Indications for Intravenous T3 and T4

Abstract

Therapy with thyroid hormones normally is restricted to substitution therapy of patients with primary or secondary hypothyroidism. Typically, thyroid hormones are given orally. There are few indications for intravenous use of thyroid hormones. Indications for parenteral application are insufficient resorption of oral medications due to alterations of the gastrointestinal tract, partial or total loss of consciousness, sedation in the intensive care unit or shock. In almost all cases, levothyroxine is the therapy of choice including congenital hypothyroidism. In preterm infants with an altered thyroid hormone status, studies with thyroid hormones including intravenous liothyronine showed a normalisation of T3 levels and in some cases an amelioration of parameters of ventilation. A benefit for mortality or later morbidity could not be seen. Effects on neurological improvements later in life are under discussion. Decreased thyroid hormone levels are often found after cardiac surgery in infants and adults. Intravenous therapy with thyroid hormones improves the cardiac index, but in all other parameters investigated, no substantial effect on morbidity and mortality could be demonstrated. Oral liothyronine therapy in these situations was equivalent to an intravenous route of application. In myxoedema coma, intravenous levothyroxine is given for 3 to 10 days until the patient can take oral medication and normal resorption in the gastrointestinal tract is achieved by restoring at least peripheral euthyroidism. Intravenous levothyroxine is the standard in treating patients with myxoedema coma. A protective effect on the heart of i.v. levothyroxine in brain-dead organ donors may be possible.

