Triiodothyronine supplementation in a sheep model of intensive care

Maiden,Matthew J.; Maiden,Matthew J.; Torpy,David J.; Torpy,David J.; Ludbrook,Guy L.; Ludbrook,Guy L.; Clarke,Iain J.; Clarke,Iain J.; Chacko,Binila; Chacko,Binila; Nash,Coralie H.; Nash,Coralie H.; Matthews,Loren; Matthews,Loren; Porter,Susan; Porter,Susan; Kuchel,Tim R.; Kuchel,Tim R.

doi:10.3892/etm.2024.12611

Triiodothyronine supplementation in a sheep model of intensive care

Authors:
- Matthew J. Maiden
- David J. Torpy
- Guy L. Ludbrook
- Iain J. Clarke
- Binila Chacko
- Coralie H. Nash
- Loren Matthews
- Susan Porter
- Tim R. Kuchel
View Affiliations

Affiliations: Discipline of Acute Care Medicine, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia 5005, Australia, Endocrine and Metabolic Unit, Department of Medicine, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, South Australia 5000, Australia, Department of Physiology, Faculty of Science, Monash University, Clayton, Victoria 3800, Australia, Intensive Care Unit, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, South Australia 5000, Australia, Preclinical, Imaging and Research Laboratories, South Australian Health and Medical Research Institute, Hillcrest, South Australia 5086, Australia
Published online on: June 17, 2024 https://doi.org/10.3892/etm.2024.12611
Article Number: 321

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Triiodothyronine (T3) concentrations in plasma decrease during acute illness and it is unclear if this contributes to disease. Clinical and laboratory studies of T3 supplementation in disease have revealed little or no effect. It is uncertain if short term supplementation of T3 has any discernible effect in a healthy animals. Observational study of intravenous T3 (1 µg/kg/h) for 24 h in a healthy sheep model receiving protocol‑guided intensive care supports (T3 group, n=5). A total of 45 endpoints were measured including hemodynamic, respiratory, renal, hematological, metabolic and endocrine parameters. Data were compared with previously published studies of sheep subject to the same support protocol without administered T3 (No T3 group, n=5). Plasma free T3 concentrations were elevated 8‑fold by the infusion (pmol/l at 24 h; T3 group 34.9±9.9 vs. No T3 group 4.4±0.3, P<0.01, reference range 1.6 to 6.8). There was no significant physiological response to administration of T3 over the study duration. Supplementation of intravenous T3 for 24 h has no physiological effect on relevant physiological endpoints in healthy sheep. Further research is required to understand if the lack of effect of short‑term T3 may be related to kinetics of T3 cellular uptake, metabolism and action, or acute counterbalancing hormone resistance. This information may be helpful in design of clinical T3 supplementation trials.

