Yoram G. Weiss

Hydrocortisone therapy for patients with septic shock.

BACKGROUND Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. METHODS In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. RESULTS Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. CONCLUSIONS Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)

Adrenal function in sepsis: The retrospective Corticus cohort study

Objective:To refine the value of baseline and adrenocorticotropin hormone (ACTH)-stimulated cortisol levels in relation to mortality from severe sepsis or septic shock. Design:Retrospective multicenter cohort study. Setting:Twenty European intensive care units. Patients:Patients included 477 patients with severe sepsis and septic shock who had undergone an ACTH stimulation test on the day of the onset of severe sepsis. Interventions:None. Measurements and Main Results:Compared with survivors, nonsurvivors had higher baseline cortisol levels (29.5 ± 33.5 vs. 24.3 ± 16.5 &mgr;g/dL, p = .03) but similar peak cortisol values (37.6 ± 40.2 vs. 35.2 ± 22.9 &mgr;g/dL, p = .42). Thus, nonsurvivors had lower &Dgr;max (i.e., peak cortisol minus baseline cortisol) (6.4 ± 22.6 vs. 10.9 ± 12.9 &mgr;g/dL, p = .006). Patients with either baseline cortisol levels <15 &mgr;g/dL or a &Dgr;max ≤9 &mgr;g/dL had a likelihood ratio of dying of 1.26 (95% confidence interval, 1.11–1.44), a longer duration of shock, and a shorter survival time. Patients with a &Dgr;max ≤9 &mgr;g/dL but any baseline cortisol value had a likelihood ratio of dying of 1.38 (95% confidence interval, 1.18–1.61). Conclusions:Although delta cortisol and not basal cortisol level was associated with clinical outcome, further studies are still needed to optimize the diagnosis of adrenal insufficiency in critical illness. Etomidate influenced ACTH test results and was associated with a worse outcome.

The Heat Shock Response in Moss Plants Is Regulated by Specific Calcium-Permeable Channels in the Plasma Membrane

Land plants are prone to strong thermal variations and must therefore sense early moderate temperature increments to induce appropriate cellular defenses, such as molecular chaperones, in anticipation of upcoming noxious temperatures. To investigate how plants perceive mild changes in ambient temperature, we monitored in recombinant lines of the moss Physcomitrella patens the activation of a heat-inducible promoter, the integrity of a thermolabile enzyme, and the fluctuations of cytoplasmic calcium. Mild temperature increments, or isothermal treatments with membrane fluidizers or Hsp90 inhibitors, induced a heat shock response (HSR) that critically depended on a preceding Ca2+ transient through the plasma membrane. Electrophysiological experiments revealed the presence of a Ca2+-permeable channel in the plasma membrane that is transiently activated by mild temperature increments or chemical perturbations of membrane fluidity. The amplitude of the Ca2+ influx during the first minutes of a temperature stress modulated the intensity of the HSR, and Ca2+ channel blockers prevented HSR and the onset of thermotolerance. Our data suggest that early sensing of mild temperature increments occurs at the plasma membrane of plant cells independently from cytosolic protein unfolding. The heat signal is translated into an effective HSR by way of a specific membrane-regulated Ca2+ influx, leading to thermotolerance.

Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) provokes three pathologic processes: unchecked inflammation, interstitial/alveolar protein accumulation, and destruction of pulmonary epithelial cells. The highly conserved heat shock protein HSP-70 can limit all three responses but is not appropriately expressed in the lungs after cecal ligation and double puncture (2CLP), a clinically relevant model of ARDS. We hypothesize that restoring expression of HSP-70 using adenovirus-mediated gene therapy will limit pulmonary pathology following 2CLP. We administered a vector containing the porcine HSP-70 cDNA driven by a CMV promoter (AdHSP) into the lungs of rats subjected to 2CLP or sham operation. Administration of AdHSP after either sham operation or 2CLP increased HSP-70 protein expression in lung tissue, as determined by immunohistochemistry and Western blot hybridization. Administration of AdHSP significantly attenuated interstitial and alveolar edema and protein exudation and dramatically decreased neutrophil accumulation, relative to a control adenovirus. CLP-associated mortality at 48 hours was reduced by half. Modulation of HSP-70 production reduces pathologic changes and may improve outcome in experimental ARDS.

