Shinzoh Sumita

Suppression of the thyrotropin response to thyrotropin-releasing hormone and its association with severity of critical illness.

Objective: To study whether the suppression of the thyrotropin (thyroid‐stimulating hormone, TSH) response to thyrotropin‐releasing hormone (TRH) correlates with severity of illness and death in patients with nonthyroidal critical illness. Design: Prospective study. Setting: Intensive care unit (ICU) of a university hospital. Patients: Forty‐one critically ill patients without thyroid disease with multiple organ failure who were admitted to the ICU. Measurements and Main Results: The TSH response to TRH was tested within 24 hrs of ICU admission. Blood samples were obtained just before, and at 15, 30, 60, 90, and 120 mins after 500‐&mgr;g injection of synthetic TRH. Triiodothyronine, free‐triiodothyronine, thyroxine, free‐thyroxine and TSH concentrations were measured in the samples obtained just before TRH injection. Acute Physiology and Chronic Health Evaluation (APACHE II) scores and Sepsis scores were calculated based on the data obtained within 24 hrs of ICU admission. Individual variables were compared between survivors and nonsurvivors. The APACHE II scores and Sepsis scores of nonsurvivors were significantly higher than those scores of survivors. The overall occurrence of suppressed TSH response to TRH was 88%. Peak TSH concentration of the TSH response was significantly lower in nonsurvivors than in survivors. Serial measurement of the TSH response showed that nonsurvivors experienced a decrease in peak TSH concentration from 1.55 ± 0.78 to 0.55 ± 0.30 &mgr;IU/mL; in survivors, it increased from 2.10 ± 0.26 to 7.38 ± 1.83 &mgr;IU/mL. Conversely, the basal TSH concentration did not change in either survivors or nonsurvivors. The “severity” of illness of nonsurvivors remained high; their mean APACHE II score varied from 20.0 ± 1.9 to 22.1 ± 1.3 and the mean Sepsis score varied from 20.0 ± 4.3 to 25.4 ± 4.0, while the same scores for survivors decreased significantly ( p < .05): their APACHE II score decreased from 16.2 ± 0.7 to 7.6 ± 2.0 and the Sepsis score went from 14.0 ± 1.9 to 6.0 ± 1.6. Conclusions: In critically ill patients with multiple organ failure, suppression of the TSH response to TRH frequently occurs and correlates with severity of illness and outcome. Our data indicate that measurement of the TSH response is helpful in evaluating the severity of illness and prognosis for critically ill patients. (Crit Care Med 1994; 22:1603–1609)

Alteration in diaphragmatic contractility during septic peritonitis in rats: effect of polyethylene glycol-absorbed superoxide dismutase.

Objectives To assess the alterations in diaphragmatic contractility measured in vitro during experimental septic peritonitis and to evaluate the effect of polyethylene glycol-absorbed superoxide dismutase (PEG-SOD) on the alterations in contractility. Design Prospective, randomized, controlled animal trial. Setting Research laboratory. Subjects A total of 321 male Wistar rats, weighing 250–300 g. Interventions Rats were treated with cecal ligation and puncture (CLP). In the first experiment, diaphragmatic contractility was measured at 4, 10, 12, and 16 hrs after CLP. In the second experiment, PEG-SOD (4000 units/kg) was administered intraperitoneally, and then diaphragmatic contractility was measured at 10 and 16 hrs after CLP. Levels of lipid peroxides and antioxidant enzymes in the diaphragm tissue were measured at 10 and 16 hrs after CLP. Measurements and Main Results In experiment 1, diaphragmatic twitch characteristics and force-frequency relationships were determined at 4, 10, 12, and 16 hrs after CLP. In experiment 2, the effects of administration of PEG-SOD on twitch characteristics and force-frequency relationships were determined at 10 and 16 hrs after CLP. The levels of diaphragmatic thiobarbituric acid reactive substances and superoxide dismutase (SOD) and glutathione peroxidase activities were measured at 10 and 16 hrs after CLP. Twitch tension and force-frequency curves were significantly lower in the CLP groups than in the sham-operated group. Administration of PEG-SOD attenuated the reduction in twitch tension and the downward shift of force-frequency curves after CLP. Diaphragmatic levels of thiobarbituric acid reactive substances increased after CLP. However, the administration of PEG-SOD prevented increases in levels of diaphragmatic thiobarbituric acid reactive substances after CLP. Diaphragmatic SOD activity, but not glutathione peroxidase activity, was increased after CLP. Conclusions Intra-abdominal sepsis (CLP) induced a marked reduction in diaphragmatic contractility, but PEG-SOD attenuated this reduction. Therefore, we conclude that oxygen-derived free radicals play an important role in the alterations in diaphragmatic contractility during intra-abdominal sepsis.

Geranylgeranylacetone attenuates septic diaphragm dysfunction by induction of heat shock protein 70.

ObjectiveThe purposes of the present study were to evaluate the induction of heat shock protein (HSP) 70 expression in the diaphragm by geranylgeranylacetone (GGA) administration and to determine the effect of HSP70 induction on diaphragm contractility measured in vitro and the production of oxygen-derived free radicals during experimental septic peritonitis. DesignProspective laboratory study. SettingUniversity laboratory. SubjectsOne-hundred sixty male Wistar rats. InterventionsIn experiment 1, rats received GGA intragastrically, and time-dependent induction of HSP70 expression in the diaphragm was determined at 0, 12, 24, and 36 hrs after GGA administration. To evaluate dose-dependent inhibition of GGA-induced HSP70 expression by quercetin, rats were pretreated with progressive doses of quercetin before GGA administration. In experiment 2, rats received gum arabic solution (vehicle), 100, 200, or 400 mg/kg of GGA. In experiment 3, rats were pretreated with quercetin or glycerol before GGA or vehicle administration. Intra-abdominal sepsis was induced by cecal ligation and perforation (CLP) under inhalation anesthesia after GGA or vehicle administration in experiments 2 and 3. Measurements and Main ResultsWestern blot analysis using diaphragm homogenates obtained from normal rats showed that HSP70 expression peaked at 24 or 36 hrs after GGA administration and that pretreatment with >10 mg/kg of quercetin blocked the induction of HSP70 expression by GGA. CLP induced diaphragmatic dysfunction and increased diaphragmatic malondialdehyde concentrations and superoxide dismutase and glutathione peroxidase activities. GGA attenuated CLP-induced diaphragm dysfunction and increased malondialdehyde concentrations in a dose-dependent manner but did not affect superoxide dismutase and glutathione peroxidase activities after CLP. Diaphragm dysfunction and increased diaphragmatic malondialdehyde concentrations after CLP were maintained on quercetin pretreatment despite GGA administration. ConclusionsGGA induces HSP70 expression in the diaphragm, and this induction attenuates septic diaphragm impairment by inhibiting the production of oxygen-derived free radicals.