View Figures

View References

1	Maiden MJ and Torpy DJ: Thyroid hormones in critical illness. Crit Care Clin. 35:375–388. 2019.PubMed/NCBI View Article : Google Scholar
2	Ray DC, Macduff A, Drummond GB, Wilkinson E, Adams B and Beckett GJ: Endocrine measurements in survivors and non-survivors from critical illness. Intensive Care Med. 28:1301–1308. 2002.PubMed/NCBI View Article : Google Scholar
3	Meyer S, Schuetz P, Wieland M, Nusbaumer C, Mueller B and Christ-Crain M: Low triiodothyronine syndrome: A prognostic marker for outcome in sepsis? Endocrine. 39:167–174. 2011.PubMed/NCBI View Article : Google Scholar
4	den Brinker M, Dumas B, Visser TJ, Hop WC, Hazelzet JA, Festen DA, Hokken-Koelega AC and Joosten KF: Thyroid function and outcome in children who survived meningococcal septic shock. Intensive Care Med. 31:970–976. 2005.PubMed/NCBI View Article : Google Scholar
5	Joosten KF, de Kleijn ED, Westerterp M, de Hoog M, Eijck FC, Hop WCJ, Voort EV, Hazelzet JA and Hokken-Koelega AC: Endocrine and metabolic responses in children with meningoccocal sepsis: Striking differences between survivors and nonsurvivors. J Clin. Endocrinol. Metab. 85:3746–3753. 2000.PubMed/NCBI View Article : Google Scholar
6	Yildizdas D, Onenli-Mungan N, Yapicioglu H, Topaloglu AK, Sertdemir Y and Yuksel B: Thyroid hormone levels and their relationship to survival in children with bacterial sepsis and septic shock. J Pediatr Endocrinol Metab. 17:1435–1442. 2004.PubMed/NCBI
7	Angelousi AG, Karageorgopoulos DE, Kapaskelis AM and Falagas ME: Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: A systematic review. Eur J Endocrinol. 164:147–155. 2011.PubMed/NCBI View Article : Google Scholar
8	Fliers E and Boelen A: An update on non-thyroidal illness syndrome. J Endocrinol Invest. 44:1597–1607. 2021.PubMed/NCBI View Article : Google Scholar
9	Beltrao FEL, Beltrao DCA, Carvalhal G, Beltrão FEL, Brito ADS, Capistrano KHRD, Bastos IHA, Hecht F, Daltro CHDC, Bianco AC, et al: Thyroid hormone levels during hospital admission inform disease severity and mortality in COVID-19 patients. Thyroid. 31:1639–1649. 2021.PubMed/NCBI View Article : Google Scholar
10	Van den Berghe G: Non-thyroidal illness in the ICU: A syndrome with different faces. Thyroid. 24:1456–1465. 2014.PubMed/NCBI View Article : Google Scholar
11	Adler SM and Wartofsky L: The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am. 36:657–672, vi. 2007.PubMed/NCBI View Article : Google Scholar
12	Kaptein EM, Sanchez A, Beale E and Chan LS: Clinical review: Thyroid hormone therapy for postoperative nonthyroidal illnesses: A systematic review and synthesis. J Clin Endocrinol Metab. 95:4526–4534. 2010.PubMed/NCBI View Article : Google Scholar
13	Macdonald PS, Aneman A, Bhonagiri D, Jones D, O'Callaghan G, Silvester W, Watson A and Dobb G: A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Crit Care Med. 40:1635–1644. 2012.PubMed/NCBI View Article : Google Scholar
14	Maiden MJ, Chapman MJ, Torpy DJ, Kuchel TR, Clarke IJ, Nash CH, Fraser JD and Ludbrook GL: Triiodothyronine administration in a model of septic shock: A randomized blinded placebo-controlled trial. Crit Care Med. 44:1153–1160. 2016.PubMed/NCBI View Article : Google Scholar
15	Maiden MJ and Forehan S: The use of triiodothyronine during critical illness. Curr Opin Clin Nutr Metab Care. 27:163–167. 2024.PubMed/NCBI View Article : Google Scholar
16	Burman KD and Wartofsky L: Thyroid function in the intensive care unit setting. Crit Care Clin. 17:43–57. 2001.PubMed/NCBI View Article : Google Scholar
17	Gardner DF, Kaplan MM, Stanley CA and Utiger RD: Effect of tri-iodothyronine replacement on the metabolic and pituitary responses to starvation. N Engl J Med. 300:579–584. 1979.PubMed/NCBI View Article : Google Scholar
18	Stathatos N, Levetan C, Burman KD and Wartofsky L: The controversy of the treatment of critically ill patients with thyroid hormone. Best Pract Res Clin Endocrinol Metab. 15:465–478. 2001.PubMed/NCBI View Article : Google Scholar
19	National Health and Medical Research Council (Australian Government): Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. 7th edition. National Health and Medical Research Council, Canberra, p85, 2004.
20	Bocking AD, McMillen IC, Harding R and Thorburn GD: Effect of reduced uterine blood flow on fetal and maternal cortisol. J Dev Physiol. 8:237–245. 1986.PubMed/NCBI
21	Snow TR, Deal MT, Connelly TS, Yokoyama Y and Novitzky D: Acute inotropic response of rabbit papillary muscle to triiodothyronine. Cardiology. 80:112–117. 1992.PubMed/NCBI View Article : Google Scholar
22	Tielens ET, Forder JR, Chatham JC, Marrelli SP and Ladenson PW: Acute L-triiodothyronine administration potentiates inotropic responses to beta-adrenergic stimulation in the isolated perfused rat heart. Cardiovasc Res. 32:306–310. 1996.PubMed/NCBI View Article : Google Scholar
23	Wang YG, Dedkova EN, Fiening JP, Ojamaa K, Blatter LA and Lipsius SL: Acute exposure to thyroid hormone increases Na+ current and intracellular Ca²⁺ in cat atrial myocytes. J Physiol. 546:491–499. 2003.PubMed/NCBI View Article : Google Scholar
