The amount of oxygen reaching specific organs is the product of local blood flow and the arterial oxygen content (C_aO₂). The latter is dependent on the Hb concentration and the degree to which it is saturated with O₂ (S_aO₂), with a small amount of O₂ also dissolved in blood. Thus, global systemic O₂ delivery can be expressed by the following equation:

O₂ delivery to the brain can be conceptualized using the same equation, but by substituting cerebral blood flow (CBF) for cardiac output (CO). Flow through the cerebral vasculature is determined by the cerebral perfusion pressure (CPP), the length and caliber of the vessels, and the viscosity of blood, as described by the Hagen-Poiseuille equation:

Regulation of CBF and cerebral O₂ delivery in response to physiologic stressors is achieved largely by homeostatic variations in the caliber of cerebral vessels (the 'r' in the above equation; Figure 1).

CPP is the difference between mean arterial pressure and cerebral venous pressure; intracranial pressure is widely used as a surrogate for the latter. The response of the cerebral vasculature to changes in CPP is referred to as CBF autoregulation ('pressure-reactivity'). Cerebral arterioles vasoconstrict in response to raised CPP and vasodilate when there are reductions, thereby maintaining constant CBF (Figure 1a). Autoregulation is sometimes impaired in neurocritical care patients, such that CBF becomes directly dependent on CPP, making the brain more vulnerable to both hypo- and hyperperfusion 303132.

There are numerous other stimuli that may modify cerebral vascular resistance and CBF. Both global and regional CBF are tightly coupled to metabolism. Thus, physiologic changes that lead to a reduction in cerebral metabolic rate (CMRO₂) (e.g. hypothermia or sedation) will also proportionally reduce CBF (Figure 1b). In addition, CBF is influenced by variations in the partial pressures of carbon dioxide (PCO₂; 'CO₂-reactivity'), and to a lesser degree, O₂ (PO₂) (Figures 1c, d). CBF increases in response to a decrease in PO₂, although this effect is probably minimal until the level approaches 60 mmHg 30.

In response to worsening anemia, neuronal O₂ delivery is initially preserved both by the systemic cardiovascular response and mechanisms that are more specifically neuroprotective.

A falling Hb concentration is sensed by aortic and carotid chemoreceptors, resulting in stimulation of the sympathetic nervous system, which in turn raises heart rate and contractility, thereby augmenting CO 333435. The reduction in blood viscosity results in a corresponding reduction in afterload, as well as enhanced flow through post-capillary venules, greater venous return, and increased preload 363738. Thus, stroke volume, CO, and blood pressure (as well as CPP) increase in response to isovolemic anemia. Tissues are further protected from falling O₂ delivery because of their capacity to increase O₂ extraction and maintain constant O₂ consumption. In the brain, irreversible ischemia may not occur until the O₂ extraction fraction (OEF) exceeds 75% 3940414243. Systemic anaerobic metabolism does not develop until the Hb concentration falls well below 5 g/dl in otherwise healthy individuals 44. On the other hand, many neurocritical care patients have concomitant cardiac disease and left ventricular dysfunction which may prevent an appropriate increase in CO in response to sympathetic stimulation. This is commonly the case even in the absence of pre-existing heart disease; for example, among patients with acute 'high-grade' aneurysmal subarachnoid hemorrhage (SAH) (Hunt-Hess grades 3 to 5), more than one-third have regional left ventricular wall motion abnormalities detectable by echocardiography 45.

