Role of Levothyroxine Supplementation in Delayed Recovery Following Cardiac Surgery

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.

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.

Eligibility Criteria:
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.