Acute thyroid hormone administration increases systemic oxygen delivery and consumption immediately following resuscitation from cardiac arrest without changes in thyroid-stimulating hormone.

This study determined the acute effects of intravenous levothyroxine sodium (LT4) on systemic oxygen delivery and consumption for 6 h following resuscitation from 9 min of normothermic cardiac arrest in dogs. Male mongrel dogs (15-25 kg) were randomly assigned to two groups of seven. The treated group received a pre-cardiac arrest infusion of 15 micrograms/kg per h of LT4 for 1.5 h prior to arrest and for 6 h after, while controls received a comparable volume of 0.9 N saline infusion. Neurologic outcome was recorded at 1, 2 and 6 h following resuscitation. Systemic oxygen consumption (VO2), carbon dioxide production (VCO2) and respiratory quotient (RQ) were calculated from directly measured cardiac output, arterial and mixed venous blood gases and contents. Serum levels of circulating canine thyroid-stimulating hormone (cTSH), total thyroxine (T4), free thyroxine (FT4), total 3,5,3'-triiodothyronine (T3), free 3,5,3'-triiodothyronine (FT3), reverse 3,3',5'-triiodothyronine (rT3), and plasma markers of oxidant injury (malonaldehyde (MDA), 4-hydroxynonenal (4-OH) and erythrocyte GSH) were measured before administration and after resuscitation. Following resuscitation, treated dogs maintained significantly higher cardiac output when compared with their control counterparts at 4 h (5.5 ml/g per h vs. 2.9 ml/g per h, respectively, P < 0.05) and at 6 h (5.5 ml/g per h vs. 3.0 mg/g per h, respectively, P < 0.05). The level of VO2 was significantly higher in treated dogs than control dogs at 1, 4 and 6 h (P < 0.05). Treated dogs had significantly elevated levels of T4, FT4, T3, FT3 and rT3 (P < 0.01), compared with control dogs. No changes in cTSH were detected between groups or over time. Acute administration of LT4 enhances systemic oxygen delivery and apparently, therefore, oxygen consumption following resuscitation.

Plasma thyroid hormone profiles immediately following out-of-hospital cardiac arrest.

Previous studies have shown abnormal thyroid hormone profiles during cardiac arrest. We explored this association further by characterizing plasma thyroid hormone profiles in 473 patients with out-of-hospital cardiac arrest and correlating them with clinical outcomes. Paramedics collected blood at the end of attempted resuscitation regardless of success. Bloods were collected and processed in a similar manner from 18 control subjects randomly selected from the community. Total thyroxine and total triiodothyronine were lower and reverse triiodothyronine and thyrotropin were higher in cardiac arrest patients than control subjects (all p < 0.001). Except for reverse triiodothyronine, findings were similar for a subgroup of cardiac arrest patients considered to be previously healthy (n = 30). Being discharged alive was associated with total thyroxine, total triiodothyronine and reverse triiodothyronine concentrations closer to the control range and thyrotropin concentrations farther from it, namely higher. In a multivariate stepwise model, only total triiodothyronine and thyrotropin were significantly associated with outcome. Whether these profoundly abnormal profiles represent a pre-existing state or a sudden change of thyroid hormone concentrations cannot be answered with this retrospective study. These observations suggest that thyroid hormones may play a role in the etiology of cardiac arrest, its prognosis, or both.

Acute administration of T3 or rT3 failed to improve outcome following resuscitation from cardiac arrest in dogs.

