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’s 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.
Dr. 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.
1.
There 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.
2.
Dr. 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.
The 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.
3.
Red 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’ 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).
4.
Dr. 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.
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.
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.
We 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.
1.
Delay 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.
2.
Experimental evidence links anemia with reduced brain tissue oxygen (PbtO2) and increased neuron injury after acute brain injury [10–12]. 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., <6–7 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.
3.
A 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.
4.
Several observational studies suggest anemia in SAH is associated with worse outcome [17–19], 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].
Herein 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 “good” 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.
5.
To prevent infarction associated with vasospasm requires improved oxygen delivery. When blood is transfused, oxygenation in the brain improves [26–28]. However, it does not increase in about 20–25% of patients. This may be associated with the age of blood, patient sex, starting point of Hgb or PbtO2.
Our original comments and recommendations stand:
1.
It remains unclear whether RBCTs are simply a marker of disease severity or an independent cause of worse outcome.
2.
The results of the TRICC trial and subsequent observational studies of transfusion in general critical care do not and should not apply to SAH patients.
3.
For 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: “Decisions regarding blood transfusion in patients with SAH must be assessed individually because optimal transfusion triggers are not known…” [23].
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.
References
1. Dhar R, Zazulia AR, Videen TO, Zipfel GJ, Derdeyn CP, Diringer MN. Red blood cell transfusion increases cerebral oxygen delivery in anemic patients with subarachnoid hemorrhage. Stroke. 2009;40(9):3039–44.
PubMed CrossRef ChemPort
2. Heaton A, Keegan T, Holme S. In vivo regeneration of red cell 2,3-diphosphoglycerate following transfusion of DPG-depleted AS-1, AS-3 and CPDA-1 red cells. Br J Haematol. 1989;71:131–6.
PubMed CrossRef ChemPort
3. Koshkaryev A, Zelig O, Manny N, Yedgar S, Barshtein G. Rejuvenation treatment of stored red blood cells reverses storage-induced adhesion to vascular endothelial cells. Transfusion. 2009;49(10):2136–43.
PubMed CrossRef ChemPort
4. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA. 1993;269(23):3024–9.
PubMed CrossRef ChemPort
5. Smith MJ, Elliott JP, Winn HR, Le Roux P. Blood transfusion may increase the risk for vasospasm and poor outcome after subarachnoid hemorrhage. J Neurosurg. 2004;101:1–7.
PubMed CrossRef
6. Broessner G, Lackner P, Hoefer C, Beer R, Helbok R, Grabmer C, Ulmer H, Pfausler B, Brenneis C, Schmutzhard E. Influence of red blood cell transfusion on mortality and long-term functional outcome in 292 patients with spontaneous subarachnoid hemorrhage. Crit Care Med. 2009;37(6):1886–92.
PubMed CrossRef
7. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409–17. Erratum in N Engl J Med 1999;340(13):1056.
8. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499–507.
PubMed CrossRef
9. Vincent JL, Sakr Y, Sprung C, Harboe S, Damas P. Are blood transfusions associated with greater mortality rates? Results of the sepsis occurrence in acutely ill patients study. Anesthesiology. 2008;108(1):31–9.
PubMed CrossRef
10. Hare GM, Mazer CD, Hutchison JS, McLaren AT, Liu E, Rassouli A, Ai J, Shaye RE, Lockwood JA, Hawkins CE, et al. Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma. J Appl Physiol. 2007;103(3):1021–9.
PubMed CrossRef
11. Johannson H, Siesjo BK. Brain energy metabolism in anesthetized rats in acute anemia. Acta Physiol Scand. 1975;93(4):515–24.
PubMed CrossRef ChemPort
12. Dexter F, Hindman BJ. Effect of haemoglobin concentration on brain oxygenation in focal stroke: a mathematical modelling study. Br J Anaesth. 1997;79(3):346–51.
PubMed ChemPort
13. Borgstrom L, Johannsson H, Siesjo BK. The influence of acute normovolemic anemia on cerebral blood flow and oxygen consumption of anesthetized rats. Acta Physiol Scand. 1975;93(4):505–14.
