重症治疗与护理 >文章正文
重症治疗与护理 >文章正文
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> Ma，Penglin MD；Danner，Robert L. MD Critical Care Medicine Department National Institutes of Health Bethesda，MD Address requests for reprints to：Robert L. Danner，MD，National Institutes of Health，CCM Department，Building 10，Room 7D43，10 Center Drive，MSC 1662，Bethesda，MD 20892－1662. Sepsis，severe sepsis，and septic shock represent hierarchical stages of the systemic response to infection [1]. With each escalating level of severity comes a higher toll in organ damage，life－support requirements，and mortality rates. The pinnacle of this deadly triad，septic shock，marks the point when cascading responses to infection overwhelm basic compensatory mechanisms，causing the patient to slip into overt cardiovascular failure. The appearance of vasopressor－requiring hypotension in an infected patient substantially increases the risk of death [2，3]. Up to 75％ of septic shock nonsurvivors die in refractory shock during the first 7－10 days of illness [4]. Therefore，investigation into the prevention，treatment，and pathophysiology of cardiovascular failure per se is an attractive and vital pillar of septic shock research. Although sepsis－induced hypotension typically manifests itself as a vasodilatory，distributive shock，the underlying hemodynamic derangements are more complex （Fig. 1）. Net vascular tone is determined by the sum of regional balances between relaxation and constriction across physiologically distinct vascular beds [5]. A large number of endogenous vasodilators and vasoconstrictors are known to be elevated in septic shock （Table 1）. Many of these vasoactive substances also function as regulators of inflammation and coagulation，and some have been implicated in endothelial injury. Complicating this milieu of mediators，and possibly hampering the development of new treatments，is the important observation that these vasoregulatory pathways are intricately linked [6，7]. Intervention in one pathway has ripple effects throughout the interconnected network，often producing unexpected compensatory adjustments that tend to maintain the shock state [7]. Furthermore，in refractory septic shock，both vascular relaxation and constriction ultimately become impaired [5，8]，an abnormality analogous to endothelial dysfunction in chronic arteriosclerosis [9～11]. |
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> In this issue of Critical Care Medicine，Dr. Takakura and colleagues [12] report that peroxynitrite （ONOO－），a strong oxidant produced by the reaction of nitric oxide （NO） with superoxide （O2 －），inactivates a1－adrenoceptors and thereby may contribute to hypotension and catecholamine hyporeactivity in septic shock. Their investigation was largely conducted in a heterologous in vitro system by using Chinese hamster ovary （CHO） cells transfected with human a1a－，a1b－，and a1d－adrenoceptors. Exogenous ONOO－ decreased the binding capacity of a1a－ and a1d－ but not a1b－ adrenoceptors. Binding affinity was not altered. However，the changes in binding capacity were associated with reductions of norepinephrine－stimulated intracellular calcium release （[Ca2+]i）. Vascular hyporeactivity to pharmacologic doses of catecholamines has been clinically recognized in septic shock for decades，but basic mechanisms underlying the phenomenon have only recently come to light. Research in the late 1980s and early 1990s found that NO，a recently discovered endogenous vasodilator，was an important cause of sepsis－induced shock [13，14]. Soon after，NO was linked more specifically to the problem of vascular hyporeactivity. Inhibitors of NO－synthase were found to at least partially restore the vasoconstrictive properties of norepinephrine [15，16] and vasopressin [17]. NO－induced vasodilation occurs primarily through the activation of soluble guanylate cyclase [18]. Activation of large conductance Ca2+－activated K+ channels by phosphorylation via cyclic guanosine 3，5－monophosphate－dependent protein kinase and，to a lesser degree，by direct nitrosylation causes vessel relaxation [19]. The resulting persistent membrane hyperpolarization appears to account for much of the observed vascular hyporeactivity of septic shock [18～20]. However，it also has become clear that this NO pathway alone fails to fully explain the vascular failure and hyporeactivity of septic shock [20，21]. Notably，NO synthase inhibitors only partially restore vasopressor responsiveness to the septic vasculature. Furthermore，hypotension and death can still be produced in endotoxin－challenged animals lacking inducible NO synthase，the isoform most closely associated with septic shock [22]. The mechanism of vascular hyporeactivity investigated by Dr. Takakura and colleagues [12]，sepsis－induced loss of a1－adrenoceptor number，was first recognized in rodent models before the discovery of NO，but its underlying causes were unknown [23]. More recently，ONOO－ wasshown to attenuate both a－ and b－adrenoceptor agonist－induced responses in rats [24]，thus linking adrenergic receptor dysfunction directly with ONOO－. The incremental advance provided by Dr. Takakura and colleagues [12] was to directly demonstrate that ONOO－ could reduce human 1－adrenoceptor binding capacity and function [12]. Notably，ONOO－－damaged receptors were less responsive to norepinephrine. Furthermore，these mechanistic studies conducted in a transfected cell line were shown to be consistent with the effects of ONOO－ on isolated rat aortas. |