Documentation of profound changes in serum thyroid hormone concentrations associated with cardiac arrest and resuscitation, as well as other acute emergencies, have spurred evaluation of possible therapeutic thyroid hormone administration. Acute and significant, this state, characterized by abnormally low serum thyroid hormone concentrations, may indicate selective thyroid replacement therapy. In a previous investigation, post-resuscitation infusion of levothyroxine sodium (L-T4) to normalize serum 3,5,3'-triiodothyronine (T3) concentrations was associated with significant reduction of neurologic deficit caused by severe global cerebral ischemia. Since L-T4 has been reported to act directly or via one of its metabolites, most likely T3, this most active form of thyroid hormone was tested. When L-T4 reduced the neurologic deficit, an increase in 3,3',5'-triiodothyronine (rT3) was also observed. This study therefore determined whether a post-resuscitation treatment with either T3 (n = 8) or rT3 (n = 8) provided protection against global cerebral ischemia comparable to that of L-T4. Global cerebral ischemia was achieved with 9 min of ventricular fibrillation. Following resuscitation, one of three solutions (saline group as a control) was infused for 24 h at rates that reproduced the normal serum T3 concentrations or the rT3 concentrations achieved previously during the L-T4 therapy. The successful elevation of T3 and mimicking rT3 concentrations was assessed and confirmed by radioimmunoassay (RIA). In addition, TSH levels were measured by a novel RIA specific for canine thyroid-stimulating hormone (cTSH). Neurologic deficit was assessed with a well-standardized neurologic deficit examination. In contrast to previous studies using L-T4 infusion, no significant reduction of neurologic deficit was observed. Serum thyroid hormone changes confirmed previously described decreases and in no case did changes in cTSH appear causal in these changes. Thus, we concluded that L-T4 may offer a therapeutic advantage over T3 or rT3.

Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs.

Circulating concentrations of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (rT3) were followed in dogs subjected to 9 min of normothermic ventricular fibrillation. Significant decreases were detected 12 h post-arrest when compared to pre-arrest levels in total T4 (P < 0.0005), free T4 (P < 0.0005), total T3 (P < 0.003), and free T3 (P < 0.003), and levels of reverse T3 were significantly elevated (P = 0.0001). Similar changes occurred with only 30 s of arrest. Post-arrest replacement therapy with 7.5 micrograms/kg per h (Rx-7.5) and 15 micrograms/kg per h (Rx-15) levothyroxine sodium (L-T4) increased total T4, free T4, and total T3 (P < 0.01). Free T3 decreased in the Rx-7.5 group (P < 0.01) and did not fall in the Rx-15 group (P = 0.16). Reverse T3 increased with either treatment (P < 0.005). Both treatment groups had higher levels of all five hormones than non-treated animals (P < 0.001). Neurologic function, assessed with a standardized scoring system, showed significant improvement in the treated groups by 6 h (P < 0.05, compared to non-treated group) and remained significant through 24 h post-arrest (P < 0.05). The documentation of rapid and dramatic changes in thyroid hormones immediately following cardiac arrest and resuscitation indicates a significant acute hypothyroid state that may potentially benefit from replacement therapy.

A study in normal human volunteers to compare the rate and extent of levothyroxine absorption from Synthroid and Levoxine.

Numerous branded and generic formulations of levothyroxine (LT4) sodium tablets are currently available. Results from previous studies attempting to examine the comparative bioavailability of these formulations are difficult to interpret because of subject heterogeneity, single time-point blood sampling, varying degrees of hypothyroidism, and other factors. This study was devised to compare the rate and extent of absorption of LT4 from different LT4 sodium tablet formulations, in a simple model using a single-dose two-way single-blind, randomized cross-over design in 30 normal, healthy, nonpregnant, female subjects. This design controlled for many factors that limited previous LT4 bioavailability studies. Subjects were given a single 600 micrograms dose of LT4 as either Synthroid (Boots Pharmaceuticals, Inc., Lincolnshire, IL) tablets (formulation A) or Levoxine tablets (Daniels Pharmaceuticals, St. Petersburg, FL; formulation B). Measurements of baseline-corrected total T4 serum concentrations determined at multiple time points demonstrated statistically significant differences between the two formulations at the 1.00, 3.00, 5.00, and 18.00 hour sampling times. Statistically significant differences for area under the curve (AUC) (0 to 48 hours) (formulation A, 159.9 +/- 9.4 micrograms-hour/dL; formulation B, 193.4 +/- 10.1 micrograms-hour/dL) and maximum peak plasma concentration (Cmax) (formulation A, 5.91 +/- .34; formulation B, 7.12 +/- .32) also were demonstrated. Furthermore, the ratio of the baseline-corrected total T4 concentrations (B/A x 100) were 120.9% for AUC and 120.5% for Cmax. These data demonstrate that the administration of Synthroid and Levoxine result in a significantly different rate and extent of absorption of LT4, and therefore these two formulations cannot be considered bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolism of aluminum and aluminum-related encephalopathy.

