, Dean Fergusson1 and Lauralyn McIntyre1, 2
(1)
Centre for Transfusion Research, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
(2)
Department of Medicine (Critical Care), The University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada
Abstract
The neurocritically ill patient population is a unique patient group whose disease processes are a common reason for intensive care unit (ICU) admission. Brain injury patients are typically younger than general ICU patients, and the significant morbidity and mortality associated with them makes their potential life years lost enormous. The overriding goal in management is the prevention of secondary neurologic injury. It is biologically plausible that correction of low hemoglobin with red blood cell (RBC) transfusion may improve outcomes through an increase in oxygen delivery. This study question has not been adequately tested, and these patients have not been well represented in the existing quality trials that provide the key evidence that guides red blood cell (RBC) transfusion in many other critically ill populations. In this chapter, we review the physiologic and clinical significance of anemia as well as the evidence for RBC transfusion in three important neurocritically ill patient subgroups: those with ischemic stroke, traumatic brain injury, and intracranial hemorrhage (intracerebral hemorrhage and subarachnoid hemorrhage).
6.1 Oxygen Transport and Anemia Physiology in the Normal Brain
The brain relies on the steady delivery of oxygenated arterial blood to maintain normal function. The oxygen content of arterial blood (CaO2) is determined predominantly by hemoglobin concentration ([Hb]) and oxygen saturation (SaO2) and to a very small extent by partial pressure of oxygen in arterial blood (PaO2):
![$$ {\mathrm{C}}_{\mathrm{a}}{\mathrm{O}}_2=\left[\mathrm{Hb}\right]\times {\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2+0.0031\times {\mathrm{P}}_{\mathrm{a}}{\mathrm{O}}_2. $$](/wp-content/uploads/2016/11/A318254_1_En_6_Chapter_Equa.gif)
Oxygen delivery (DO2) is in turn dependent not only on oxygen content but, as expressed by the equation DO2 = CO × CaO2, is also dependent upon cardiac output (CO)[1]. DO2 to the brain is dependent on cerebral blood flow (CBF). CBF determinants include brain compliance, blood viscosity, and vascular resistance.
Although hemoglobin concentration is directly related to DO2, the hematocrit, which is a contributor to blood viscosity, is inversely related to CBF. Normal brain oxygen delivery is approximately 150 ml O2/min, which is approximately triple of what the brain consumes (VO2) under normal conditions [2]. An increase in VO2 or a decrease in any DO2 variable requires a compensatory change to maintain adequate oxygen delivery as well as the ability to compensate for hypoxia and ischemic insult. Normal brain responses to a decrease in hemoglobin (anemia), which decreases CaO2, include increases in heart rate, stoke volume (to increase CO), and a decrease in blood viscosity to improve cerebral blood flow [3]. In brain injury, CBF determinants such as brain compliance, blood viscosity, and vascular resistance may be altered. In addition, the normal compensatory mechanisms to anemia may be disrupted.
6.2 Oxygen Transport and Anemia Physiology in the Injured Brain
Following brain injury, many processes can result in secondary injury including alterations in cerebral metabolism, ischemia, tissue hypoxia, or the downstream effects of these processes [4]. A decrease in arterial oxygen content and/or a change in CBF are central, potentially reversible causes of secondary injury. Contributing factors can include anemia, hypoxemia, elevated intracranial pressure, vasospasm, loss or compromised cerebral autoregulation, and uncoupling of flow and metabolism [5]. Vasospasm plays a particularly important role following subarachnoid hemorrhage, but all of these processes can be present to varying degrees in all etiologies of brain injury.
Patients suffering from acute neurological stresses including ischemic stroke, traumatic brain injury, and intracranial hemorrhage are thought to be particularly susceptible to secondary ischemia from altered or decreased tissue oxygen delivery and/or tissue oxygen uptake and utilization. The normal physiologic vasodilation in response to anemia (and decreased CaO2) leads to increased cerebral blood volume and may potentiate hyperemia, edema, and increased intracranial pressure. As physiologic compensatory responses to anemia are exhausted or stretched, secondary ischemic injury may occur, which can further worsen a vicious cycle of edema, increased pressure, and altered cerebral blood flow. The net result is propagation of the ischemic injury.
Numerous preclinical models of brain injury exist which have improved the understanding of the pathophysiology of anemia in brain injury. In a rat model of traumatic brain injury, anemia was shown to increase hypoxic cerebral injury after neurotrauma compared to otherwise healthy controls [6]. In a mathematical modeling exercise using a rabbit model of stroke, a hemoglobin of 10 g/dL was the anemia threshold below which oxygen uptake in the ischemic penumbra decreased [7]. These animal models suggest that the injured brain may be susceptible to anemia.