Apart from the increased flow produced by higher CPP and lower blood viscosity, anemia also induces cerebral vasodilatation 464748. When Hb (and therefore C_aO₂) falls, there appears to be a disproportionate increase in CBF in relation to other organs (Figure 1d) 49. The mechanisms underlying this increase in vessel caliber are still being clarified, but include some of the same factors involved in CBF pressure-autoregulation; these have recently been reviewed in detail 46. Importantly, anemia results in upregulation of nitric oxide (NO) production by perivascular neurons and vascular smooth muscle surrounding cerebral blood vessels. The importance of these pathways is supported by the observation that inhibition of NO synthase blunts hypoxia- and anemia-induced cerebral vasodilatation 505152. However, additional factors are undoubtedly involved 535455. Sympathetic β2 receptor stimulation is an example of one such mechanism that contributes to vasodilatation and maintenance of CBF 56. Other biochemical mediators that are upregulated in the brain in response to anemia include vascular endothelial growth factor, hypoxia inducible factor 1α, and erythropoietin 4657. Although it seems likely that these mediators are neuroprotective, it remains possible that they could also have harmful pathophysiologic effects 46.

As anemia worsens, the resultant increases in CBF and OEF eventually become insufficient to overcome the reduced C_aO₂ produced by a low Hb concentration (Figure 2). The point at which this threshold is reached is not clear and probably varies somewhat between patients. A sophisticated mathematical model based on animal data suggested that CMRO₂ is well preserved in normal brain, even with severe reductions in Hb concentration. In contrast, penumbral brain appears to be much more vulnerable, with O₂ delivery and CMRO₂ progressively declining as Hb falls below 10 to 12 g/dl 5859606162. As with cerebral ischemia, impairment of the usual protective mechanisms induced by anemia has also been demonstrated as a result of brain trauma 63.

A study of euvolemic hemodilution in healthy human volunteers confirmed that even profound anemia (Hb about 5 g/dl) was relatively well tolerated; however, subtle abnormalities in neurocognitive testing began to emerge when Hb concentrations fell below 7 g/dl 6465. The co-existence of other physiologic stressors may also make anemia less tolerable; for example, experimental studies have found that cerebral O₂ delivery is preserved in the presence of both severe anemia and hypotension individually, but not when they are both present 6667. Additionally, anemia-induced cerebral vasodilatation appears to interfere with the usual response to variations in PCO₂ 47686970. These observations raise concerns that relatively inadequate O₂ delivery could occur at Hb levels well above 7 g/dl in critical care patients with cerebrovascular disease, pre-existing central nervous system pathology (e.g. an ischemic or 'traumatic' penumbra) or deranged regulation of CBF. Thus, there is strong physiologic rationale for believing that a restrictive transfusion threshold of 7 g/dl, although clearly safe in many critical care patients 2526, may not be without risk in neurocritical care patients.

Even if anemia is harmful, this does not necessarily prove that liberal use of allogeneic RBCs to normalize Hb concentrations is justified. Emerging data indicates that stored blood has important differences from patients' own blood. A number of changes occur over time as RBCs are being stored; some of these alterations could have important implications after transfusion, and they are collectively referred to as the 'storage lesion'. Biochemical changes include reductions in ATP, loss of membrane phospholipids, and oxidative damage to proteins. The consequence is a gradual change in RBC appearance from the usual biconcave discs to irreversibly deformed and stellate-shaped spheroechinocytes 7172. Loss of RBC membrane function, as well as an increased tendency to adhere to endothelium, may interfere with microcirculatory flow 7273. RBC 2-3-diphosphoglycerate levels become depleted to the point of being essentially undetectable after one week of storage. Although levels are usually restored within 24 to 72 hours after transfusion, the transiently increased binding affinity of Hb interferes with the release of O₂ for use by tissues 74.

Thus, although blood transfusions are generally given with the intention of raising O₂ delivery, the storage-induced changes may prevent RBCs from achieving their intended purpose. For example, studies using gastric tonometry parameters as a surrogate for mesenteric perfusion have not shown improvements following transfusion 7576. Similarly, RBCs also appear to have little effect on skeletal muscle O₂ tension in postoperative patients or on global O₂ consumption in the critically ill 7778.

Transfusion-related acute lung injury is now the most common cause of transfusion-related mortality reported to the Food and Drugs Administration 79. Transfusion may have immunosuppressive effects, which are thought to be due to concomitant white blood cell transmission. Several studies have suggested a link between the use of allogeneic RBCs and both nosocomial infections and acute respiratory distress syndrome 80818283. Alternatively, RCTs, where well-matched groups were transfused with differing intensities, have not yet convincingly confirmed these associations 2526. Furthermore, the risk of complications may be less since the implementation of universal leukoreduction in many jurisdictions 84.

