In a prospective study of critically ill hypothyroxinemic patients, we assessed the relationship between serum TSH and T₄ during the return of serum T₄ normal during recovery. In this longitudinal study of 60 patients with a variety of critical illnesses, including burns, septicemia, and acute renal failure, serum T₄ fell to less than 2.7 μg/dl (35 nmol/liter) in 24 patients, of whom 14 survived with return of T₄ to normal. A rise in total T₄ of more than 1.9 μg/dl (25 nmol/liter) within 96 h occurred 13 times in 10 patients, while 4 patients had slower increases in T₄. All 13 episodes of rapid T₄ rise [1.7 ± 0.8 (± SD) to 5.6 ± 2.1 μg/dl] were associated with a marked increase in serum TSH (1.1 ± 0.8 to 7.0 ± 5.2 mU/liter), and TSH was transiently above normal during 8 episodes of T₄ recovery. In the 6 episodes with sampling less than 6 h apart, the TSH rise consistently preceded the T₄ rise. In the 4 patients who received dopamine, TSH and T₄ remained low until cessation of therapy. During the TSH rise, only minor changes, which could not account for the increase in total T₄, occurred in T₄-binding globulin (12.9 ± 3.3 to 14. 8 ± 3.3 mg/liter), prealbumin (208 ± 73 to 234 ± 82 mg/liter), and albumin (28.3 ± 2.9 to 31.9 ± 2.9 g/liter). Mean free T₄ increased (0.60 ± 0.34 to 1.45 ± 0.56 ng/dl), as did total T₃ (16 ± 14 to 76 ± 44 ng/dl), during the phase of TSH rise, suggesting that the increase in TSH was not simply a consequence of diminished negative feedback due to increased plasma binding. The very close and consistent temporal relationship between TSH and T₄ during the recovery phase suggests that TSH may have an essential role in the return of T₄ to normal during recovery from critical nonthyroidal illness

Context Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2i). Objective To determine the incidence, characteristics and outcomes of DKA in SGLT2i-users vs non-users with type 2 diabetes. Design Retrospective, multi-center, controlled cohort study. Setting All public hospitals in Melbourne and Geelong (combined population 5 million), Australia, from 1 September 2015 - 31 October 2017. Patients Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes Main Outcome Measures In SGLT2i users vs non-users: (i) Odds ratio of DKA developing during hospital admission and (ii) Incidence of DKA Results There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs two (2%) non-SGLT2i users, (odds ratio 37.4 [95% CI 8.0-175.9], p<0.0001). The incidence of diabetic ketoacidosis was 1.02/1000 (95% CI 0.74-1.41/1000) in SGLT2i users vs 0.69/1000 (0.58-0.82/1000) in non-SGLT2i users (odds ratio 1.48 (1.02-2.15), p=0.037). Fifteen SGLT2i users (41%) had peak blood glucose <250 mg/dl (14 mmol/l) compared to one (0.8%) non-SGLT2i user (p<0.001). Conclusions SGLT2i users were more likely to develop DKA as an inpatient compared to non-SGLT2i users. SGLT2i use was associated with a small, but significant increased risk of DKA.

The diuretic furosemide inhibits serum protein binding of T₄ in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [¹²⁵I]T₄ from isolated preparations of T₄-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 (μg/ml furosemide increased the free T₄ and free T₃ fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [¹⁴C]furosemide to TBG was inhibited by unlabeled T₄, suggesting that furosemide and T₄ share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [¹²⁶I]T₄ (using serum diluted 1:10) from 4.1 ‡ 1.0 (‡SE) to 10.8 ‡ 4.3 (P < 0.01) after 2 h, while decreasing total T₃ from 75 ‡ 5 to 56 ‡ 13 ng/dl (P < 0.01) and total T₄ from 6.7 ‡ 0.9 to 4.8 ‡ 0.8 μg/ dl (P < 0.01) after 5 h. Various ligands inhibited [¹²⁵I]T₄ binding to serum proteins in the following relative molar relationship: T₄, 1; furosemide, 1.5 × 10³; fenclofenac, 2 × 10⁴; mefenamic acid, 2.5 × 10⁴; diphenylhydantoin, 4 X 10⁴; ethacrynic acid, 10⁵; heparin, 5 × 10⁶; 2-hydroxybenzoylglycine, 10⁶; and sodium salicylate, 1.5 × 10⁶. These studies demonstrate that furosemide competes for T₄- binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T₄ and T₃ levels. The drug is much more potent on a molar basis than other drug inhibitors of T₄ binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T₄ or T₃. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T₄- and T₃-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.

Background: Although hospital-acquired hyponatremia is well described, severe community-acquired hyponatremia has been studied less extensively. Aim: To assess characteristics and outcomes of patients admitted with severe hypotonic hyponatremia (SHH) (defined as serum sodium ≤ 120 mmol/L). Methods: All patients with serum sodium of ⪙ 120 mmol/L who were admitted to 2 large teaching hospitals from January 2000 to August 2007 were identified, and data were obtained from medical records. Main outcome measures were incidence of osmotic demyelination and mortality. Results: Two hundred fifty-five patients were admitted who had SHH (female to male ratio 2:1), and the mean age was 72 ± 14 years. The most common etiological factors were thiazide/indapamide diuretics (41%), syndrome of inappropriate antidiuretic hormone secretion (38%), and hypovolemia (24%). Inappropriately rapid correction of serum sodium (> 12 mmol/L over the first 24 hours) occurred in 37 patients (15%), with 4 patients (11%) developin...