Following brain injury in humans, anemia appears to exacerbate tissue hypoxia. In a prospective evaluation of 20 consecutive patients with severe subarachnoid hemorrhage (Hunt and Hess 4 or 5), Oddo et al. [8] demonstrated that a hemoglobin of <9 g/dL was associated with lower brain tissue oxygen levels and increased levels of lactate and pyruvate, which are metabolic markers of cellular hypoxia; these were consistent with greater brain hypoxia. This association remained significant after adjustment for other important variables in the subarachnoid hemorrhage patient population (cerebral perfusion pressure, central venous pressure, vasospasm, and PaO2/FiO2 ratio). In another small study of eight subarachnoid hemorrhage patients with vasospasm, isovolemic hemodilution was shown to increase cerebral blood flow but decrease global cerebral delivery rate of oxygen [9]. Both cerebral blood flow and oxygen delivery were decreased in hypervolemic hemodilution, and an increase in ischemic brain volume was seen at a hematocrit of 0.28 (approximately 8 g/dL).
In summary, there is a strong pathophysiological rationale, and some supportive clinical data, that the injured brain is more susceptible to the effects of anemia than other organs. This may be potentiated when normal compensatory mechanisms are exhausted or altered, making the acute brain-injured population a unique and potentially distinct subgroup from other critical care populations with respect to anemia and its management.
6.3 Epidemiology and Clinical Impact of Anemia in Brain Injury
Anemia in the critically ill is common, with up to 70 % of patients suffering some degree of hemoglobin (Hb) drop and 30 % having a Hb < 10 g/dL at some point over the course of their ICU stay [10–12]. The brain injury patient is also at high risk for anemia. Several recent reviews have summarized the existing data on anemia and its management in brain injury [3, 5, 13, 14]. A hemoglobin of <12 g/dL in females and <13 g/dL in males was observed in 97 % of severe ischemic stroke patients (defined as an ICU length of stay >5 days) in a recent small single-center cohort study [15]. Anemia in severe traumatic brain injury, defined as a post-resuscitation Glasgow Coma Scale score of 8 or less, is common and affects up to 50 % of these patients [3]. Similarly, moderate anemia (Hb < 10 g/dL) in aneurysmal subarachnoid hemorrhage, which is the most common type of primary subarachnoid hemorrhage, affects more than 50 % of cases [14, 16]. In this group, anemia develops within a mean of 3.5 days (median = 2 days) from admission and is associated with female sex, history of hypertension, poor clinical grade of subarachnoid hemorrhage, and a baseline hematocrit <36 % [16].
The etiology of anemia in neurocritical care patients is multifactorial and thereby mimics that of other ICU populations. Causes include blood loss (i.e., both disease related and iatrogenically driven from procedures and frequent phlebotomy) as well as inflammatory-related consumption, myelosuppression, and erythropoietin and iron metabolism abnormalities [15, 16].
In brain injury, both anemia that is prevalent at baseline and anemia that develops following the neurologic event appear to be associated with adverse clinical outcomes [3]. The vast majority of the evidence, however, is retrospective in nature and subject to the many limitations inherent to these types of study. It is not entirely clear whether anemia is purely a marker of comorbid illness and disease severity or if it is independently a poor prognostic factor.
6.3.1 Impact of Anemia in Ischemic Stroke
In a study of 135 consecutive ischemic stroke patients, the relationship between baseline hemoglobin and infarct size at presentation as well as between baseline hemoglobin and infarct progression was examined [17]. The authors determined that baseline hemoglobin was inversely related to both initial infarct size and infarct progression, which remained significant when controlling for age, gender, admission glucose, time to diagnosis, and stroke subtype. Decreasing hemoglobin levels also predicted poor functional outcome and mortality after ischemic stroke at 3 months [18]. The same authors more recently demonstrated that among severe ischemic stroke patients (admitted for >5 days to ICU), lower hemoglobin and anemia (hemoglobin <12 g/dL in women and <13 g/dL in men) were independently associated with longer ICU length of stay and duration of mechanical ventilation. However, anemia was not associated with mortality or adverse long-term outcome in their sample [15]. The authors attribute the lack of an association between anemia and mortality to two important limitations: (1) their retrospective study was limited to a severely injured patient population whose severe neurologic injuries may have predefined these outcomes, and (2) the study may not have been sufficiently powered to detect a signal of effect.