Uncertainty and Optimal Social Security Systems

This paper examines the annuity aspect of social security within the framework of an overlapping-generations model. The duration of life is assumed to be uncertain. Under a fully funded system, demand for social security is determined by each generation so as to maximize expected lifetime utility, taking into account the welfare of future generations. Under a pay-as-you-go system with intergenerational transfers, demand for retirement benefits by the working population takes into account taxes paid by descendants. It is shown that the two modes of finance are equivalent in terms of all real aggregates. Effects of changes in expected lifetime and in the birth rate are analyzed. Starting at the optimal level, a compulsory balanced increase in social security taxes and benefits is shown to increase short-run savings.

Enhanced heat shock protein 70 expression alters proteasomal degradation of Iκb kinase in experimental acute respiratory distress syndrome

Objectives:Acute respiratory distress syndrome is a common and highly lethal inflammatory lung syndrome. We previously have shown that an adenoviral vector expressing the heat shock protein (Hsp)70 (AdHSP) protects against experimental sepsis-induced acute respiratory distress syndrome in part by limiting neutrophil accumulation in the lung. Neutrophil accumulation and activation is modulated, in part, by the nuclear factor-&kgr;B (NF-&kgr;B) signal transduction pathway. NF-&kgr;B activation requires dissociation/degradation of a bound inhibitor, I&kgr;B&agr;. I&kgr;B&agr; degradation requires phosphorylation by I&kgr;B kinase, ubiquitination by the SCF&bgr;-TrCP (Skp1/Cullin1/Fbox &bgr;-transducing repeat-containing protein) ubiquitin ligase, and degradation by the 26S proteasome. We tested the hypothesis that Hsp70 attenuates NF-&kgr;B activation at multiple points in the I&kgr;B&agr; degradative pathway. Design:Laboratory investigation. Setting:University medical center research laboratory. Subjects:Adolescent (200 g) Sprague-Dawley rats and murine lung epithelial-12 cells in culture. Interventions:Lung injury was induced in rats via cecal ligation and double puncture. Thereafter, animals were treated with intratracheal injection of 1) phosphate buffer saline, 2) AdHSP, or 3) an adenovirus expressing green fluorescent protein. Murine lung epithelial-12 cells were stimulated with tumor necrosis factor-&agr; and transfected. NF-&kgr;B was examined using molecular biological tools. Measurements and Main Results:Intratracheal administration of AdHSP to rats with cecal ligation and double puncture limited nuclear translocation of NF-&kgr;B and attenuated phosphorylation of I&kgr;B&agr;. AdHSP treatment reduced, but did not eliminate, phosphorylation of the &bgr;-subunit of I&kgr;B kinase. In vitro kinase activity assays and gel filtration chromatography revealed that treatment of sepsis-induced lung injury with AdHSP induced fragmentation of the I&kgr;B kinase signalosome. This stabilized intermediary complexes containing I&kgr;B kinase components, I&kgr;B&agr;, and NF-&kgr;B. Cellular studies indicate that although ubiquitination of I&kgr;B&agr; was maintained, proteasomal degradation was impaired by an indirect mechanism. Conclusions:Treatment of sepsis-induced lung injury with AdHSP limits NF-&kgr;B activation. This results from stabilization of intermediary NF-&kgr;B/I&kgr;B&agr;/I&kgr;B kinase complexes in a way that impairs proteasomal degradation of I&kgr;B&agr;. This novel mechanism by which Hsp70 attenuates an intracellular process may be of therapeutic value.

The effects of cardiac surgery on early and late pulmonary functions

Background: Impaired pulmonary functions are common in cardiac patients. Early and late effects of cardiac surgery on pulmonary function tests (PFTs) are presented.