Keywords

thyroid - hypothyroidism - liothyronine - levothyroxine - triiodothyronine

Publication History

Received: 12 March 2024

Accepted after revision: 02 May 2024

Accepted Manuscript online:
02 May 2024

Article published online:
05 June 2024

• References

• 1 von Heppe JH, Krude H, L'Allemand D. et al. The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism. J Pediatr Endocrinol Metab 2004; 17: 967-974
• 2 Balhara B, Misra M, Levitsky LL. Clinical monitoring guidelines for congenital hypothyroidism: laboratory outcome data in the first year of life. J Pediatr 2011; 158: 532-537
• 3 Stagi S, Municchi G, Ferrari M. et al. An overview on different l-thyroxine (l-T(4)) formulations and factors potentially influencing the treatment of congenital hypothyroidism during the first 3 years of life. Front Endocrinol 2022; 13: 859487
• 4 Donaldson M, Jones J. Optimising outcome in congenital hypothyroidism; current opinions on best practice in initial assessment and subsequent management. J Clin Res Pediatr Endocrinol 2013; 5: 13-22
• 5 Léger J, Olivieri A, Donaldson M. et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr 2014; 81: 80-103
• 6 van Trotsenburg P, Stoupa A, Léger J. et al. Congenital hypothyroidism: a 2020-2021 consensus guidelines update – an ENDO-European reference network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid 2021; 31: 387-419
• 7 Meijer WJ, Verloove-Vanhorick SP, Brand R. et al. Transient hypothyroxinaemia associated with developmental delay in very preterm infants. Arch Dis Childhood 1992; 67: 944-947
• 8 Pop VJ, Brouwers EP, Vader HL. et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003; 59: 282-288
• 9 Reuss ML, Paneth N, Pinto-Martin JA. et al. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Eng J Med 1996; 334: 821-827
• 10 Simpson J, Williams FL, Delahunty C. et al. Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. J Clin Endocrinol Metab 2005; 90: 1271-1279
• 11 van Wassenaer AG, Kok JH, Dekker FW. et al. Thyroid function in very preterm infants: influences of gestational age and disease. Pediatr Res 1997; 42: 604-609
• 12 Williams FL, Ogston SA, van Toor H. et al. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab 2005; 90: 5954-5963
• 13 Liu C, Wang K, Guo J. et al. Small for gestational age is a risk factor for thyroid dysfunction in preterm newborns. BMC Pediatr 2020; 20: 179
• 14 Lin X, Chen X, Yang CY. An analysis of perinatal factors of low T3 syndrome in preterm neonates with a gestational age of 28-35 weeks. Ann Med 2021; 53: 1722-1726
• 15 Paneth N. Does transient hypothyroxinemia cause abnormal neurodevelopment in premature infants?. Clin Perinatol 1998; 25: 627-643
• 16 Fisher DA. Thyroid function in premature infants. The hypothyroxinemia of prematurity. Clin Perinatol 1998; 25: 999-1014 viii
• 17 Rabin CW, Hopper AO, Job L. et al. Incidence of low free T4 values in premature infants as determined by direct equilibrium dialysis. J Perinatol 2004; 24: 640-644
• 18 Amato M, Guggisberg C, Schneider H. Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Horm Res 1989; 32: 213-217
• 19 Amato M, Pasquier S, Carasso A. et al. Postnatal thyroxine administration for idiopathic respiratory distress syndrome in preterm infants. Horm Res 1988; 29: 27-30
• 20 Chowdhry P, Scanlon JW, Auerbach R. et al. Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia. Pediatrics 1984; 73: 301-305
• 21 Schönberger W, Grimm W, Emmrich P. et al. Reduction of mortality rate in premature infants by substitution of thyroid hormones. Eur J Pediatr 1981; 135: 245-253
• 22 Smith LM, Leake RD, Berman N. et al. Postnatal thyroxine supplementation in infants less than 32 weeks' gestation: effects on pulmonary morbidity. J Perinatol 2000; 20: 427-431
• 23 Valerio PG, van Wassenaer AG, de Vijlder JJ. et al. A randomized, masked study of triiodothyronine plus thyroxine administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects. Pediatr Res 2004; 55: 248-253
• 24 Vanhole C, Aerssens P, Naulaers G. et al. l-Thyroxine treatment of preterm newborns: clinical and endocrine effects. Pediatr Res 1997; 42: 87-92
• 25 Cuestas RA, Lindall A, Engel RR. Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood. N Eng J Med 1976; 295: 297-302
• 26 Cools F, van Wassenaer AG, Kok JH. et al. Changes in plasma thyroid hormone levels after a single dose of triiodothyronine in premature infants of less than 30 weeks gestational age. Eur J Endocrinol 2000; 143: 733-740
• 27 Biswas S, Buffery J, Enoch H. et al. Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants less than 30 weeks gestation: results of the THORN trial--thyroid hormone replacement in neonates. Pediatr Res 2003; 53: 48-56
• 28 Osborn DA, Hunt RW. Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants. Cochrane Database System Rev. 2007 1. Cd005948 DOI: 10.1002/14651858
• 29 La Gamma EF, van Wassenaer AG, Golombek SG. et al. Neonatal thyroxine supplementation for transient hypothyroxinemia of prematurity : beneficial or detrimental?. Treat Endocrinol 2006; 5: 335-346
• 30 Salomo LH, Laursen AH, Reiter N. et al. Myxoedema coma: an almost forgotten, yet still existing cause of multiorgan failure. BMJ Case Rep 2014; 2014: bcr2013203223
• 31 Roy N, Majumder A, Sanyal D. et al. Legions of presentations of myxedema coma: a case series from a tertiary hospital in India. J ASEAN Fed Endocr Soc 2020; 35: 233-237
• 32 Bourcier S, Coutrot M, Ferré A. et al. Critically ill severe hypothyroidism: a retrospective multicenter cohort study. Ann Intensive Care 2023; 13: 15
• 33 Wartofsky L. Myxedema coma. Endocrinol Metab Clin North America 2006; 35: 687-698 vii–viii
• 34 Yamamoto T, Fukuyama J, Fujiyoshi A. Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Thyroid 1999; 9: 1167-1174
• 35 Beynon J, Akhtar S, Kearney T. Predictors of outcome in myxoedema coma. Crit Care 2008; 12: 111
• 36 Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med 2007; 22: 224-231
• 37 Constant EL, de Volder AG, Ivanoiu A. et al. Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. J Clin Endocrinol Metab 2001; 86: 3864-3870
• 38 Dutta P, Bhansali A, Masoodi SR. et al. Predictors of outcome in myxoedema coma: a study from a tertiary care centre. Crit Care 2008; 12: R1
