From (Neurocritical Care 2012;16:343)<\/p>\n
Peter Le Roux and Michael Diringer<\/p>\n
To the Editor,<\/p>\n
We read Dr. Marik\u2019s letter with interest. He makes some valuable comments and is correct when he states: more research is needed. We respectfully disagree, however, with his conclusion that the consensus conference recommendations about anemia and transfusion in subarachnoid hemorrhage (SAH) are not supported by the literature. We believe that a more critical appraisal of a wider body of literature is entirely consistent with them. In addition, we feel that his letter emphasizes many potential risks (not all of which apply to SAH patients) but ignores the potential benefit of transfusion in this population.
\nDr. Marik makes the following points to support his conclusion that transfusion use should be restricted: (1) transfusion has immunosuppressive and pro-inflammatory properties; (2) improved oxygen delivery does not necessarily lead to increased offloading; (3) aged blood may have adverse effects and nitric oxide depletion could potentially exacerbate vasospasm; and (4) studies associate transfusion with worse outcome.
\n1.
\nThere is little doubt that transfusion of aged non-leuko-reduced blood has immunosuppressive and pro-inflammatory consequences. Still, the link between these properties and mortality and functional outcome is not well defined. Furthermore, these risks appear to be attenuated with leuko-reduction and reduced storage time. Finally, the potential benefit that transfusion may have in patients with cerebral ischemia and prevention of stroke may far exceed the increased risk of infection.
\n2.
\nDr. Marik suggests that even if transfusion improves oxygen delivery it will not improve offloading to tissue. He cites two clinical studies of septic patients that demonstrate that increased oxygen delivery did not translate into increased global oxygen uptake, even in patients with an oxygen debt. There are a number of reasons to question the relevance of those studies to the issue at hand. In the first, patients had sepsis and multi-organ failure, a very different pathologic state than SAH. In addition, measurements were only made over that first few hours after transfusion, too soon for the blood to have had time to rejuvenate (see below). Finally, the measurements were global; organ specific responses could easily have been diluted. The second paper cited investigated the effects of dobutamine on oxygen offloading and not transfusion.
\nThe work by Dhar et al. [1] is cited to argue that transfusion does not improve oxygen offloading in SAH, since the CMRO2 did not change. However, as was discussed in that paper, CMRO2 would not increase unless there was ongoing active ischemia. The timing of the transfusion was such that patients primarily had regions of oligemia; in those regions transfusion lowered abnormally high oxygen extraction fraction (OEF), indicating improved flow-metabolism coupling and reduced risk of ischemia.
\n3.
\nRed blood cells (RBC) deteriorate during storage losing 2,3-DPG and nitric oxide (NO). The clinical consequences are incompletely understood. Over several hours after transfusion the cells undergo a rejuvenation process with restoration of normal levels of these factors [2]. In addition, pre-transfusion use of rejuvenation solutions improves post-transfusion RBC function [3]. Thus, while, as Dr. Marik has shown in sepsis [4], transfused blood may initially be ineffective, over several hours this may not be the case. In SAH where onset of ischemia is delayed, maintaining higher hemoglobin (Hgb) levels with transfusion before the onset of ischemia will allow time for rejuvenation. Thus the concerns that lack of stored NO may exacerbate vasospasm are theoretical at best and ignore that NO is rapidly restored as the RBCs are rejuvenated [2]. Dr. Marik cites one paper that found an association between transfusion and angiographic vasospasm [5]. However, in this study, patient outcome was not associated with transfusion during a patients\u2019 ICU course. Furthermore, the study was retrospective in nature and so it is conceivable that the association exists simply because the patients were transfused to treat delayed cerebral ischemia (DCI).
\n4.
\nDr. Marik argues that the literature indicates that transfusion is associated with worse outcome in SAH patients. Four cohort studies are cited that suggest an association between transfusion and worse outcome after SAH. Yet the work of Broessner et al. [6] who observed that transfusion of RBCs was not associated with ICU mortality or unfavorable long-term outcome in SAH patients was not cited. Due to the retrospective nature of the cited studies each has a potentially fatal flaw; none of the analyses took into account timing, i.e., did transfusion precede the onset of DCI or was it administered as part of the management of DCI? Hence the cause of the poor outcome may be the DCI not the transfusion. We have attempted to address this problem using a propensity score to correct for likelihood of receiving a transfusion and found that transfusion may not have an adverse effect on patients with DCI. Instead any potential deleterious effects may only occur in those at low risk for ischemia.<\/p>\n
Two randomized clinical trials (RCT) in transfusion are cited. The one performed in children does not apply to the SAH population. Even the TRICC trial does not since patients with SAH were not included. Furthermore, only 13% (838 of 6,451) of the screened patients were randomized and so, many patients with impaired cardiovascular or cerebrovascular reserve, who are less tolerant to anemia, may have been excluded from the trial [7]. In addition, the quality of transfused blood has changed since 1999 when the TRICC trial was published and this likely will alter outcomes. For example, findings in the Anemia and Blood Transfusion in Critically Ill Patients (ABC) study were consistent with TRICC [8]. However, in the Sepsis Occurrence in Acutely Ill Patients (SOAP) study that used the same methodology as ABC, but was performed several years later, transfusion was not associated with worse outcomes [9]. In the last several years leuko-depletion, which may be associated with fewer adverse transfusion effects, has been widely adopted, and, in general, transfusion has become safer.<\/p>\n
Dr. Marik cited the American College of Surgeons National Surgical Quality Improvement Database to indicate that transfusion is harmful. By contrast, a more recent study of septic patients found no such relationship [9]. Still neither of these populations is comparable to SAH. It is important to point out that over the years we have repeatedly learned that generalization of study findings beyond the target population is an unwise and sometimes dangerous proposition.
