Clinical trial NCT06660823
Conditions: Cardiac Surgery Intensive Care Treatment Delayed Recovery From Anaesthesia Euthyroid Sick Syndrome Cardiac Surgery Requiring Cardiopulmonary Bypass
Keywords: L-Thyroxine Delayed recovery post cardiac surgery hypthyroidism
Sponsor: Ain Shams University
Start date: 2024-11-30; Completion date: 2025-06-25
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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 :

1. 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.
2. Liver profile checked and liver support added,
3. Renal profile checked, stoppage of nephrotoxic drugs, fluids chart, renal dose adjustment of medications.
4. Blood sugar hourly monitored.
5. 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.

Arms: arm 1: group A will receive levothyroxine via Ryle, dose of 25 to 50 ug/ day according to BMI arm 2: group B will receive placebo in form of inert starch tablet
Interventions: intervention 1: L-thyroxine intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: 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. intervention 2: patients will receive placebo oral tablet

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: Role of Levothyroxine Supplementation in Delayed Recovery Following 
Cardiac Surgery 
NCT Number: NCT06660823 
Document Date: November 1, 2024  


 
 
 
Protocol Of A Paper For Partial Fulfilment Of Research In 
Anesthesia, ICU and pain management 
  
 The title: Role of Levothyroxine supplementation in delayed 
recovery following cardiac surgery. 
 
NAME OF RESEARCHER:  Sarah Hamdy Mohamed El 
Ghareeb 
Academic Position: lecturer of Anaesthesia, Intensive Care and Pain management 
Department: Faculty of Medicine-Ain Shams University 
 
NAME OF RESEARCHER:  Ahmed Monier Ahmed    
Youssef   
 
Academic Position: Lecturer of Anaesthesia, Intensive Care and Pain management 
Department: Faculty of Medicine-Ain Shams University 
 
  
 
 
 
 
 
 
Faculty of Medicine 
Ain Shams University 
2024 
 
 
 
 
 
 
 


 
 
 
  
  
  
1. INTRODUCTION/ REVIEW (Maximum 1000 words) “References are needed”  
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 [1], atherogenic lipid 
profile, and coagulation abnormality [2].  
 
Hypothyroidism was reported to be strongly related to cardiovascular disease, 
respiratory complications, neurological complications, and a significant difference in 
ventilator weaning time [3].   
 
Severe thyroid dysfunction is related to muscle relaxation and lead to respiratory 
muscle depression and disturbed conscious level.[3]  
 
Surgical stress of cardiac surgery might be followed by a prolonged recovery process 
and cardiac dysfunction [3]. 
 
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 [4], and Society of Thoracic Surgeons (STS) 
score [5] do not include thyroid function assessment, even though it has a significant 
impact on the metabolic, cardiovascular, and circulation system. 
  
 
   
 
 
  
2. AIM/ OBJECTIVES (Maximum 300 words)  
The primary aim of this study is to investigate the effect of supplementation of oral 
levothyroxine  in delayed recovery patients post cardiac surgery.    
 
  
  


 
 
  
3. METHODOLOGY:   
Patients and Methods/ Subjects and Methods/ Material and Methods (Maximum 
1000 words) “References may be needed”  
This study is a prospective, randomized controlled trial that will study the postoperative     
clinical outcomes of levothyroxine supplementation in delayed recovery or prolonged 
ventilation patients post cardiac surgery. 
Randomization will be performed using a computer-generated randomization sequence 
and allocation concealment to be maintained all through the time of procedure, by using 
opaque, numbered, and sealed envelopes. 
The study protocol will receive ethical approval from the Research Ethical Committee/ 
Institutional Review Boards, Faculty of Medicine Ain Shams University. 
Informed consent will be obtained from each patient before patients' allocation. 
 
Type of the study: prospective randomized clinical trial study protocol.  
 
Study Setting: The operating theaters and ICU of Cardiothoracic institute of Ain 
Shams University Hospitals.  
 
 
Study period: one year.  
 
 
Sample Size:  
 
Using PASS 15 program for sample size calculation, setting power at 80% and alpha 
error at 0.05, it is estimated that sample size of 25  patients per group total 50 patients  
can detect an effect size .80 or  the difference between two groups regarding  different 
qualitative outcome measures using two-sized a z test  
Study population:  
 
Inclusion criteria: 
• Age group: Adult patients from age of 45 to70 years. 
Hypothyroidism was reported to be strongly related to cardiovascular disease, 
respiratory complications, neurological complications, and a significant difference in 
ventilator weaning time [3].   
• Sex: Both sexes  
• Elective, urgent and emergency open heart surgeries. 
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. 
 
 
Sampling method:  
 
Patients will be randomly allocated by computer generated randomization into two 
groups A and B: 
 
• Group A (Study group): patients receiving oral supplementation of 
levothyroxine.  
 
