关于重症患者的贫血与促红素

如果让我预测未来危重病学的临床进展，我想关于危重患者的贫血问题可能是最需要尽快解决的问题之一。我们已经熟知的早期目标治疗（针对血液动力学指标的改善），血糖控制，感染以及营养等等都已经在拯救脓毒症的指南中有所体现，实际上这些措施如果换一眼睛来看，就是针对危重症患者种种常见的临床异常指标而去的，比如血压，比如血糖，比如白细胞、尿量...可是关于血色素，这个“常见到以至于忽略”的指标真的没有在指南中专章表述，不失为一种遗憾。
今天看到《Mayo clinic proceedings》刊登了题为《Anemia in the eldly》的综述(本篇可免费阅读全文)，文章提出贫血发病率在正常老年人群中就很常见，但是围绕老年人的血色素正常值以及贫血的界定目前为止仍无定论。如果是这样，那危重病房中的那些银发组岂不更是如此！
关于促红素在危重患者贫血中的应用，推荐三篇文献：
1. Anaemia in the critically ill patient: monitoring of erythropoietin therapy.(BJU Int. 2006 Jun;97(6):1161-4.)
2. Alternatives to blood product transfusion in the critically ill: Erythropoietin.(Crit Care Med 2006; 34[Suppl.]:S160–S169)
3. Erythropoietin: High Profile, High Scrutiny.(Journal of Clinical Oncology.2007;25:1021-1023)
第一篇谈及了危重患者贫血的分型，以及对应的适合促红素和/或补铁治疗的类型；第二篇比较全面的回顾了已有的关于促红素在危重患者中应用的临床试验，对该领域已知和未知的问题作了极好地阐述，第三篇是述评，回顾了多项癌症性贫血患者应用促红素未能对预后产生影响的原因，因此对危重患者应用促红素是一个上佳的借鉴。
作为最关键的第二篇，其结论部分摘录如下：
Anemia is commonly seen in critically ill patients. Approximately 95% of patients have subnormal Hb values by day 3 of their ICU stay. This anemia is often of sufficient severity to require replacement of RBCs via transfusion. Recent surveys of ICU practice document that approximately 50% of ICU patients receive RBC transfusions. ICU-associated anemia is the result of the additive effects of blood loss and decreased RBC production(失血与造血双方面的原因). Critically ill patients may have overt blood loss, such as acute gastrointestinal bleeding or trauma-associated bleeding. Some patients lose blood more insidiously, such as with occult gastrointestinal bleeding. The volume of blood collected via phlebotomy for the extensive laboratory monitoring this patient population undergoes can directly impact RBC transfusion needs. （静脉采血的影响！）The other major factor influencing the development of anemia in critically ill patients is decreased RBC production. It appears that decreased RBC production results from the combined effects of abnormal iron metabolism (i.e., inability to use iron that is “locked up” in storage for erythropoiesis), inappropriately low production of EPO, diminished erythropoietic response to EPO, and direct suppression of bone marrow RBC production. Inflammatory mediators such as TNF-a, IL-1, IL-6, and IFN-a play a central role in the pathogenesis of decreased RBC production in this setting. Because ICU-related anemia is related, at least in part, to the inadequate production of and a diminished response to endogenously produced EPO, rHuEPO has been evaluated as a potential therapeutic modality.
Single-center and multicenter trials, involving from a small number (e.g., 21 subjects) to over 1,000 subjects, have been conducted utilizing different doses, dosing schedules, and routes of administration of rHuEPO (intravenous or subcutaneous).
These trials have disclosed that rHuEPO in ICU patients（EPO的已知作用如下）
● will significantly increase serum EPO concentrations, in comparison with nontreated subjects;
● will produce significantly higher reticulocyte counts, in comparison with nontreated subjects;
● will produce statistically significant increases in reticulocyte counts, in comparison with baseline counts in treated subjects;
● will produce statistically significant increases in serum transferrin receptor levels, in comparison with baseline levels in treated subjects;
● will significantly reduce the number of RBC units transfused, in comparison with nontreated subjects;
● will significantly reduce the number of subjects requiring any RBC transfusions, in comparison with nontreated subjects;
● will result in a significantly higher rise  in Hb and hematocrit from baseline values, in comparison with baseline values for nontreated subjects; and
● will result in a significantly higher final Hb and hematocrit, despite receipt of fewer RBC transfusions, in comparison with nontreated subjects.
It appears that rHuEPO can overcome the so-called “blunted response to EPO” in patients with ICU-associated anemia. Questions that need clarification include the appropriate dosing schedule and the subset of ICU patients who can most benefit from rHuEPO therapy. There is evidence to suggest that 40,000 U of rHuEPO administered subcutaneously on a weekly basis will overcome the blunted response to EPO. Although early initiation of therapy seems advisable, it would also appear that the use of rHuEPO is probably not cost-effective if the ICU LOS is anticipated to be \u00013 days.
The key question, however, is “Do the increased erythropoiesis and decreased RBC transfusion requirements associated with rHuEPO therapy result in improved outcomes for critically ill patients?” It is tempting to reflexively answer yes, for a number of reasons. The ability of critically ill patients to tolerate anemia is a great concern. Studies published in the latter half of the 1990s provided evidence suggesting that anemia increased the risk of death for surgical patients and for critically ill patients with cardiac disease (34, 35). A study of critical care patients in Western Europe documented that lower mean hemoglobin levels were associated with a greater extent of organ dysfunction, a longer ICU LOS, and a higher mortality rate (8). A similar study of critical ill patients in the United States showed that a nadir Hb of   < 9 g/dL was associated with a higher mortality rate (4).
However, although it is apparent that anemia adversely affects critically ill patients, RBC transfusions do not appear to be the best approach to the problem. The Western European study demonstrated that RBC transfusions were associated with increased ICU LOS, diminished organ function, and increased mortality (8). Similarly, the U.S. study demonstrated that the number of RBC transfusions was independently associated with increased ICU and hospital LOS and increased mortality (4). Thus, a more conservative approach to RBC transfusion therapy appears desirable. The Transfusion Requirements in Critical Care (TRICC) trial has served to reinforce the concept that a restrictive strategy of RBC transfusion is at least as effective and is possibly superior to a liberal strategy for critically ill patients (31). Other techniques to correct anemia in critically ill patients, such as rHuEPO, therefore need to be appropriately evaluated. Unfortunately, clinical trials conducted to this point have not been able to adequately address the question of whether rHuEPO improves clinical outcome for critically ill patients.(最最关键的是EPO目前还没有被证实对预后有显著作用！) In the absence of evidence of improved patient outcome, the cost-effectiveness of rHuEPO therapy in this setting has been questioned. Thus, is administration of rHuEPO to combat ICU-related anemia the right thing to do? Currently, the answer to this question is not known. The  results of clinical trials with the sufficient power and extent of follow-up to address the question of patient benefit are much anticipated.