• 39 Arlot S, Debussche X, Lalau JD. et al. Myxoedema coma: response of thyroid hormones with oral and intravenous high-dose l-thyroxine treatment. Intensive Care Med 1991; 17: 16-18
• 40 McCulloch W, Price P, Hinds CJ. et al. Effects of low dose oral triiodothyronine in myxoedema coma. Intensive Care Med 1985; 11: 259-262
• 41 Mir SA, Wani AI, Masoodi SR. et al. Lithium toxicity and myxedema crisis in an elderly patient. Indian J Endocrinol Metab 2013; 17: S654-S656
• 42 Savage MW, Mah PM, Weetman AP. et al. Endocrine emergencies. Postgrad Med J 2004; 80: 506-515
• 43 Gupta KJ. Myxedema coma: a sleeping giant in clinical practice. Am J Med 2013; 126: e3-e4
• 44 Rajendran A, Bhavani N, Nair V. et al. Oral levothyroxine is an effective option for myxedema coma: a single-centre experience. Eur Thyroid J 2021; 10: 52-58
• 45 Pereira VG, Haron ES, Lima-Neto N. et al. Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. J Endocrinol Invest 1982; 5: 331-334
• 46 Reinhardt W, Mann K. [Incidence, clinical picture and treatment of hypothyroid coma. Results of a survey]. Med Klin (Munich) 1997; 92: 521-524
• 47 Chernow B, Burman KD, Johnson DL. et al. T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. Crit Care Med 1983; 11: 99-104
• 48 Escobar-Morreale HF, Obregón MJ, Escobar del Rey F. et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 1995; 96: 2828-2838
• 49 Fliers E, Boelen A. An update on non-thyroidal illness syndrome. J Endocrinol Invest 2021; 44: 1597-1607
• 50 Nistal-Nuno B. Euthyroid sick syndrome in paediatric and adult patients requiring extracorporeal circulatory support and the role of thyroid hormone supplementation: a review. Perfusion 2021; 36: 21-33
• 51 Leeuwen L, van Heijst AFJ, van Rosmalen J. et al. Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation. J Perinatol 2017; 37: 906-910
• 52 Talwar S, Khadgawat R, Sandeep JA. et al. Cardiopulmonary bypass and serum thyroid hormone profile in pediatric patients with congenital heart disease. Congenit Heart Dis 2012; 7: 433-440
• 53 Portman MA, Slee A, Olson AK. et al. Triiodothyronine supplementation in infants and children undergoing cardiopulmonary bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis. Circulation 2010; 122: S224-S233
• 54 Portman MA, Slee AE, Roth SJ. et al. Triiodothyronine supplementation in infants undergoing cardiopulmonary bypass: a randomized controlled trial. Semin Thorac Cardiovasc Surg 2023; 35: 105-112
• 55 Marwali EM, Boom CE, Sakidjan I. et al. Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease. Pediatr Crit Care Med 2013; 14: 701-708
• 56 Choi YS, Shim JK, Song JW. et al. Efficacy of perioperative oral triiodothyronine replacement therapy in patients undergoing off-pump coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2013; 27: 1218-1223
• 57 Shih JL, Agus MS. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr 2009; 21: 536-540
• 58 Bennett-Guerrero E, Jimenez JL, White WD. et al. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. JAMA 1996; 275: 687-692
• 59 Güden M, Akpinar B, Sagğbaş E. et al. Effects of intravenous triiodothyronine during coronary artery bypass surgery. Asian Cardiovasc Thorac Ann 2002; 10: 219-222
• 60 Klemperer JD, Klein I, Gomez M. et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Eng J Med 1995; 333: 1522-1527
• 61 Klemperer JD, Klein IL, Ojamaa K. et al Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996; 61: 1323-1327 discussion 1328–1329
• 62 Mullis-Jansson SL, Argenziano M, Corwin S. et al. A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. J Thorac Cardiovasc Surg 1999; 117: 1128-1134
• 63 Novitzky D, Cooper DK, Barton CI. et al Triiodothyronine as an inotropic agent after open heart surgery. J Thorac Cardiovasc Surg 1989; 98: 972-977 discussion 977–978
• 64 Vavouranakis I, Sanoudos G, Manios A. et al. Triiodothyronine administration in coronary artery bypass surgery: effect on hemodynamics. J Cardiovasc Surg (Torino) 1994; 35: 383-389
• 65 Kaptein EM, Sanchez A, Beale E. et al. Clinical review: thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab 2010; 95: 4526-4534
• 66 Choi YS, Kwak YL, Kim JC. et al. Peri-operative oral triiodothyronine replacement therapy to prevent postoperative low triiodothyronine state following valvular heart surgery. Anaesthesia 2009; 64: 871-877
• 67 Magalhães AP, Gus M, Silva LB. et al. Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery. Braz J Med Biol Res 2006; 39: 969-978
• 68 Sirlak M, Yazicioglu L, Inan MB. et al. Oral thyroid hormone pretreatment in left ventricular dysfunction. Eur J Cardiothorac Surg 2004; 26: 720-725
• 69 Tharmapoopathy M, Thavarajah A, Kenny RPW. et al. Efficacy and safety of triiodothyronine treatment in cardiac surgery or cardiovascular diseases: a systematic review and meta-analysis of randomized controlled trials. Thyroid 2022; 32: 879-896
• 70 Rosendale JD, Kauffman HM, McBride MA. et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation 2003; 75: 1336-1341
• 71 Novitzky D, Mi Z, Sun Q. et al. Thyroid hormone therapy in the management of 63,593 brain-dead organ donors: a retrospective analysis. Transplantation 2014; 98: 1119-1127
• 72 Dhar R, Stahlschmidt E, Marklin G. A randomized trial of Intravenous thyroxine for brain-dead organ donors with impaired cardiac function. Prog Transplant 2020; 30: 48-55
• 73 Dhar R, Stahlschmidt E, Yan Y. et al. A randomized trial comparing triiodothyronine (T3) with thyroxine (T4) for hemodynamically unstable brain-dead organ donors. Clin Transplant 2019; 33: e13486
• 74 Bajwa SJ, Jindal R. Endocrine emergencies in critically ill patients: challenges in diagnosis and management. Indian J Endocrinol Metab 2012; 16: 722-727
• 75 Dubbs SB, Spangler R. Hypothyroidism: causes, killers, and life-saving treatments. Emerg Med Clin North Am 2014; 32: 303-317
• 76 Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am 2012; 96: 385-403
• 77 Mathew V, Misgar RA, Ghosh S. et al. Myxedema coma: a new look into an old crisis. J Thyroid Res 2011; 493462
• 78 Pimentel L, Hansen KN. Thyroid disease in the emergency department: a clinical and laboratory review. J Emerg Med 2005; 28: 201-209
• 79 Bürgi U, Perrig M. [Endocrine crises]. Ther Umsch 2005; 62: 369-373