Role of Levothyroxine Supplementation in Delayed Recovery Following Cardiac Surgery (L-Thyroxine)
Research indicates that hypothyroidism decreases heart contractility, reduces stroke volume and rate, affects the vascular endothelium, and increases the risk of atherosclerosis, systemic vascular resistance, hypertension, atherogenic lipid profile, and coagulation abnormality .
Hypothyroidism was reported to be strongly related to cardiovascular disease, respiratory complications, neurological complications, and a significant difference in ventilator weaning time.
Once subclinical hypothyroidism patients are treated with levothyroxine, their physical fitness measured by a 6-minute walk is significantly improved, also showed that levothyroxine treatment can optimize the treatment of heart failure with preserved functions (HFpEF) and heart failure with reduced functions (HFrEF) patients with systolic left ventricular dysfunction and sub clinical hypothyroidism (SCH).
The primary aim of this study is to investigate the effect of supplementation of oral levothyroxine in delayed recovery patients post cardiac surgery.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Research indicates that hypothyroidism decreases heart contractility, reduces stroke volume and rate, affects the vascular endothelium, and increases the risk of atherosclerosis, systemic vascular resistance, hypertension , atherogenic lipid profile, and coagulation abnormality .
Hypothyroidism was reported to be strongly related to cardiovascular disease, respiratory complications, neurological complications, and a significant difference in ventilator weaning time. Severe thyroid dysfunction is related to muscle relaxation and lead to respiratory muscle depression and disturbed conscious level.Surgical stress of cardiac surgery might be followed by a prolonged recovery process and cardiac dysfunction .
The exact physiology of thyroid disease and the relationship with post cardiac surgery remain unclear. Thus far, large-scale clinical statistical analysis evidence on the complication rate and long-term mortality is lacking. Current important prognostic assessment tools such as EuroSCORE II , and Society of Thoracic Surgeons (STS) score do not include thyroid function assessment, even though it has a significant impact on the metabolic, cardiovascular, and circulation system.
Once subclinical hypothyroidism patients are treated with levothyroxine, their physical fitness measured by a 6-minute walk is significantly improved, also showed that levothyroxine treatment can optimize the treatment of heart failure with preserved functions (HFpEF) and heart failure with reduced functions (HFrEF) patients with systolic left ventricular dysfunction and sub clinical hypothyroidism (SCH).
The heart is a major target of thyroid hormones, with maintenance of euthyroid hormone balance critical for proper function. Moreover, thyroid hormones have been shown a vital role in cardiac repair after injury beyond their roles in development and metabolism homeostasis.
After cardiac surgery with cardiopulmonary bypass (CPB), however, serum thyroid hormone levels are often decreased, especially in pediatric patients. This is called as the euthyroid sick syndrome (ESS).
It is reported that after cardiac surgery with CPB, 50% to 75% of adult patients present a decreased serum level of triiodothyronine (T3) (type 1 ESS) and 100% of pediatric patients display decreased serum levels of both T3 and tetraiodothyronine (T4) (type 2 ESS).
Because ESS has been associated with increased morbidity after cardiac surgery, it is deemed that intravenous supplementation of thyroid hormones in postoperative period is benefit to infants and small children. This view is supported by the largest randomized clinical trial so far, the Triiodothyronine for Infants and Children Undergoing CPB (TRICC) study, in which subgroup analysis shows a significant reduction in mechanical ventilation time, less use of inotropic drugs, and better cardiac function with intravenous T3 supplementation after surgery in pediatric patients aged <5 months.
Ischemia and reperfusion occur during almost every cardiac surgery and myocardial ischemia/reperfusion injury (IRI) is an important cause of morbidity and mortality in the early postoperative period after cardiac surgery. It has been shown that thyroid hormones can limit myocardial IRI via a fine balance between proapoptotic and prosurvival signaling pathways.Furthermore, thyroid hormones can provide a protection against myocardial IRI by inducing pharmacological preconditioning.The available evidence also indicates that perioperative oral T3 therapy can significantly attenuate the postoperative decline in serum T3 level or maintain total and free serum T3 levels within normal limits in adult and pediatric patients undergoing cardiac surgery.Given that oral administration is a safe, convenient and feasible route of perioperative medication. This has been proven by the single-center, prospective, double blind, randomized placebo-controlled clinical pilot trial including 40 patients receiving a dose of 0.4mg/kg (trial group, thyroid tablet taken orally once a day, for 4 days before surgery).In summary, this pilot study demonstrated that children after cardiac surgery with CPB are at a high risk to develop postoperative ESS. Preoperatively short-term oral thyroid hormones can reduce severity of postoperative ESS without negative effects and provides a protection against myocardial IRI by increasing HSP70 and MHCa expression.