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> The septic vasculature produces increased amounts of NO and O2 － （Fig. 1），the essential ingredients necessary for ONOO－ formation. Both molecules have unpaired electrons，which make them very reactive and short－lived. Although these molecules have distinct effects individually，NO has been shown to block leukocyte adhesion to endothelium by scavenging O2 － [25]. Furthermore，ONOO－ has its own repertoire of effects，ranging from vasodilation to cell injury，that appear to be distinct from the actions of either precursor. The responses elicited are determined largely by the context，the relative amounts of each species produced，and the subcellular compartments into which the radicals are released. ONOO－ formation is likely limited to very specific conditions involving high output NO and O2 － fluxes produced in roughly equal amounts and in close proximity to each other [26]. Superoxide dismutase diverts O2 － away from NO under homeostatic conditions. Conversely，production imbalances between the two radicals lead to rapid scavenging reactions that probably explain their tendency toward antagonism. Assuming distinct high output sources for each molecule，separated by a finite distance，excess NO near its source will result in direct NO effects and nitrosative reactions，whereas oxidant reactions will predominate near the O2 － source [27]. ONOOformation and its effects will only occupy a narrow space between the two sources. However，this model may break down in vasculopathic conditions such as septic shock and atherosclerosis，where NO synthase may release both NO and O2 － [11，28]. Interestingly，the reported coregulation of NO synthase and superoxide dismutase during shear stress [29] may serve as a protective mechanism to inactive NO synthase－generated O2 － [28]. In addition to reversible and irreversible activation of Ca2+－sensitive K+ channels [19] and the mechanism investigated by Dr. Takakura and colleagues，several other pathways contributing to vascular hyporeactivity in septic shock have been identified and warrant discussion. Both NO [30] and O2 － [31] have been reported to inactive catecholamines. Furthermore，metabolites of 3－nitro－l－tyrosine，an ONOO tyrosine reaction product，may function as 1－adrenoceptor blockers [12]. Szabo et al. [32] and Chabot et al. [33] showed that single－strand breaks in DNA caused by ONOO－ activate poly－adenosine diphosphate－ribose synthetase，which subsequently can consume cellular stores of oxidized nicotinamide adenine dinucleotide and adenosine 5－triphosphate and lead to vascular dysfunction. Notably，this pathway represents an extreme，cytotoxic effect of ONOO－. Severe energy depletion by poly－adenosine diphosphate－ribose synthetase eventually blocks energyrequiring apoptotic pathways and results in cell necrosis. This suggests that if this form of vascular failure occurs in septic patients，it is likely to be a late，preterminal event. In summary，infection－induced refractory hypotension and vascular hyporesponsiveness to therapeutic intervention are important determinants of septic shock mortality. However，vascular failure in septic shock involves a large network of redundant and interacting vasodilators and vasoconstrictors whose functions overlap extensively with effectors of inflammation and coagulation. The daunting complexity and dynamic nature of this syndrome suggest that basic investigations，such as the work by Dr. Takakura and colleagues [12]，are essential for the development of effective treatments. Unfortunately，in a recent clinical trial，L－NG－methylarginine，a nonspecific inhibitor of NO synthase，raised blood pressure but increased mortality rate [34]. Ultimately，functional genomic approaches，driven by the human，animal，and humanpathogen genome projects，may lead to a much broader understanding of the complex pathophysiology involved in this syndrome [35，36]. Eventually，it may become possible to biochemically identify stages of septic shock that require different types of intervention. Furthermore，care individualized by genotypic considerations and therapies targeted to specific vascular beds are likely to be fertile directions for future research. |
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> 32. Szabo C，Cuzzocrea S，Zingarelli B，et al： Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly （ADP－ribose） synthetase by peroxynitrite. J Clin Invest 1997；100：723－735 [Context Link] 33. Chabot F，Mitchell JA，Quinlan GJ，et al：Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery： Role of poly （adenosine 5 －diphosphoribose） synthase. Br J Pharmacol 1997；121：485－490 [Context Link] 34. Freeman BD，Danner RL，Banks SM，et al：Safeguarding patients in clinical trials with high mortality rates. Am J Respir Crit Care Med 2001；164：190－192 [Context Link] 35. NIH－sponsored conference on the functional genomics of critical illness and injury. NIH Web site. Available at： http：//www.cc.nih.gov/ccmd/ Symposium2002/index.html Accessed Feb. 8，2002 [Context Link] 36. Consortium for expression profile studies in sepsis （CEPSIS）. Web site. Available at：http：//www.CIA.wustl.edu/CEPSIS.html Accessed Feb. 8，2002 [Context Link] |