24	Walker JD, Crawford FA Jr, Mukherjee R and Spinale FG: The direct effects of 3,5,3'-triiodo-L-thyronine (T3) on myocyte contractile processes. Insights into mechanisms of action. J Thorac Cardiovasc Surg. 110:1369–1380. 1995.PubMed/NCBI View Article : Google Scholar
25	Sigtermans M, Dahan A, Mooren R, Bauer M, Kest B, Sarton E and Olofsen E: S(+)-ketamine effect on experimental pain and cardiac output: A population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology. 111:892–903. 2009.PubMed/NCBI View Article : Google Scholar
26	Coulson NM, Januszkiewicz AJ and Ripple GR: Physiological responses of sheep to two hours anaesthesia with diazepam-ketamine. Vet Rec. 129:329–332. 1991.PubMed/NCBI View Article : Google Scholar
27	Folkesson HG, Norlin A, Wang Y, Abedinpour P and Matthay MA: Dexamethasone and thyroid hormone pretreatment upregulate alveolar epithelial fluid clearance in adult rats. J Appl Physiol (1995). 88:416–424. 2000.PubMed/NCBI View Article : Google Scholar
28	Lei J, Nowbar S, Mariash CN and Ingbar DH: Thyroid hormone stimulates Na-K-ATPase activity and its plasma membrane insertion in rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 285:L762–L772. 2003.PubMed/NCBI View Article : Google Scholar
29	Lin HH and Tang MJ: Thyroid hormone upregulates Na,K-ATPase alpha and beta mRNA in primary cultures of proximal tubule cells. Life Sci. 60:375–382. 1997.PubMed/NCBI View Article : Google Scholar
30	Amato M, Guggisberg C and Schneider H: Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Horm Res. 32:213–217. 1989.PubMed/NCBI View Article : Google Scholar
31	Acker CG, Flick R, Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Greenberg A and Johnson JP: Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am J Transplant. 2:57–61. 2002.PubMed/NCBI View Article : Google Scholar
32	St Germain DL and Galton VA: The deiodinase family of selenoproteins. Thyroid. 7:655–668. 1997.PubMed/NCBI View Article : Google Scholar
33	Debaveye Y, Ellger B, Mebis L, Visser TJ, Darras VM and Van den Berghe G: Effects of substitution and high-dose thyroid hormone therapy on deiodination, sulfoconjugation, and tissue thyroid hormone levels in prolonged critically ill rabbits. Endocrinology. 149:4218–4228. 2008.PubMed/NCBI View Article : Google Scholar
34	Tu HM, Legradi G, Bartha T, Salvatore D, Lechan RM and Larsen PR: Regional expression of the type 3 iodothyronine deiodinase messenger ribonucleic acid in the rat central nervous system and its regulation by thyroid hormone. Endocrinology. 140:784–790. 1999.PubMed/NCBI View Article : Google Scholar
35	Kim SW, Harney JW and Larsen PR: Studies of the hormonal regulation of type 2 5'-iodothyronine deiodinase messenger ribonucleic acid in pituitary tumor cells using semiquantitative reverse transcription-polymerase chain reaction. Endocrinology. 139:4895–4905. 1998.PubMed/NCBI View Article : Google Scholar
36	Kronenberg H and Williams RH: Williams Textbook of Endocrinology. Saunders Elsevier, Philadelphia, PA, 2008.
37	Bassett JH, Harvey CB and Williams GR: Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol. 213:1–11. 2003.PubMed/NCBI View Article : Google Scholar
38	Brooks I, Flynn SB, Owen DA and Underwood AH: Changes in cardiac function following administration of thyroid hormones in thyroidectomised rats: Assessment using the isolated working rat heart preparation. J Cardiovasc Pharmacol. 7:290–296. 1985.PubMed/NCBI View Article : Google Scholar
39	Gay RG, Raya TE, Lancaster LD, Lee RW, Morkin E and Goldman S: Effects of thyroid state on venous compliance and left ventricular performance in rats. Am J Physiol. 254:H81–H88. 1988.PubMed/NCBI View Article : Google Scholar
40	Ojamaa K, Kenessey A, Shenoy R and Klein I: Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol Endocrinol Metab. 279:E1319–E1324. 2000.PubMed/NCBI View Article : Google Scholar
41	Marcus RH, Butkow N, Wheatley AM, Lippe I, Norton G and Rosendorff C: Independent mechanisms for the chronotropic and inotropic responses in hyperthyroidism. Basic Res Cardiol. 82:261–270. 1987.PubMed/NCBI View Article : Google Scholar
42	Ladenson PW, Goldenheim PD and Ridgway EC: Rapid pituitary and peripheral tissue responses to intravenous L-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab. 56:1252–1259. 1983.PubMed/NCBI View Article : Google Scholar
43	Portman MA, Qian K, Krueger J and Ning XH: Direct action of T3 on phosphorylation potential in the sheep heart in vivo. Am J Physiol Heart Circ Physiol. 288:H2484–H2490. 2005.PubMed/NCBI View Article : Google Scholar
44	DiPierro FV, Bavaria JE, Lankford EB, Polidori DJ, Acker MA, Streicher JT and Gardner TJ: Triiodothyronine optimizes sheep ventriculoarterial coupling for work efficiency. Ann Thorac Surg. 62:662–669. 1996.PubMed/NCBI View Article : Google Scholar
45	Schmidt BM, Martin N, Georgens AC, Tillmann HC, Feuring M, Christ M and Wehling M: Nongenomic cardiovascular effects of triiodothyronine in euthyroid male volunteers. J Clin Endocrinol Metab. 87:1681–1686. 2002.PubMed/NCBI View Article : Google Scholar