\nWe do not argue that transfusion is risk free; however, we believe many of those discussed in the letter do not necessarily apply to SAH patients. Yet, even assuming that risk does exist, use of transfusion needs to be considered not only in terms of risk but also in terms of potential benefit. There are several reasons to suggest that transfusion may be helpful to SAH patients at risk for DCI.
\n1.
\nDelay cerebral ischemia is the most common cause of preventable secondary injury in SAH. This occurs despite the use of several high-risk interventions including hypervolemia, induced hypertension and angioplasty. Transfusion could provide a lower risk more effective treatment for DCI.
\n2.
\nExperimental evidence links anemia with reduced brain tissue oxygen (PbtO2) and increased neuron injury after acute brain injury [10\u201312]. In the normal brain, compensatory vasodilation occurs with Hgb <10 g\/dL [13], so brain hypoxia usually is manifest only at lower Hgb levels (e.g., <6\u20137 g\/dL). However, when cerebrovascular reserve is impaired, e.g., in patients with SAH, tissue hypoxia and cell injury may develop at a higher Hgb. Using cerebral microdialysis in poor-grade SAH patients, Hgb ? 9 g\/dL was identified as an independent factor associated with cerebral tissue injury [14]. In a similar study, Kurtz et al. [15] who excluded patients who required an FiO2 >60% linked Hgb <10 g\/dL with cellular energy dysfunction.
\n3.
\nA recent paper compared the impact of three different interventions to treat DCI in SAH patients. The ability of fluid boluses, induced hypertension and transfusion to improve oxygen delivery to oligemic brain regions was measured using PET [16]. Transfusion of 1 unit of blood was far more effective that either of the other two routinely utilized interventions.
\n4.
\nSeveral observational studies suggest anemia in SAH is associated with worse outcome [17\u201319], and therefore avoidance of low Hgb may be warranted. The optimal Hgb threshold for RBCT in SAH patients remains unclear although a recent clinical study suggests that an Hgb > 11 g\/dL is associated with less cerebral infarction and improved outcome after SAH [17].
\nHerein in this dilemma for the physician: over-transfuse or under-transfuse. To make this decision requires an understanding of patient physiology. In the ICU, clinicians routinely adjust treatment dose and care based on multiple factors. It is difficult to simulate this in a clinical trial [20]. Randomization to two relatively fixed treatment protocols may not be interpretable in a way that easily informs practitioners and can disrupt the potentially important relationship between level of disease and dose of therapy in a very specific manner, or practice misalignment [21]. This was apparent in the TRICC trial where patients with ischemic heart disease had a significantly different response and in an opposite direction to the two fixed RBCT thresholds than patients without ischemic heart disease [21], i.e., transfusion was \u201cgood\u201d in those with reduced cardiovascular reserve. Consistent with this, physicians working in U.S. and Canadian academic neurocritical care units who regularly care for SAH patients transfuse SAH patients based on their perceived cerebrovascular reserve. In particular clinicians are less willing to accept a restrictive transfusion threshold in the setting of DCI: in these patients 30% say they target Hgb >11 g\/dl [22]. This practice is entirely consistent with the most recent Guidelines for Transfusion [23] recommendations of the American Society of Anesthesiologists Task Force, [24] and the Canadian Guidelines [25] that suggest transfusion requirements may need to be titrated to parameters of illness severity rather than arbitrarily defined Hgb levels.
\n5.
\nTo prevent infarction associated with vasospasm requires improved oxygen delivery. When blood is transfused, oxygenation in the brain improves [26\u201328]. However, it does not increase in about 20\u201325% of patients. This may be associated with the age of blood, patient sex, starting point of Hgb or PbtO2.
\nOur original comments and recommendations stand:
\n1.
\nIt remains unclear whether RBCTs are simply a marker of disease severity or an independent cause of worse outcome.
\n2.
\nThe results of the TRICC trial and subsequent observational studies of transfusion in general critical care do not and should not apply to SAH patients.
\n3.
\nFor now, clinicians will need to base transfusion decisions for SAH patients in the context of conflicting information and so should focus on an individualized assessment of anemia tolerance, consider blood conservation strategies, and understand the potential risks and benefits of blood transfusion. This sentiment is echoed in recent published recommendations which state: \u201cDecisions regarding blood transfusion in patients with SAH must be assessed individually because optimal transfusion triggers are not known\u2026\u201d [23].<\/p>\n
The risks of transfusion are well understood. However there also are patients who benefit from transfusion. The important question is who will benefit from a transfusion. Perhaps how we transfuse is wrong, i.e. to a Hgb threshold. Perhaps some other endpoint of resuscitation is needed? Here we agree with Dr. Marik: more research and research specific to the SAH population is needed.<\/p>\n
References
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From (Neurocritical Care 2012;16:343) The Risks of Blood Transfusion in Patients with Subarachnoid Hemorrhage: Response to Dr. Paul E. Marik Peter Le Roux and Michael Diringer To the Editor, We read Dr. Marik\u2019s letter with interest. He makes some valuable comments and is correct when he states: more research is needed. We respectfully disagree, however, […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_genesis_hide_title":false,"_genesis_hide_breadcrumbs":false,"_genesis_hide_singular_image":false,"_genesis_hide_footer_widgets":false,"_genesis_custom_body_class":"","_genesis_custom_post_class":"","_genesis_layout":"","footnotes":""},"categories":[15],"tags":[],"yoast_head":"\n