The dialysis encephalopathy syndrome is at once the most widely recognized and most severe manifestation of aluminum toxicity. Evidence linking this syndrome and aluminum intoxication is virtually incontrovertible. The syndrome is characterized by speech and motor difficulties, dementia, and seizures. Less widely recognized symptoms include subtle changes in cognition and personality and directional disorientation. Since the widespread use of water treatment, aluminum exposure in the dialysis population has been primarily via intravenous (IV) medications and oral aluminum-containing, phosphate-binding antacid gels. In addition to the encephalopathy syndrome, aluminum has been linked to toxicity in bone, parathyroid gland, RBC, and kidney. These organ toxicities seem to be the result of specific protein enzyme inhibition. Currently identified factors that affect aluminum accumulation and modulate aluminum balance include uremia, renal function, parathyroid hormone withdrawal and suppression, 1,25-dihydroxycholecalciferol, and serum aluminum binding. Impaired renal function is not a prerequisite for increased tissue aluminum burdens. It is likely that aluminum-related disease will be increasingly observed in populations other than those with chronic renal failure.

Encephalopathy in chronic renal failure responsive to deferoxamine therapy. Another manifestation of aluminum neurotoxicity.

We describe a patient undergoing chronic hemodialysis who developed a neurologic syndrome consisting of seizures, progressive myoclonus, and mild dementia and who responded to chelation therapy with deferoxamine mesylate. Neither her serum nor bone aluminum concentrations indicated aluminum toxicity. However, the presence of a positive deferoxamine-infusion test was suggestive of an elevated body burden of aluminum. Treatment with deferoxamine resulted in marked clinical improvement in her neurologic status within two months. The utility of using the deferoxamine-infusion test rather than serum aluminum levels in evaluating aluminum toxicity in chronic renal failure is suggested.

1,25-Dihydroxyvitamin D3 increases serum and tissue accumulation of aluminum in rats.

We examined the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in both hypercalcemic and hypocalcemic rat models and the effect of exogenous 25-hydroxyvitamin D3 (25(OH)D3) on serum and tissue aluminum (Al) burdens. Rats fed a 0.2% Al diet received daily subcutaneous injections of either 1,25(OH)2D3 (80.9 ng/kg, n = 5 and 809 ng/kg, n = 8), 25 (OH)D3 (809 ng/kg, n = 4, and 8090 ng/kg, n = 8) or propylene glycol vehicle for 18 days. Rats given 809 ng/kg of 1,25(OH)2D3 were hypercalcemic and when compared with pair-fed controls had higher serum (33.1 vs. 14.3 micrograms/L, P less than 0.01), bone (21.2 vs. 13.2 micrograms/gm, P less than 0.01), and kidney (6.5 vs. 2.0 micrograms/gm, P less than 0.01) but not brain (1.2 vs. 1.5 micrograms/gm) or liver (0.9 vs. 0.8 micrograms/gm dry tissue) Al concentration. The lower dose of 1,25(OH)2D3 had no effect on serum or tissue Al. Treatment with 25(OH)D3 did not increase serum Ca and Al or tissue Al concentration. To dissociate a specific effect of exogenous 1,25(OH)2D3 from the concurrent hypercalcemia, endogenous production of 1,25(OH)2D3 was stimulated. Animals were fed a low Ca diet until hypocalcemia developed and were then divided into four groups: one given low Ca (n = 7) for 21 days, one given low Ca plus 0.2% Al (n = 7) for 21 days, one returned to a normal Ca diet (n = 4) for 30 days, and one returned to a normal Ca diet for 9 days and continued with a normal diet plus 0.2% Al (n = 5) for 21 days. Hypocalcemic rats fed the Al diet, when compared with hypocalcemic controls, had higher serum (143.6 vs. 31.8 micrograms/L, P less than 0.01), bone (16.0 vs. 2.9 micrograms/gm, P less than 0.01), and kidney (8.2 vs. 2.8 micrograms/gm, P less than 0.005) but not brain (3.4 vs. 2.3 micrograms/gm) or liver (3.8 vs. 2.3 micrograms/gm) Al concentrations. Serum, bone, and kidney Al concentration was also significantly higher than that in normocalcemic rats fed the Al diet. These results indicate that pharmacologic doses of 1,25(OH)2D3 and dietary hypocalcemia enhance gastrointestinal Al absorption and serum, kidney, and bone Al concentration.

Evaluation of bidirectional aluminum transfer across hollow fiber dialyzers.

