70 ± 9 [SD] vs 66 ± 10 years, p<0.05) at
baseline. Patients who developed atrial
fibrillation also had a longer hospitalization
period (9.9 ± 9.6 vs 5.9 ± 5.2 days, p<0.001). Of
note, 8% of patients who did not develop atrial
fibrillation received prophylactic procainamide
therapy, which makes interpretation of these
results difficult.
to patient outcomes, T supplementation should
3
not be given routinely to patients undergoing
cardiopulmonary bypass for either inotropic
support or prevention of atrial fibrillation.
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1
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liothyronine sodium (Triostat; Jones Pharma, St.
1
991;7:77–9.
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6
Louis, MO). The average wholesale price of a
4
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1
-ml vial containing 0.01 mg/ml is $399.46.
1
1
1
1. Suko J. The calcium pump of cardiac sarcoplasmic reticulum:
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Thus, if a patient weighs 70 kg and the
4
2
previously described dosing strategy (0.8-µg/kg
intravenous bolus and 0.12-µg/kg/hr intravenous
infusion for 6 hrs) is used, at least 106.4 µg (11
vials) would be needed at an average wholesale
2. Rohrer D, Dillmann WH. Thyroid hormone markedly increases
+2
the mRNA coding for sarcoplasmic reticulum Ca -ATPase in
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activities, and sialic acid content of rat cardiac membrane
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4
6
price of $4394.06. If a one-time bolus is used,
the average wholesale price would be approxi-
mately $399.46 for one vial of liothyronine
1
1
1
1
4. Rodgers RL, Black S, Katz S, McNeill JH. Thyroidectomy of
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4
6
sodium.
Conclusion
Despite early data demonstrating a benefit of
T supplementation for inotropic support in
3
patients undergoing cardiopulmonary bypass,
large, randomized, blinded investigations did not
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