Positive end-expiratory pressure-induced hemodynamic changes are reflected in the arterial pressure waveform

OBJECTIVE To examine whether the hemodynamic changes due to mechanical ventilation with positive end-expiratory pressure (PEEP) can be assessed by the respiratory-induced variations in the arterial pressure waveform during normovolemia and experimental acute ventricular failure. DESIGN Prospective, controlled experimental study. SETTING Institutional experimental laboratory. SUBJECTS Adult mongrel dogs. INTERVENTIONS Experimental acute ventricular failure was induced by the infusion of pentobarbital (a cardiodepressant) and methoxamine (a vasoconstrictor), combined with volume loading. Both the control and acute ventricular failure groups were subjected to ventilation with incremental levels of PEEP up to 20 cm H2O. MEASUREMENTS AND MAIN RESULTS Cardiac function was evaluated by cardiac output and left and right ventricular change in pressure over time (dP/dt) measurements. Arterial pressure waveform analysis was performed by measuring the systolic pressure variation, which is the difference between the maximal and minimal systolic blood pressure values during one mechanical breath. The components of the systolic pressure variation, namely, dUp and dDown, which are the increase and decrease in the systolic pressure during the mechanical breath relative to the systolic pressure during apnea, were also measured at each PEEP level. PEEP caused significant reduction of cardiac output in normovolemic dogs, and was associated with significant increases in systolic pressure variation and dDown. Acute ventricular failure decreased the variations in the systolic pressure and caused the dDown component to disappear. The application of PEEP did not affect cardiac output in dogs with acute ventricular failure, nor did it change systolic pressure variation and the dDown. CONCLUSIONS Analysis of arterial pressure waveforms during mechanical ventilation reflected the decrease in cardiac output in dogs with normal cardiac function subjected to incremental PEEP. In dogs with acute ventricular failure in which PEEP did not affect cardiac output, the systolic pressure variation was similarly unaffected by PEEP. In the absence of cardiac output measurement during mechanical ventilation with PEEP, the analysis of the respiratory variations in the arterial pressure waveform may be useful in assessing changes in cardiac output.

Cecal ligation and double puncture impairs heat shock protein 70 (HSP-70) expression in the lungs of rats.

Induction of the heat shock response may improve outcome from pathophysiological disturbances. This improvement is associated with and believed to result from expression of heat shock protein (HSP)-70. Therefore, we examined the temporal expression of HSP-70 in an animal model of acute respiratory distress syndrome (ARDS) secondary to fecal peritonitis. Specifically, we hypothesize that sepsis in rats impairs pulmonary HSP-70 expression. ARDS was induced in adolescent rats via cecal ligation and double puncture (2CLP). Sham-operated animals served as controls. Lung tissue was collected 0, 3, 6, 16, 24, and 48 h after 2CLP and sham operation. Northern blot hybridization analysis was performed to detect steady-state HSP-70 messenger ribonucleic (mRNA) levels. HSP-70 protein levels were determined via immunoblotting and immunohistochemistry. Mortality after 2CLP was 50% at 24 h and 75% at 48 h. Northern blot hybridization analysis revealed no significant change in steady-state HSP-70 mRNA levels in lung at any time after 2CLP. HSP-70 steady-state mRNA levels increased after sham operation and was higher than values in 2CLP at 6, 16, and 24 h. HSP-70 protein levels did not change over time in either group. Thus, the expression of HSP-70 does not change after 2CLP. Although lack of an increase in protein levels may be adaptive after sham operation, it is not appropriate after 2CLP. Therefore, failed HSP-70 expression represents a form of pulmonary epithelial dysfunction that may contribute to lung injury in sepsis.

Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock

PurposeTo compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock.MethodsIn the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a ‘gold standard’ reference method in a subset of samples.ResultsA total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratoty immunoassay and local hospital assays was 0.98 (CI 0.97–0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54–0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases.ConclusionIn samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.