The ultrafiltrable fraction of plasma aluminum (UFAl) determined utilizing the hollow fiber dialyzer is variable and ranges from 10% to 50%. This extreme variability in UFAl led us to examine the possibility of Al binding to the hollow fiber dialyzer. Ultrafiltrate of aqueous Al solutions was obtained by applying a negative pressure of 250 mm Hg to a hollow fiber dialyzer (TriEx-1). In the first of three experimental protocols, Al was measured before and after recirculation of solutions containing 344 to 9244 micrograms/L Al through a hollow fiber dialyzer until the entire volume was collected as ultrafiltrate. UFAl ranged from 0.9% to 37.6% and did not correlate with the initial Al concentration. Total Al binding ranged from 42 micrograms to 1.3 mg. In the second, 16 L of aqueous AlCl3 solution (n = 3), containing from 205 to 411 micrograms/L Al were passed through the blood compartment of a hollow fiber dialyzer. The percentage of UFAl ranged from 4.1% to 17.3% during the first 20 minutes and 79.3% to 81.8% at 120 minutes. Finally, to investigate Al transfer from dialysate, 16 L of deionized distilled water were passed through the blood compartment while 16 L of AlCl3 solutions of 330 micrograms/L and 398 micrograms/L AI passed through the dialysate compartment. Samples were collected from blood and dialysate outflow ports every 20 minutes for 120 minutes. The transfer of Al from dialysate to blood compartment increased with time. However the concentration of Al at the blood outflow port never reached that at the dialysate outflow port.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo and in vitro effects of aluminum treatment on rat liver mitochondrial function.

This study examines the effect on mitochondrial respiration and permeability of in vivo and in vitro aluminium (Al) exposure. Rats were treated intraperitoneally with AlCl3 to achieve serum and liver Al concentrations comparable to those seen in Al-related disorders. Mitochondria isolated from Al-treated rats had higher (p<0.01) Al concentration, lower (p<0.05) state 3 respiration, respiratory control (RCR), and ADP/O ratio (succinate substrate), and greater passive swelling in 100 mM KCl or 200 mM NH4NO3 than controls. The in vitro addition of Al (0-180 µM) to mitochondria from normal rats also decreased (p<0.01) state 3 respiration, RCR, and ADP/O and stimulated passive swelling in KCl and NH4NO3 at 42-180 µM Al. These studies show that Al depresses mitochondrial energy metabolism and increases membrane permeability. The toxicity associated with Al may be related to its effect on mitochondria.

Renal handling of aluminum in the rat: clearance and micropuncture studies.

Previous uncertainty regarding glomerular ultrafilterability (UF) of aluminum has limited the definition of renal Al handling. Glomerular micropuncture was therefore performed in hydropenic Munich-Wistar rats infused with AlCl3 to achieve plasma (P) Al levels between 2 and 10 mg/liter. Glomerular fluid, P, and urine Al concentrations were measured by flameless atomic-absorption spectrophotometry. UFA1 was inversely correlated with PA1 [%UFA1 = 10.3 - 8.4 (log PA1), r = -0.90, P less than 0.01]. When this equation was used to calculate the filtered load (FLA1), A1 excretion (UA1V, ng/min) in simultaneously collected samples was found to be a direct function of FLA1 [UA1V = 5.7 + 0.37 (FLA1), r = 0.93, P less than 0.01]. Fractional excretion (FE) of A1 was 39.4 +/- 4.2% in these hydropenic experiments (FENa = 0.3 +/- 0.1%). We next evaluated the tubular handling of A1 (using these UF data) during step-wise extracellular fluid volume expansion with isotonic saline (2.5, 5.0, 7.0, and 7.0% body wt) and during the infusion of increasing doses (2.7, 5.3, 8.0, and 8.0 mg X kg-1 X h-1) of furosemide as urinary losses were quantitatively replaced. The natriuresis produced by volume expansion (FENa = 1.0, 3.0, 8.4, and 7.9%) and furosemide (FENa = 4.2, 6.0, 6.6, and 6.7%) were comparable. At similar FLA1, 7% volume expansion but not furosemide (at any dose) increased UA1V (240 and 95 ng/min, respectively, vs. 116 ng/min in hydropenia) and FEA1 (84.5 and 29.4 vs. 37.4%, respectively). These data indicate that at pharmacological PA1 levels, less than 8.4% of PA1 is ultrafilterable, suggesting extensive plasma protein binding.(ABSTRACT TRUNCATED AT 250 WORDS)