Anemia and Cerebral Outcomes: Many Questions, Fewer Answers

Abstract

A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold (hemoglobin [Hb] concentration, 7-8 g/dL), and well above the threshold for cerebral tissue hypoxia (Hb 3-4 g/dL). However, hypoxic and nonhypoxic mechanisms of anemia-induced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide (NO), may help to maintain cerebral oxygen delivery during anemia as all three NO synthase (NOS) isoforms (neuronal, endothelial, and inducible NOS) have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor (HIF)-1alpha, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations (Hb 6-7 g/dL). This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1alpha degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1alpha transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore, NOS-derived NO may also stabilize HIF-1alpha in the absence of tissue hypoxia. Thus, during anemia, HIF-1alpha has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1alpha may have either neuroprotective or neurotoxic capacity depending on the cell type in which it is up-regulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1alpha, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.

Severe anemia: a case report

“…Transfusion is necessary to minimize symptoms and risks associated with symptomatic chronic anemia when hemoglobin is at 6 g/dl. Trials of acute normovolemic hemodilution in healthy volunteers and surgical patients found the limit of critical oxygen delivery in humans at about 50 g/l (12,13). Th e goal of early volume replacement is to delay or prevent the chain of events that leads to irreversible shock (13,15).…”

“…Rapid respiration and shortness of breath at rest should be considered as disturbing evidence of oxygen defi cit and evidence of cardiac decompensation. Dizziness and fainting are common as anemia progresses, but apprehension, changes in mentation and leg cramps are indications of severe oxygen deprivation and presage coma and death, or course that may lead to organ failure (1,11,12,13). When the amount of blood lost rapidly is equivalent to 30% of the blood volume, a subject may develop oligaemic shock (14).…”

Impact of Hemoglobin Levels and Anemia on Mortality in Acute Stroke: Analysis of UK Regional Registry Data, Systematic Review, and Meta‐Analysis

“…This is particularly important because of the natural variance in the normal hemoglobin ranges between sexes. The literature describes various plausible mechanisms that explain how anemia could directly contribute to poor outcomes 12. There is a paucity of information, however, investigating the impact of an important clinical factor: whether stroke patients with anemia receive fewer preventative medications pertinent to stroke, such as antiplatelets and anticoagulants (antithrombotics).…”

New practice guidelines for perioperative beta blockade from the United States and Europe: incremental progress or a necessary evil?

“…Thus, much of the current controversy in this area regarding the role of blood pressure, anemia, and cerebral circulatory physiology in response to specific pharmacologic interventions, e.g., beta blockade, brought to the forefront by the POISE study, would perhaps have been predefined. [53][54][55] Also, a stronger focus would guide the groups to relevant questions, such as: a) What are the parameters of physiologic beta blockade among various types of patients, including age, gender, race, and pharmacogenetics, and how are they influenced by concurrent physiologic processes, e.g., aging, anemia, transfusion, altered loading conditions? Although there is a rich background of literature, only passing consideration has been given to this topic by either group.…”

“…Ainsi, une grande partie de la controverse dans ce domaine concernant le rôle de la tension artérielle, de l'anémie et de la physiologie circulatoire cérébrale en réaction à des interventions pharmacologiques spécifiques, comme par exemple le bêta-blocage, et mise en exergue par l'étude POISE, aurait peut-être été prédéfinie. [53][54][55] De plus, une direction plus claire aiderait les différents groupes à se concentrer sur des questions pertinentes telles que : a) Quels sont les paramètres du bêta-blocage physiologique chez différents types de patients, y compris l'âge, le sexe, la race et la pharmacogénétique, et comment sont-ils influencés par des processus physiologiques survenant simultanément, comme le vieillissement, l'anémie, la transfusion, des conditions de charge modifiées? Bien que la littérature dans le domaine soit abondante, une attention que très limitée n'a été accordée à ce sujet par l'un et l'autre groupe d'élaboration des directives.…”