In another reported double blind, placebo-controlled trial in 100 infants with normal thyroid function. Subjects underwent cardiac surgery and were randomly assigned during a 16-month period into 2 groups (50 in the thyroxine supplementation group and 50 in the placebo group) to determine whether there was an association between oral thyroxine (T4) supplementation and changes in cardiac index (CI), along with other important outcomes. Subjects in the study group received an oral dose of 5 µg/kg of T4 starting 12 hours before surgery and every morning thereafter while in the intensive care unit. Subjects in the study group had higher CI than did the placebo group (CI 0.30 L/min/m2 higher; P = .04).
It has been well described that early after the initiation of CPB, particularly DHCA, thyroid-stimulating hormone concentration is raised, responding to decreased concentrations of triiodothyronine (T3), and that levels restore during a period of days, beginning with thyroid stimulating hormone and followed by T3, an entity referred as ''euthyroid sick syndrome.'' An actual etiology for these changes has not been precisely described; however, hemodilution, hypothermia, and inflammation have been implicated. As of now, thyroid hormone supplementation remains the mainstay therapy for euthyroid sick syndrome.
This study , like several others, demonstrates that perioperative thyroid hormone supplementation is associated with improved outcomes. They demonstrated that Thyroid hormone levels are reduced significantly in the immediate postoperative period after open-heart surgery. Oral T4 supplementation improves the CI and reduces the inotropic requirement. In addition, it reduces the duration of mechanical ventilation, ICU and hospital stay, and TISS in infants after surgery for complex congenital heart defects.
Routinely, patients with delayed recovery and/or prolonged mechanical ventilation are managed as follow :
- Full neurological examination, CT brain, repeated CT brain after 48-hour, MRI stroke protocol, adding of brain stimulants medications and if fits developed antiepileptics would be added accordingly.
- Liver profile checked and liver support added,
- Renal profile checked, stoppage of nephrotoxic drugs, fluids chart, renal dose adjustment of medications.
- Blood sugar hourly monitored.
- Sepsis surveillance by withdrawing pan cultures, replacing old IV catheters upgrading antibiotics accordingly.
This is typically included in institutional ICU protocol. The primary aim of this study is to investigate the effect of supplementation of oral levothyroxine in delayed recovery patients post cardiac surgery.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Cairo, Egypt
- Faculty of Medicine ,Ain Shams University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
• Age group: Adult patients from age of 45 to70 years. (Majority of our patients falls in this age group 45-70 years, below these patients are relatively young and usually do not show delayed recovery or prolonged ventilation, while above 70 years are considered frail and more vulnerable to anesthetic medications, so we preferred to exclude them)
- Sex: Both sexes
- Elective, urgent and emergency open heart surgeries. (Most of urgent and emergency cases are either mechanical valve thrombosis or aortic dissection patients, and are more prone to prolonged mechanical ventilation and delayed recovery compared to elective patients)
Exclusion Criteria:
• Patients refuse to give informed consent.
- Patient younger than 45 years old, older than 70 years old.
- Off pump patients.
- Patients known hypothyroidism on levothyroxine supplementation.
- Patients known hyperthyroidism on Carbimazole.
- Those developing any form of arrhythmia L-Thyroxine will be stopped immediately and the patient will be excluded from the study.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Active Comparator: Group A (Study group)
group A will receive levothyroxine via Ryle, dose of 25 to 50 ug/ day according to BMI
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Patients who show signs of delayed recovery defined as either prolonged ventilation for 48 hours or delayed conscious level recovery for 48 hours despite exclusion of muscle relaxants and/or sedative drugs. Those patients will undergo CT brain, CT chest and neurological examination to exclude structural damage as per institutional protocols. Also, metabolic profile screening including full kidney function, full liver function, electrolyte to exclude correctable metabolic abnormalities. and thyroid profile (TSH, free T3, free T4) sick euthyroid patients who are having normal FreeT3, normal Free T4, low TSH and low level of free T3 or freeT4 will be included in the study according lab reference.Daily assessment of conscious level according to Glasgow Coma Scale (GCS) and spontaneous breathing trial by ICU consultant (the investigator) till ICU discharge. Patients will receive levothyroxine via Ryle, dose of 25 to 50 ug/ day according to BMI. |
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Placebo Comparator: Group B (Control)
group B will receive placebo in form of inert starch tablet
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patients will receive placebo oral tablet
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Change in Glasgow Coma Scale (GCS) From Intervention Initiation to ICU Discharge (Δ)
Time Frame: From intervention initiation (48 hours postoperatively) to ICU discharge, up to 1 month postoperatively. (i.e., within 28 days after baseline).