It has been suggested that the use of fresher blood might further minimize the risks of transfusion, while also maximizing their physiologic effect. Results have been conflicting, and there is little data specifically in neurocritical care patients 717576. A recent animal study found fresh blood to be more effective at raising brain tissue oxygen tension (P_btO₂) and preserving CBF in comparison to stored blood 85. Alternatively, Weiskopf and colleagues performed isovolemic hemodilution to Hb concentrations of 55 to 74 g/L in healthy volunteers and then transfused them with autologous blood stored for either less than five hours or more than 14 days; neurocognitive test performance did not differ between the two groups 86.

A great deal of what is known about the neurologic effects of anemia has been reported in the cardiac surgical literature. A substantial proportion of patients undergoing cardiac surgery receive blood transfusions, even though large volume hemorrhage is comparatively less common 92. Perioperative stroke occurs in 1 to 6% of patients and is strongly associated with greater morbidity and mortality 9394. An even larger proportion (≥50%) develops at least transient neurocognitive dysfunction that is likely to be, at least in part, due to cerebral ischemia 9596. Thus, the prevention and treatment of cerebral ischemia is of major concern in the perioperative period.

We identified 12 studies assessing the association between perioperative Hb concentrations and subsequent neurologic complications (Table 1). When defined as an Hb concentration less than 12.5 g/dl, about one-quarter of patients are anemic preoperatively 97. Blood loss and hemodilution during cardiopulmonary bypass usually lead to nadir intraoperative Hb concentrations of 7.0 to 8.5 g/dl; levels at ICU admission are typically 8.5 to 9.5 g/dl 98. Several, but not all, studies have suggested that the degree of Hb reduction is an independent predictor of stroke, delirium, neurocognitive dysfunction, and other adverse outcomes 979899100101102103104105106107108 (Table 1). Although it has not been proven with certainty that these relations are causative, it seems prudent to avoid major reductions in Hb as best as possible with relevant blood-conservation strategies 109110111112113.

A recent RCT involving 121 elderly patients undergoing coronary artery bypass compared two intraoperative hematocrit targets (15 to 18% vs. ≥ 27%) 102. The study was terminated early because of high complication rates in both groups; however, a greater degree of postoperative neurocognitive dysfunction was observed among patients managed with more extreme hemodilution. In addition, although not necessarily directly applicable to adults, further evidence that excessive hemodilution may have harmful neurologic effects comes from the neonatal literature. Combined data from two RCTs suggested that hematocrit levels below 23.5% during cardiopulmonary bypass were associated with impaired psychomotor development at one year of age 114115116.

Whether using RBC transfusions to maintain higher perioperative Hb levels helps avoid neurologic complications remains uncertain. For example, although Karkouti and colleagues found nadir hematocrit levels during cardiopulmonary bypass to be a predictor of stroke in a multivariable analysis, the same was also true for the perioperative use of transfusions 105. An association between transfusion and focal or global neurologic deficits has been confirmed in numerous other studies (Table 2) 117118119120121122123124125.

One study compared clinical outcomes, including the risk of perioperative stroke, between 49 Jehovah's Witnesses who underwent cardiac surgery without blood products and a matched control group of 196 patients, in whom RBC transfusions were used. No significant differences were observed; however, only nine patients in total experienced a stroke, such that this study lacked statistical power to detect a difference. The severity of anemia in Jehovah's Witness patients was not reported 123.

In a large, single-center, retrospective study, Koch and colleagues explored whether the association between RBCs and worse outcomes could be related to the duration of blood storage. Outcomes were compared among cardiac surgical patients depending on whether they were transfused with exclusively 'newer' (≤14 days old; median 11 days) or 'older' (>14 days old; median 20 days) blood during the perioperative period 126. In-hospital mortality and postoperative complications, including sepsis, renal failure, and need for mechanical ventilation, were greater among patients receiving older blood. However, there was no significant difference in the incidence of stroke and coma.

