Document Detail

Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis.
MedLine Citation:
PMID:  11990925     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: The major forms of human inter-alpha-inhibitor proteins circulating in the plasma are inter-alpha-inhibitor (IalphaI, containing one light peptide chain called bikunin and two heavy chains) and pre-alpha-inhibitor (PalphaI, containing one light and one heavy chain). Although it has been reported that a decrease in IalphaI/PalphaI is correlated with an increased mortality rate in septic patients, it remains unknown whether administration of IalphaI/PalphaI early after the onset of sepsis has any beneficial effects on the cardiovascular response and outcome of the septic animal. The aim of this study, therefore, was to determine whether IalphaI and PalphaI have any salutary effects on the depressed cardiovascular function, liver damage, and mortality rate after polymicrobial sepsis. DESIGN: Prospective, controlled, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture or sham operation followed by the administration of normal saline (i.e., resuscitation). MEASUREMENTS AND MAIN RESULTS: At 1 hr after cecal ligation and puncture, human IalphaI/PalphaI at a dose of 30 mg/kg body weight or vehicle (normal saline, 1 mL/rat) were infused intravenously over a period of 30 mins. At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output was measured by using a dye dilution technique, and blood samples were collected for assessing oxygen content. Oxygen delivery, consumption, and extraction ratio were determined. Plasma concentrations of liver enzymes alanine aminotransferase and aspartate aminotransferase as well as lactate and tumor necrosis factor-alpha also were measured. In additional animals, the necrotic cecum was excised at 20 hrs after cecal ligation and puncture with or without IalphaI/PalphaI treatment, and survival was monitored for 10 days thereafter. The results indicate that administration of human IalphaI/PalphaI early after the onset of sepsis maintained cardiac output and systemic oxygen delivery, whereas it increased oxygen consumption and extraction at 20 hrs after cecal ligation and puncture. The elevated concentrations of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-alpha, and lactate were attenuated by IalphaI/PalphaI treatment. In addition, administration of human IalphaI/PalphaI improved the survival rate from 30% to 89% in septic animals at day 10 after cecal ligation and puncture and cecal excision. CONCLUSION: Human IalphaI/PalphaI appears to be a useful agent for maintaining hemodynamic stability and improving survival during the progression of polymicrobial sepsis.
Shaolong Yang; Yow-Pin Lim; Mian Zhou; Philomena Salvemini; Horst Schwinn; Djuro Josic; Douglas J Koo; Irshad H Chaudry; Ping Wang
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Critical care medicine     Volume:  30     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-05-06     Completed Date:  2002-05-24     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  617-22     Citation Subset:  AIM; IM    
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, USA.
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MeSH Terms
Alpha-Globulins / pharmacology*
Analysis of Variance
Cardiac Output / drug effects
Hemodynamics / drug effects*
Lactic Acid / blood
Membrane Glycoproteins / pharmacology
Oxygen Consumption / drug effects
Random Allocation
Rats, Sprague-Dawley
Sepsis / drug therapy*,  physiopathology
Serine Proteinase Inhibitors / pharmacology*
Survival Analysis
Transaminases / blood,  drug effects
Trypsin Inhibitor, Kunitz Soybean*
Tumor Necrosis Factor-alpha / drug effects,  metabolism
Grant Support
Reg. No./Substance:
0/Alpha-Globulins; 0/Membrane Glycoproteins; 0/SPINT2 protein, human; 0/Serine Proteinase Inhibitors; 0/Tumor Necrosis Factor-alpha; 39346-44-6/inter-alpha-inhibitor; 50-21-5/Lactic Acid; 9088-41-9/Trypsin Inhibitor, Kunitz Soybean; EC 2.6.1.-/Transaminases
Comment In:
Crit Care Med. 2002 Mar;30(3):717-8   [PMID:  11990949 ]

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