• Group B (Control): patients receiving Placebo drug.  
 
 
Anesthetic management: 
Full standard preoperative assessment for cardiac surgery will be done for all patients 
included in the study before planned procedures.  
Premedication will be given according to standard protocol in cardiac anesthesia. 
Routine monitoring included a five-lead electrocardiogram, pulse oximeter and invasive 
blood pressure. Anesthesia will be induced with midazolam 0.02mg/kg and fentanyl 2-
5 microgram /kg and muscle relaxation were achieved cisatracurium 0.15 mg/kg 
intravenous. After tracheal intubation, central venous line and TEE inserted, then 
anesthesia will be maintained throughout the procedure with morphin20 microgram/kg 
/min, cisatracurium 2mg/kg/min and sevoflurane 2%. Ventilation will be adjusted to 
maintain end-tidal carbon dioxide in the range of 30-40 mmHg.  
On ICU arrival all patients will be subjected to standardized management as per 
institutional protocols. 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 and thyroid profile (TSH, free T3, free T4) to exclude 
correctable metabolic abnormalities.   
Patients then divided into two groups: group A will receive levothyroxine via Ryle, dose 
of 25 to 50 ug/ day according to BMI, while group B will receive placebo in form of 
inert starch tablet. 
Daily assessment of conscious level according to Glasgow Coma Scale (GCS) and 
spontaneous breathing trial by ICU consultant till ICU discharge. 
Assessment of thyroid profile (free T3, free T4, TSH) before hospital discharge.  


 
 
Endpoints of the study: 
Primary end point: 
1. Improvement of Glasgow coma scale and spontaneous breathing trial before 
ICU discharge. 
 
Secondary end points: 
1. Total ventilation time. 
2. Total ICU stay. 
3. Total hospital stay. 
4. Total amount of inotropic support.  
5. Improvement of cardiac function by echocardiography. 
  
 
 
 
Ethical considerations:  
 
The study protocol will receive ethical approval from the Research Ethical 
Committee, Faculty of Medicine Ain Shams University.  
Informed consent will be obtained from each patient before patients' allocation.  
 
 
Sample Size Calculation 
Using PASS 15.0 (NCSS LLC), detecting an effect size of 0.80 in GCS change (α = 
0.05, power = 80%) required 25 patients per arm. To ensure adequate power for 
secondary endpoints and allow for dropouts, we enrolled 35 patients per group (total n 
= 70). 
Statistical Analysis 
Analyses adhered to the intention-to-treat principle. Continuous variables are reported 
as mean ± SD or median (IQR) and compared using Student’s t-test or Mann–Whitney 
U test, as appropriate. Categorical variables are expressed as counts (%) and 
compared by χ² or Fisher’s exact test. 
• Primary analysis: Linear mixed-effects regression modeled GCS trajectories 
over time, with group, time, and their interaction as fixed effects and patient as 
a random effect. 
• Time-to-event outcomes: Kaplan–Meier curves and Cox proportional hazards 
models yielded hazard ratios (HRs) and 95% confidence intervals (CIs). 
• Mediation: The Sobel test quantified the proportion of EF preservation 
attributable to changes in free T3. 


 
• Sensitivity and subgroup analyses: Inverse probability weighting assessed 
robustness; prespecified subgroups included diabetes status and CPB duration > 
200 minutes. 
All tests were two-tailed with α < 0.05. Statistical analyses were performed using R 
v4.3.1 with the lme4, lavaan, and survminer packages. 
 
 
 
 
 
 
4. REFERENCES (Maximum 20 references)   
1. Hsu, A.; Tsou, Y.-A.;Wang, T.-C.; Chang,W.-D.; Lin, C.-L.; Tyler, R.S. 
Hypothyroidism and related comorbidities on the risks of 
developing tinnitus. Sci. Rep. 2022, 12, 3401.  
2. Biondi, B.; Klein, I. Hypothyroidism as a risk factor for cardiovascular disease. 
Endocrine 2004, 24, 1–13.  
3. Montazer, M.; Shadvar, K.; Fathalizadeh, A.; Farmani, J. The role of 
hypothyroidism in weaning patients from mechanical 
ventilation: A clinical trail. J. Res. Clin. Med. 2020,  
4.Nashef, S.A.; Roques, F.; Sharples, L.D.; Nilsson, J.; Smith, C.; Goldstone, A.R.; 
Lockowandt, U. Euroscore ii. Eur. J. Cardio-Thoracic 
Surg. 2012, 41, 734–745.  
5. Shroyer, A.L.W.; Coombs, L.P.; Peterson, E.D.; Eiken, M.C.; DeLong, E.R.; Chen, 
A.; Ferguson, T.B., Jr.; Grover, F.L.; Edwards, F.H. 
The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk 
models. Ann. Thorac. Surg. 2003, 75, 1856–1865. 
 
 
 
Page 2