Prolonged critical illness is characterized by reduced pulsatile TSH secretion whereby reduced thyroid hormone release, and by profound changes in thyroid hormone metabolism, resulting in low circulating T3 and elevated rT3 levels. To further unravel the underlying mechanisms, we investigated the effects of exogenous TRH and growth hormone releasing peptide-2 (GHRP-2) in an in vivo model of prolonged critical illness. Burn-injured, parenterally fed rabbits were randomized to receive 4-d treatment with either saline; 60 µg/kg/h GHRP-2; 60 µg/kg/h TRH or 60 + 60 µg/kg/h TRH+GHRP-2, started on day 4 of the illness (n = 8 per group). Activity of the deiodinases D1, D2 and D3 in snap-frozen liver, kidney and muscle, as well as impact on circulating thyroid hormone levels was studied.

Compared with healthy controls, hepatic D1 activity in the saline-treated, ill animals was significantly downregulated (P = 0.02) and D3 activity tended to be upregulated (P = 0.06). Infusion of TRH and TRH+GHRP-2 restored the catalytic activity of D1 (P = 0.02) and increased T3 levels back within physiological range (P = 0.008). D3 activity was normalized by all three interventions but only addition of GHRP-2 to TRH prevented the rise of rT3 seen with TRH alone (P = 0.02). Liver D1 and D3 activity were correlated, respectively positively and negatively, with the changes in circulating T3 (R=0.84 and R0.65) and the T3/rT3 ratio (R=0.71 and R0.60).

We conclude that D1 activity during critical illness is suppressed, related to the alterations within the thyrotropic axis, whereas D3 activity tends to be increased and under the joint control of the somatotropic and thyrotropic axes.