Two valuable studies are available on replacement therapy using thyroid hormone in patients with NTIS.  In the study by Brent and Hershman ( 49), replacement with 1.5 ug T4 i.v. per kilogram body weight daily, in 12 patients, promptly returned serum T4 levels to normal (thereby proving that a binding defect was not the cause of the low T4) , but did not normalize T3 levels over a period of 2 - 3 weeks. However, in both the treated and control group, mortality was 80% ( 49). Clearly, this excellent small study, which used for primary therapy what would now be considered the wrong hormone, failed to show either an advantageous, or disadvantageous, effect. It is possible that the failure to show a positive effect was due to the failure of T3 levels to be restored to normal. In a study of severely burned patients given 200 ug T3 daily, again there was no evidence of a beneficial or disadvantageous effect ( 117). Mortality was not so great, as in the Brent and Hershman study, but it is entirely possible that the high levels of T3 provided worsened the hypermetabolism known to be present in burn patients, and could have, at these levels, been disadvantageous.

An important study by Acker et al certainly advises caution regarding T4 therapy in patients with acute renal failure. Numerous studies in animals have documented a beneficial effect of T4 therapy in experimental acute renal failure(118). In a randomized controlled prospective study of patients with acute renal failure, they treated patients received 150 mg of thyroxine four times intravenously over two days. The single difference recognized in the subsequent laboratory data  was a suppression of TSH. T4 treatment had no effect on any measure of ARF severity. Among other questions, it is not clear that serum T3 levels were ever altered.  However, mortality was higher in the thyroxine group (43 vs. 13%) than in the control group. It is of interest that, as the authors state, “the observed mortality in the controls in this study was less than that typically seen in our institution in ARF and ICU patients, whereas the 43% mortality noted in the thyroid group better approximates both our experience and that reported in the literature for ICU patients.” It will be difficult to replicate this study (although this reader believes it should be replicated). But it is uncertain whether the small dose of thyroxine administered over two days actually is related to the mortality, considering that the mortality in the treated group was that usually observed, whereas the control happened to have a much lower mortality (119). The same group has also studied the effect of thyroid hormone treatment on post-transplant acute tubular necrosis. T3 treatment during the post-transplant period did not alter outcome in a beneficial or derogatory manner (120).

  Studies from animals are often quoted in the literature as an argument against treatment of NTIS, or for the therapy. A study of sepsis induced in animals showed no difference in mortality, but some animals treated with thyroid hormone died earlier than did those that were untreated ( 121). Chopra et al. induced an NTIS in rats by injection of turpentine oil. The reduction in T4, T3, Free T4 Index, and TSH were associated with no clear evidence of tissue hypothyroidism, and urinary nitrogen excretion was normal. Thyroid hormone replacement with T4 or T3 did not significantly alter enzyme activities or urinary nitrogen excretion ( 122). Healthy pigs were subjected to 20 minutes of regional myocardial ischemia by Hsu and collaborators ( 123), and this was associated with a drop in T3, free T3, and elevated rT3. Some animals were treated with 0.2 ug T3 per kilogram for five doses over two hours. While myocardial infarction size was not altered, the pigs treated with T3 showed a more rapid improvement in cardiac index. Oxygen consumption did not alter. It should be noted that the T3 levels fell back to normal levels within four hours of the last T3 dose, suggesting that more prolonged therapy might have been beneficial. Katzeff  et al (124)studied a model of NTI induced by caloric restriction in young rats. In these animals T3 was reduced, and there was a decrease in LV relaxation time, SERCA2 mRNA, and alpha-MHC mRNA. All changes were were reversed to normal values by supplementation with T3, suggesting that the low-T3 syndrome was related to the pathological cardiac changes. Sepsis and multisystem organ failure are often associated with disseminated intravascular coagulation and consumption of coag inhibitors such as antithrombin-III. Chapital studied a model of sepsis in rats, and showed that T3 supplementation reduced the decrease in ATIII levels, which presumably would reflect a beneficial effect (125).Dogs subjected to hemorrhagic shock recover more cardiovascular function when given T3 intravenously than did untreated animals ( 126).Neurological outcome after anoxia is improved in dogs by T3 treatment ( 127).

Short term studies on T3 replacement of patients in shock, in patients with respiratory disease, in subjects who are brain dead and potential organ donors, and in patients undergoing coronary artery bypass grafts, all suggest modest cardiovascular benefits from the administration of T3 through .  One study reports benefit by replacing T3 to elevate the depressed T3 levels in premature infants(128).  A few studies found no apparent effects .    Children treated with T3 postoperatively when they have undergone cardiac surgery also require less cardiac support .  T3 administration (one dose of approximately 6 ug iv) did not alter cardiac performance in brain dead transplant donors.(129-130)   Coronary artery bypass, as studied by Klemperer and collaborators ( 32), was associated with a drop in serum T3. Administration of T3 iv elevated T3 above normal and augmented cardiac output and reduced need for pressor support, but had no other effect. In this study, however, the patients had a very favorable prognosis and minimal NTIS, and the study primarily shows that administration of T3 had no adverse effect under these circumstances. In a study reported several years ago,T3 administration to critically ill neonates with severe respiratory distress appeared to improve survival. Infants of less than 37 weeks gestational age, or weighing less than 220 grams, were given prophylactic doses of thyroxine and T3 daily and had a lower mortality rate than untreated infants ( 128).   Goarin et al studied the effect of T3 administration in brain dead organ donors and found that, although it returned T3 levels to normal, it did not improve hemodynamic status or myocardial function (131). The general outcome of these studies is that they weakly support the use of T3, and none of the studies  found evidence of damage caused by treatment(132-138).

In summary, it can be stated that there is no clear evidence that thyroxine or triiodothyronine treatment of the NTIS in animals or man is disadvantageous, and no certain proof that it is advantageous. However, what evidence there is suggests it may be beneficial. The argument has been raised that administration of thyroid hormone in NTIS would prevent the elevation in TSH commonly seen in recovering patients. This seems rather specious. More objectively, the elevation of TSH is another suggestion that the few patients who survive the ordeal were originally hypothyroid, and left untreated. Lastly, it is unlikely that administration of replacment hormone during NTIS would be harmful , even if all of the evidence presented above suggesting hypothyroidism was erroneous, and the patients were in fact euthyroid.