In summary, there remains uncertainty concerning optimum Hb levels for neuroprotection of patients undergoing cardiac surgery. Many intensivists routinely employ a postoperative transfusion threshold of 7 g/dl, although this may not be the optimum Hb level for the avoidance of neurologic complications. By necessity, the recommendations of published consensus guidelines are relatively non-specific, and state that it is "not unreasonable to transfuse red cells in certain patients with critical noncardiac end-organ ischemia whose Hb levels are as high as 10 g/dl" 111. Funding was recently secured in the UK for a multi-center RCT comparing transfusion triggers of 7.5 vs. 9 g/dl 92.

The majority of patients dying from severe TBI have histologic evidence of ischemic damage 127. Early global CBF reductions occur in many patients, often to levels that are considered to be in the ischemic range 128129. Reductions in both jugular venous O₂ saturation (S_jvO₂) and P_btO₂ are not only common, but their frequency and depth are predictive of worse outcomes 130131132133. However, the fall in CBF may be appropriate for a corresponding drop in metabolic rate 134135. Recent studies using positron emission tomography (PET) have suggested that although ischemia does occur, it is less common than previously thought. Furthermore, much of the 'metabolic distress' detected by multimodal monitoring (S_jvO₂, P_btO₂, and microdialysis parameters) is not necessarily attributable to classical ischemia 39134135.

On the other hand, there appears to be a great deal of regional heterogeneity in CBF and CMRO₂ 136. Even if the overall ischemic brain volume is relatively small, certain vulnerable regions may still benefit from enhanced O₂ delivery 137. As with cardiac surgical patients, relatively extreme reductions in Hb are likely to be deleterious. A recent animal model found that although isovolemic hemodilution to Hb concentrations of 5 to 7 g/dl resulted in an overall increase in CBF, it produced larger contusion volumes, more apoptosis, and lower P_btO₂ 138.

Potentially beneficial physiologic effects of transfusion have been shown in four studies of patients with severe TBI 139140141142, each of which demonstrated that P_btO₂ increases following the administration of RBCs (Table 3) 139. However, this increment was inconsistent, relatively small and often of questionable clinical importance. Of concern, in some cases there was even a reduction in P_btO₂. It is possible that some of the variation in the cerebral effects of transfusion could be, in part, attributable to the variable age of transfused blood. Leal-Noval and colleagues recently found that only those patients having received RBCs less than 14 days old had a statistically significant improvement in P_btO₂ one hour after transfusion 141. Although these results are intriguing, they are too premature to influence clinical practice and require confirmation in larger studies. Just because P_btO₂ rises, does not necessarily mean that CMRO₂ has increased. On the contrary, Zygun and colleagues found no improvement in cerebral lactate to pyruvate ratio (LPR – a marker of ischemia and 'metabolic distress') in response to transfusion, despite an increment in P_btO₂ 142.

In a retrospective study of 169 patients with TBI, Carlson and colleagues found nadir hematocrit levels to be associated with a worse Glasgow Outcome Scale at hospital discharge. However, the association between RBC transfusion and poor outcome was even stronger 143. Other observational studies have reached similar conclusions (Table 4) 144145146147148149150151. Unfortunately, there are no large RCTs to guide practice at this time. The TRICC trial enrolled only 67 patients with severe TBI 150. Although no statistically significant benefit from a liberal transfusion strategy was observed, this subgroup was too small to reach meaningful conclusions. Thus, the optimal use of RBCs in patients with severe TBI remains unclear. A recent survey found that practice across the USA is variable, and that the majority of clinicians believe a threshold of 7 g/dl to be too restrictive, especially in the presence of intracranial hypertension 27.