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The Glasgow Coma Scale (GCS) assesses conscious level through three components: Eye response (scored 1-4): 4: Opens eyes spontaneously 3: Opens eyes to verbal command 2: Opens eyes to pain 1: No eye opening Verbal response (scored 1-5): 5: Oriented and converses 4: Confused 3: Inappropriate words 2: Incomprehensible sounds 1: No verbal response Motor response (scored 1-6): 6: Obeys commands 5: Localizes to pain 4: Withdraws from pain 3: Abnormal flexion (decorticate) 2: Abnormal extension (decerebrate) 1: No motor response The total GCS score ranges from 3 (worst) to 15 (best), with higher scores indicating better neurological function. The primary outcome is the change in total GCS score from baseline (48 hours postoperatively, before intervention) to ICU discharge. |
From intervention initiation (48 hours postoperatively) to ICU discharge, up to 1 month postoperatively. (i.e., within 28 days after baseline).
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Total Duration of Mechanical Ventilation
Time Frame: From surgery completion until extubation (assessed for ≤30 days postoperatively).
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Total time (in hours) from initiation of mechanical ventilation postoperatively until successful extubation, including time before and after study intervention.
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From surgery completion until extubation (assessed for ≤30 days postoperatively).
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Duration of Intensive Care Unit (ICU) Stay
Time Frame: From ICU admission until discharge/death (assessed for ≤30 days postoperatively).
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Total time (in days) from ICU admission after cardiac surgery until discharge from ICU or death.
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From ICU admission until discharge/death (assessed for ≤30 days postoperatively).
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Total Hospital Stay Stay.
Time Frame: 30 days
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The total hospital stay will be recorded in days and compared between both groups.
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30 days
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Average Inotropic Support Infusion Rate in ICU
Time Frame: From ICU admission until discontinuation of inotropic support or ICU discharge (assessed daily for ≤30 days).
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Average infusion rate (in ng/kg/min) of norepinephrine and epinephrine administered during ICU stay.
Calculated as total dose (ng) divided by patient weight (kg) and total infusion duration (minutes).
Does not include intraoperative inotropic support.
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From ICU admission until discontinuation of inotropic support or ICU discharge (assessed daily for ≤30 days).
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Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to ICU Discharge
Time Frame: Preoperative assessment: Within 24 hours before surgery Postoperative assessment: At ICU discharge (≤30 days postoperatively)
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Absolute change in left ventricular ejection fraction (LVEF) measured by transthoracic echocardiography, calculated as: Δ EF = Postoperative EF - Preoperative EF Δ EF
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Preoperative assessment: Within 24 hours before surgery Postoperative assessment: At ICU discharge (≤30 days postoperatively)
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Number of Participants With New-onset Supraventricular Arrhythmia
Time Frame: From ICU admission until discharge or death (≤30 days postoperatively).
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Incidence of new-onset supraventricular arrhythmias (atrial fibrillation, atrial flutter, or supraventricular tachycardia) confirmed by 12-lead ECG during ICU stay.
Excludes pre-existing arrhythmias.
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From ICU admission until discharge or death (≤30 days postoperatively).
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Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Duntas LH, Jonklaas J. Levothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient's Lifetime. Adv Ther. 2019 Sep;36(Suppl 2):30-46. doi: 10.1007/s12325-019-01078-2. Epub 2019 Sep 4.
- Flores S, Checchia PA. Inflammatory and neurohormonal modulation for congenital heart surgery: The quest continues. J Thorac Cardiovasc Surg. 2018 Sep;156(3):1207-1208. doi: 10.1016/j.jtcvs.2018.06.004. Epub 2018 Jun 22. No abstract available.
- Batra YK, Singh B, Chavan S, Chari P, Dhaliwal RS, Ramprabu K. Effects of cardiopulmonary bypass on thyroid function. Ann Card Anaesth. 2000 Jul;3(2):3-6.
- Zhang JQ, Yang QY, Xue FS, Zhang W, Yang GZ, Liao X, Meng FM. Preoperative oral thyroid hormones to prevent euthyroid sick syndrome and attenuate myocardial ischemia-reperfusion injury after cardiac surgery with cardiopulmonary bypass in children: A randomized, double-blind, placebo-controlled trial. Medicine (Baltimore). 2018 Sep;97(36):e12100. doi: 10.1097/MD.0000000000012100.
- Kumar A, Taliyan R, Sharma PL. Evaluation of thyroid hormone induced pharmacological preconditioning on cardiomyocyte protection against ischemic-reperfusion injury. Indian J Pharmacol. 2012 Jan;44(1):68-72. doi: 10.4103/0253-7613.91870.
- Plumpton K, Haas NA. Identifying infants at risk of marked thyroid suppression post-cardiopulmonary bypass. Intensive Care Med. 2005 Apr;31(4):581-7. doi: 10.1007/s00134-004-2549-1. Epub 2005 Jan 28.
- Gerdes AM, Ojamaa K. Thyroid Hormone and Cardioprotection. Compr Physiol. 2016 Jun 13;6(3):1199-219. doi: 10.1002/cphy.c150012.
- Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine. 2004 Jun;24(1):1-13. doi: 10.1385/ENDO:24:1:001.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- FMASU R237/2024
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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