PubMed CrossRef ChemPort
14. Oddo M, Milby A, Chen I, Frangos S, MacMutrie E, Maloney-Wilensky E, Stiefel MF, Kofke A, Levine JM, Le Roux P. Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage: a microdialysis study. Stroke. 2009;40(4):1275–81.
PubMed CrossRef ChemPort
15. Kurtz P, Schmidt JM, Claassen J, Carrera E, Fernandez L, Helbok R, Presciutti M, Stuart RM, Connolly ES, Badjatia N, et al. Anemia is associated with metabolic distress and brain tissue hypoxia after subarachnoid hemorrhage. Neurocrit Care. 2010;13(1):10–6.
PubMed SpringerLink ChemPort
16. Dhar R, Scalfani MT, Zazulia AR, Videen TO, Derdeyn CP, Diringer MN: Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage. J Neurosurg. 2011. doi:10.3171/2011.9.JNS11691
17. Naidech AM, Jovanovic B, Wartenberg KE, Parra A, Ostapkovich N, Connolly ES, Mayer SA, Commichau C. Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage. Crit Care Med. 2007;35:2383–9.
PubMed CrossRef ChemPort
18. Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B. Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2009;10:157–65.
PubMed SpringerLink ChemPort
19. Wartenberg KE, Mayer SA. Medical complications after subarachnoid hemorrhage: new strategies for prevention and management. Curr Opin Crit Care. 2006;12:78–84.
PubMed CrossRef
20. Tobin MJ. Counterpoint: evidence-based medicine lacks a sound scientific base. Chest. 2008;133(5):1071–4. (discussion 1074–1077).
PubMed CrossRef
21. Deans KJ, Minneci PC, Suffredini AF, Danner RL, Hoffman WD, Ciu X, Klein HG, Schechter AN, Banks SM, Eichacker PQ, Natanson C. Randomization in clinical trials of titrated therapies: unintended consequences of using fixed treatment protocols. Crit Care Med. 2007;35(6):1509–16.
PubMed CrossRef
22. Kramer AH, Diringer MN, Suarez JI, Naidech AM, Macdonald RL, Le Roux P. Red blood cell transfusion, blood conservation and multi-modal neurological monitoring in subarachnoid hemorrhage patients: A multidisciplinary North American survey. Crit Care. 2011;15(1):R30.
23. Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, Hebert PC, Anderson GL, Bard MR, Bromberg W, Chiu WC, Cipolle MD, Clancy KD, Diebel L, Hoff WS, Hughes KM, Munshi I, Nayduch D, Sandhu R, American College of Critical Care Medicine of the Society of Critical Care Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124–57.
PubMed CrossRef
24. Practice guidelines for perioperative blood transfusion and adjuvant therapies. An updated report by the American Society of Anesthesiologists Task Force on perioperative blood transfusion and adjuvant therapies. Anesthesiology. 2008;105:198–208.
25. Expert Working Group. Guidelines for red blood cell and plasma transfusion for adults and children. Can Med Assoc J. 2008;156(Suppl 11):1–24.
26. Smith MJ, Maggee S, Stiefel M, Bloom S, Gracias V, Le Roux P. Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med. 2005;33:1104–8.
PubMed CrossRef
27. Figaji AA, Kogels M, Fieggen AG, Argent AC, LeRoux P, Peter JC. The effect of blood transfusion on brain oxygen in children with severe traumatic brain injury. Pediatr Intensive Care Med. 2010;11(3):325–31.
28. Leal-Noval SR, Muñoz-Gómez M, Arellano-Orden V, Marín-Caballos A, Amaya-Villar R, Marín A, Puppo-Moreno A, Ferrándiz-Millón C, Flores-Cordero JM, Murillo-Cabezas F. Impact of age of transfused blood on cerebral oxygenation in male patients with severe traumatic brain injury. Crit Care Med. 2008;36(4):1290–6.
PubMed CrossRef