Narrowing of the cerebral vasculature (angiographic vasospasm) complicates about two-thirds of cases of SAH. Vasospasm most often emerges between days 3 and 14 after SAH and is the most important cause of secondary brain injury 87. Evidence of cerebral infarction that was not present initially is observed in as many as 50 to 70% of survivors using magnetic resonance imaging (MRI) 152153. Unlike other forms of stroke, the predictable risk of vasospasm and cerebral ischemia provides a unique opportunity for the provision of neuroprotection prior to the insult.

Three studies have assessed the association between daily Hb concentrations and eventual neurologic outcome 154155156. Each of these demonstrated that patients with an unfavorable outcome consistently have lower Hb levels throughout much of the first two weeks in hospital (Table 5). The degree of decrement in Hb levels over time was also highly predictive of outcome 154. Despite the use of multivariable analyses, there were numerous potentially confounding variables that could not be adjusted for. For example, patients who are 'sicker' tend to have more blood drawn for laboratory tests, have more invasive procedures performed, and tend to receive more intravenous fluids, all of which could contribute to lower Hb concentrations. Thus, the association between lower Hb and poor outcome has not conclusively been proven to be causative.

As in other settings, several studies have also shown a strong association between transfusion and unfavorable outcomes following SAH (Table 5) 28157158159160. One unconfirmed report suggested that the use of RBCs could contribute to the development of cerebral vasospasm, perhaps by promoting inflammation or depleting endogenous NO supplies 160. A recent observational study found no difference in complications based on the transfusion of older (>21 days) compared with newer (≤21 days) units of blood, although this assessment was based on only 85 transfused patients 28.

Hemodilution, together with hypervolemia and hypertension, has been used as part of 'triple H therapy', a therapeutic strategy to improve CBF in patients with vasospasm 161. One study used ¹³³Xenon injections to assess global CBF in eight patients with SAH. As expected, isovolemic hemodilution from a mean Hb of 11.9 to 9.2 g/dl produced an increase in global CBF and a reduction in cerebral vascular resistance. However, the increase in CBF was not sufficient to overcome the reduction in C_aO₂, such that global O₂ delivery fell and ischemic brain volume actually increased 162. Complimentary findings were subsequently reported by Muench and colleagues, who used aggressive volume expansion on days 1, 3, and 7, which produced a concomitant reduction in Hb concentration ranging from of 1.3 to 2.0 g/dl. Although this intervention consistently produced a small increment in CBF, it actually caused a proportionally larger decline in P_btO₂ (Table 3) 163.

More recently, Dhar and colleagues assessed the effects of transfusion in patients with SAH using PET 164. PET scans were performed before and after the administration of one unit of RBCs to patients with pre-transfusion Hb concentrations less than 10 g/dl. Although no change in CMRO₂ was observed, OEF dropped from 49 to 41%. Thus, it is possible that in vulnerable regions of the brain with relatively high OEF, RBC transfusions could help avoid irreversible infarction. Another recent study of 20 SAH patients found Hb concentrations less than 9 g/dl to be associated with lower P_btO₂ and higher LPR 165.

In summary, there is now extensive data to suggest that even moderate degrees of anemia are associated with worse physiologic parameters and clinical outcomes in patients with SAH. However, it is not clear that the use of RBC transfusions can modify these associations. An adequately powered, RCT comparing different transfusion thresholds is urgently required, especially in light of the vulnerability of these patients to delayed cerebral ischemia and the frequency with which they develop anemia.

Because of the known inverse relation between hematocrit and CBF, there has long been interest in the clinical use of hemodilution in the management of acute ischemic stroke 166. Some studies have suggested that relatively high Hb concentrations may predispose to the development of strokes 167168169170171172173, as well as contribute to worse outcomes when cerebral ischemia occurs 174175176177. It is conceivable that increased viscosity could have a particularly deleterious effect on microvascular flow through the ischemic penumbra. Consistent with this notion, Allport and colleagues performed serial MRI scans in 64 stroke patients and found that a higher baseline hematocrit was independently associated with infarct growth and less chance of successful reperfusion 178.