6.3.2 Impact of Anemia in Traumatic Brain Injury
Anemia has been demonstrated to be negatively associated with TBI outcome in several studies. Whether present at baseline or developing during the acute stages of illness, anemia appears to be associated with increased mortality and poor functional outcome. A recent single-center retrospective cohort study of 169 ICU patients with severe TBI demonstrated that 7-day mean hemoglobin of <9 g/dL was associated with an increase of more than three times the odds of hospital mortality than those with a mean hemoglobin ≥9 g/dL, after controlling for age, Glasgow Coma Scale scores, ventricular drain insertion, and RBC transfusion [19]. A subsequent narrative review identified 14 observational studies examining the association of anemia with outcome, of which more than half demonstrated a negative association between anemia and outcome [20]. This association may be particularly important in patients with evidence of brain tissue hypoxia [21]. However, the limitations of observational data are illustrated by a retrospective study in 169 severe TBI patients, which found an association between anemia and death or poor neurologic outcome, which disappeared when correcting for disease severity and other known predictors of poor outcome. In this study, an increase in duration of time spent with a hematocrit <30 % was associated with improved outcome [22]. The authors speculated that this finding might be explained by a subgroup of patients with low hemoglobin that had not undergone RBC transfusion, suggesting that RBC transfusion had adverse effects. These findings highlight the significant limitation of confounding by indication in observational studies.
6.3.3 Impact of Anemia in Intracranial Hemorrhage
In a recent observational study of 435 consecutive patients with primary intracerebral hemorrhage [23], anemia at admission (defined as Hb < 12 g/dL in men and <13 g/dL in women) was associated with larger hemorrhage volumes and higher probability of mortality at 1 year and was an independent predictor of poor functional outcome at 1 year. This contradicted earlier retrospective studies that demonstrated that nadir or mean hemoglobin, not admission hemoglobin, was associated with poor functional status at hospital discharge but not mortality [24, 25].
In subarachnoid hemorrhage, anemia is independently associated with poor outcome (adjusted for age, hemorrhage grade, aneurysm size, rebleed, and cerebral infarction from vasospasm) [26, 27], regardless of the severity of the subarachnoid hemorrhage [28]. In the absence of RBC transfusion, higher mean hemoglobin levels have been associated with a decreased risk of death or hospital discharge to nursing home or skilled nursing facility [29]. Whether better outcomes can be achieved with RBC transfusion remains unknown.
In summary, in the neurocritical care population, anemia appears to negatively impact outcome across a variety of patient subgroups. These data are however predominantly from retrospective observational studies and are limited due to confounding. Despite a strong physiologic rationale for RBC transfusion, it is unclear whether clinical outcomes are positively impacted by treatment of anemia with transfusion.
6.4 Effects of RBC Transfusion in the Injured Brain
Preclinical studies have demonstrated the biologic plausibility of oxygen delivery optimization in brain injury. Investigations using recent techniques for monitoring brain tissue oxygen demonstrate the benefit of improved oxygen delivery to tissue at risk from ischemia [4, 8]. Oxygen delivery (DO2) is improved with RBC transfusion as a result of increased hemoglobin concentration. For instance, observational work in brain-injured adults found that brain tissue partial pressure of oxygen is higher with higher hemoglobin concentrations [8] and, in most patients, increases with red blood cell transfusion [30]. In a prospective observational study of 35 consecutive patients with brain injury, RBC transfusion resulted in a mean increase in brain tissue oxygen by 49 %, unrelated to changes in cerebral perfusion pressure [30]. Moreover, measurement of oxygen delivery in human brains with vasospasm following subarachnoid hemorrhage demonstrated no increase with induced hypertension or fluid bolus but did significantly improve with RBC transfusion in patients with anemia (hemoglobin <9 g/dL) [31]. Perhaps equally as important, the resultant increase in hemoglobin post transfusion did not translate into a drop in CBF as a consequence of the increased viscosity. A small study of eight subarachnoid hemorrhage patients with anemia (hemoglobin <10 g/dL) demonstrated stable cerebral blood flow, an increase in oxygen delivery, and a decrease in oxygen extraction fraction following an RBC transfusion [32]. Finally, another small study of 17 subarachnoid hemorrhage patients with vasospasm, published by the same authors as an abstract [33], demonstrated that cerebral oxygen delivery improved post transfusion when targets were <10 g/dL. Transfusion above this level was associated with a drop in cerebral blood flow.
Given that hemoglobin concentration is directly related to oxygen delivery, the above findings are not surprising. However, improved delivery does not guarantee increased oxygen uptake or utilization nor improved clinical outcomes. In the non-neurologic critically ill population, it is clear that RBC transfusion increases DO2, but this has not always translated into a similar positive impact on oxygen consumption (VO2) [34–38]. Even in states of anemia, RBC transfusion in the critically ill has not consistently demonstrated an increase in VO2 [39, 40]. Older studies have showed that septic patients with a pre-transfusion low oxygen extraction fraction [36] or without a lactic acidosis [41] have an increase in VO2 following RBC transfusion, which may suggest a benefit. Understanding whether clinical outcomes change as a result of RBC transfusion to increase oxygen delivery following brain injury is essential, because pathophysiologic outcomes may not translate into clinical benefit. The decision to transfuse must always balance the potential benefits of increased oxygen delivery with the inherent risks of RBC transfusion.