The deleterious association with a higher hematocrit has, however, been inconsistent and largely observed at levels in excess of 45% (Table 6). Indeed, several studies have shown a U-shaped relation where low hematocrit levels are also associated with larger infarct size and worse outcomes 175177179180181182183184. The lowest risk of stroke and the best outcomes have generally been observed with mid-range hematocrit levels of about 42 to 45% 172175. This range was also supported by a study using ¹³³Xe to assess CBF in stroke patients, with the finding that cerebral O₂ delivery was optimized at a hematocrit level of 40 to 45% 185. Conversely, several animal studies have suggested that cerebral O₂ delivery and neuroprotection are optimized at slightly lower hematocrit or Hb values, in the range of 30 to 36% and 10 to 12 g/dl, respectively 58186187. Greater degrees of hemodilution consistently appear to be deleterious 188. Some case reports have even described patients with relatively stenotic cerebral vessels who may have developed ischemic strokes directly attributable to anemia 189190191.

Several RCTs and a meta-analysis have not shown any clear benefit to using hemodilution as a therapeutic strategy in acute ischemic stroke 192. However, there was a great deal of heterogeneity in the methodology of these studies (timing of treatment, specific type and dose of plasma expander, target hematocrit). Although each study deliberately produced reductions in hematocrit with the use of colloids and/or phlebotomy, the reductions were relatively modest, generally not beyond 37 to 38% 192193194195196.

More recently, several animal studies and phase II human trials have suggested that hemodilution with relatively high doses of albumin may reduce infarct size and enhance the efficacy of thrombolytic therapy 197198199200. It is likely that this effect was observed, in part, because of the unique properties of albumin, rather than only hemodilution. In a phase II dose-finding study, the reduction in hematocrit induced by the highest doses of albumin averaged 6 to 10% 198199.

In summary, there is currently no routine role for hemodilution in the management of acute ischemic stroke. Whether transfusing anemic stroke patients with Hb concentrations lower than 9 to 11 g/dl is beneficial has not been well evaluated.

There has been controversy regarding the importance of cerebral ischemia in causing secondary brain injury after ICH. Early studies had suggested that an expanding intracerebral hematoma could cause mechanical compression and vasoconstriction of the surrounding vasculature, thereby producing a 'perihematomal penumbra' 201202203. Imaging with PET, CT perfusion scans, and MRI have confirmed that the majority of patients with ICH have a surrounding rim of hypoperfusion 91204205206. The biochemistry of this region appears to be similar to that of traumatic cerebral contusions 207. However, OEF is not increased in the perihematomal tissues, suggesting that this hypoperfusion is due to reduced cerebral metabolism, rather than true ischemia 91. Thus, mild reductions in Hb concentration are unlikely to have a major impact in contributing to neuronal death. Nevertheless, it remains uncertain whether perihematomal tissues tolerate anemia as well as healthy brain.

Hb-based blood substitutes (HBBS) have theoretical advantages over other fluids in the resuscitation of neurocritical care patients, because they have the potential to achieve the CBF-enhancing effects of hemodilution, while concomitantly maintaining, or even raising, C_aO₂. Several animal studies performed in the setting of experimental ischemic stroke, TBI, and SAH-induced vasospasm have supported this concept 208209210211212213214215216217218219220221. Alternatively, free Hb may also have numerous deleterious effects, probably mediated, in large part, by scavenging of NO 222. Although not all products are identical, a recent meta-analysis of RCTs suggested that their use is associated with an increased risk of death and myocardial infarction 223. One phase II RCT involving 85 patients with ischemic stroke reported worse neurological outcomes with the use of diaspirin cross-linked Hb 224. Of the five RCTs involving trauma patients, none specifically assessed the subgroup of patients with TBI, although the largest study reported no statistically significant interaction between HBBS and admission Glasgow coma scale on mortality 225226227228229. Two of the three RCTs in the setting of cardiac surgery reported the occurrence of perioperative stroke; there were no differences between HBBS-treated and control patients 230231. Thus, although the use of HBSS in neurocritical care should be further investigated, there is currently no role for the routine use of these products.