6.5 Observational and Randomized Controlled Intervention Studies of the Clinical Effects of RBC Transfusion in the Injured Brain
Observational data in human subjects with various brain injury etiologies have demonstrated conflicting effects of RBC transfusion on the outcome. Although several randomized trials have examined the potential benefit of a restrictive versus liberal transfusion strategy in the management of critically ill patients, the few neurocritically ill patients in these studies significantly limit their generalizability to this patient population.
The most robust randomized comparison of a restrictive versus a liberal transfusion strategy in a mixed critically ill population is the TRICC trial [42]. Among general ICU patients, those transfused at a restrictive hemoglobin trigger of 7 g/dL had no difference in outcome as compared to patients transfused at a liberal hemoglobin trigger of 10 g/dL and actually trended toward a lower 28-day mortality (18.7 versus 23.3 %, p = 0.11) with less organ dysfunction and cardiac complications. However, few patients with neurologic injury were included in this study.
A recent systematic review of comparative studies of RBC transfusion in the neurocritically ill published prior to 2011 [43] found only six relevant citations in the literature. All were at high risk of bias, and there was a lack of long-term outcome assessment in the included papers. Of the six citations, four were in TBI patients, one in subarachnoid hemorrhage, and one in a mixed population. These will be reviewed in the subsections below, but overall, no benefit in mortality or lengths of hospital stay was demonstrated in the lower transfusion trigger groups. The authors concluded that insufficient evidence exists to support or refute a restrictive transfusion trigger in the neurocritical care population.
6.5.1 RBC Transfusion Trigger in Ischemic Stroke
Following ischemic stroke, like other areas of brain injury, maintaining euvolemia is extremely important as is optimizing oxygen delivery to “at-risk” hypoperfused areas around the infarcted brain (penumbra) to prevent infarct extension. The 2013 AHA Guidelines for the Early Management of Ischemic Stroke [44] provides no guidance with regard to the role of RBC transfusion to treat anemia and/or optimize oxygen delivery. An elevated hematocrit and resultant increased blood viscosity have been shown to contribute to hypoperfusion, increased infarct size, and increased mortality [3]. However, hemodilution or volume expansion in the acute phases has failed to lead to a reduction in mortality or functional dependence. Despite initially promising results of using high-dose albumin in the early hours of stroke management, a large phase III clinical trial was stopped early due to futility [45]. Additionally, more pulmonary edema was seen in the intervention arm. A number of studies examining the optimal hematocrit level in ischemic stroke patients point to a level of 0.40–0.45 [5]. The only study that has looked at the impact of RBC transfusion in ischemic stroke is the single-center retrospective cohort study by Kellert et al. published in 2014 [15]. In their cohort of severe ischemic stroke patients (required ICU admission for ≥5 days), the 32 % of patients that received RBC transfusion(s) were more likely to undergo tracheostomy and other interventions and had longer ICU lengths of stay and duration on mechanical ventilation. No correlation was found between RBC transfusion and either in-hospital mortality or 3-month neurologic outcome; however, a regression model was not performed to control for important potential confounders. Further, this study is likely underpowered and limited to ICU patients.
6.5.2 RBC Transfusion Trigger in Traumatic Brain Injury
Like other areas of neurocritical care, there is a lack of evidence to guide RBC transfusion in traumatic brain injury patients. The Brain Trauma Foundation Guidelines [46], now widely disseminated and adopted into clinical practice, make no specific recommendation to guide this aspect of care.
In the small subgroup analysis of the neurologic patients (n = 67) in the TRICC trial [47], the authors could not demonstrate harm in the restrictive transfusion strategy group but were also unable to demonstrate benefit in the liberal transfusion group. These patients had all suffered from trauma or isolated closed-head injuries as adjudicated by the primary research team. The very small sample makes this difficult to interpret but suggests that a restrictive transfusion strategy may well be safe. A small retrospective study that examined the effect of a hemoglobin ≥9.8 g/dL following the early resuscitative and operative phase of severe TBI failed to demonstrate any benefit or harm, regardless of whether RBC transfusion was required to achieve this level [48]. Two other retrospective studies included in the previously mentioned systematic review [43] that compared patients who received at least one RBC transfusion when their hemoglobin was between 7 and 10 g/dL as compared to those who did not receive transfusion and also did not demonstrate a mortality difference [49, 50]. The non-transfused patients tended to have shorter ICU and hospital lengths of stay. In these studies, it is impossible to disentangle transfusion effect from the effect of different severities of anemia. Similar results are reported from a small pediatric subgroup analysis of a previously published RCT. In this analysis, two transfusion thresholds were compared; however, only 3 of the 66 patients experienced the outcome (mortality) [51]. No randomized controlled trial comparing a liberal to a restrictive RBC transfusion strategy or optimal transfusion trigger has ever been completed.
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