- Email: [email protected]
Blood transfusion indications in neurosurgical patients: A systematic review
Accepted Manuscript Title: Blood Transfusion Indications in Neurosurgical Patients: A Systematic Review Authors: Shefali Bagwe, Lawrance K. Chung, Carlito Lagman, Brittany L. Voth, Natalie E. Barnette, Lekaa Elhajjmoussa, Isaac Yang PII: DOI: Reference:
S0303-8467(17)30035-5 http://dx.doi.org/doi:10.1016/j.clineuro.2017.02.006 CLINEU 4621
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
20-1-2017 7-2-2017 12-2-2017
Please cite this article as: Bagwe Shefali, Chung Lawrance K, Lagman Carlito, Voth Brittany L, Barnette Natalie E, Elhajjmoussa Lekaa, Yang Isaac.Blood Transfusion Indications in Neurosurgical Patients: A Systematic Review.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2017.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Blood Transfusion Indications in Neurosurgical Patients: A Systematic Review
Shefali Bagwe, MD1, Lawrance K. Chung, BS1, Carlito Lagman, MD1, Brittany L. Voth, MPH1, Natalie E. Barnette1, Lekaa Elhajjmoussa1, Isaac Yang, MD1,2,3,4
1
Departments of Neurosurgery, 2Radiation Oncology, 3Head and Neck Surgery, and 4Jonsson
Comprehensive Cancer Center, University of California, Los Angeles
Corresponding Author Isaac Yang, MD Associate Professor Department of Neurosurgery University of California, Los Angeles 300 Stein Plaza, Suite 562 5th Floor Wasserman Building Los Angeles, California 90095-6901 Phone: (310) 267-2621 Fax: (310) 825-9385 E-mail: [email protected]
1
Highlights
Blood transfusion practices in neurosurgery vary across institutions
Evidence-based outcomes for transfusion thresholds and indications are limited
Most studies favor a conservative blood transfusion threshold of hemoglobin 7 g/dl
Abstract
Neurosurgical procedures can be complicated by significant blood losses that have the potential to decrease tissue perfusion to critical brain tissue. Red blood cell transfusion is used in a variety of capacities both inside, and outside, of the operating room to prevent untoward neurologic damage. However, evidence-based guidelines concerning thresholds and indications for transfusion in neurosurgery remain limited. Consequently, transfusion practices in neurosurgical patients are highly variable and based on institutional experiences. Recently, a paradigm shift has occurred in neurocritical intensive care units, whereby restrictive transfusion is increasingly favored over liberal transfusion but the ideal strategy remains in clinical equipoise. The authors of this study perform a systematic review of the literature with the objective of capturing the changing landscape of blood transfusion indications in neurosurgical patients.
Keywords: Blood transfusion Cerebral neoplasm Intracranial aneurysm Neurosurgery Subarachnoid hemorrhage Traumatic brain injury
2
1. Introduction
Neurosurgical procedures can be complicated by significant blood losses requiring red blood cell transfusions (RBCTs). However, the precise level or extent of anemia that is clinically relevant is unclear, as the effect of low tissue perfusion and oxygenation is likely tissue dependent and can vary between patients [1]. Decreased tissue perfusion becomes particularly important in neurosurgical patients due to the possibility of secondary cerebral injury. Still, controversy exists regarding thresholds for transfusion and what types of transfusions are most meaningful in these patients. Evidence-based guidelines concerning blood transfusion in neurosurgery are also relatively scarce. Thus, transfusion medicine within neurosurgical practices are highly variable and often based on institutional preferences. The authors of this study perform a systematic review of the literature with the objective of capturing the changing landscape of blood transfusion practices in neurosurgical patients, specifically those undergoing surgery for intracranial aneurysms, management of subarachnoid hemorrhage (SAH), treatment of traumatic brain injury (TBI), and resection of brain tumors.
Anemia is defined by the World Health Organization (WHO) as a hemoglobin (Hb) level of less than 12 g/dL in women and less than 13 g/dL in men [2]. Some reports suggest that a Hb level of 7-9 g/dL will not cause secondary neuronal injury, but the exact value at which anemia is harmful in neurosurgical patients is unknown [3, 4]. Currently, RBCT is the quickest and most effective way to raise Hb concentration [5]. Blood transfusions typically fall into 2 general categories, with advantages and disadvantages inherent to each:
3
1. Allogeneic blood transfusions require constant availability of blood donors, as well as facilities for blood grouping, cross matching, storage, and transportation; such requirements, make allogeneic transfusions expensive. In addition, transmission of viral diseases such as HIV and Hepatitis-B are associated risks of allogeneic transfusions. 2. Autologous blood transfusions involve donation of red blood cells (RBCs) by the patient, transfusion of the blood products, and hemodilution. Preoperative autologous RBCT results in anemia and an increased frequency of RBCT [6]. However, autologous RBCT is more cost-effective than allogenic RBCT [7].
Oxidative metabolism is the primary means of energy production in the brain. Thus, maintenance of cerebral perfusion pressure is critical for brain function and health. Major factors involved in ischemic brain injury include increased intracellular cytosolic calcium concentration, metabolic acidosis, and production of free radicals [8]. Increased accumulation of excitatory amino acids such as glutamate and aspartate, during ischemia, also contribute to selective neuronal death. In feline experiments, Shimada et al. demonstrated that decreasing cerebral blood flow (CBF) to 20 ml/100 g/min from a baseline CBF of 55 ± 3.3 ml/100 g/min in a control group, led to increased extracellular glutamate release and accumulation, possibly because of impaired uptake of glutamate due to deficient adenosine triphosphate supplies [9].
Increased extracellular glutamate is associated with large calcium influxes coupled with impaired intracellular calcium sequestration mechanisms. The rises in intracellular calcium activate a series of catabolic enzymes that ultimately lead to neuronal death. Hence, the basic principle in neurocritical care is to avoid secondary injury of the already compromised brain parenchyma by
4
ensuring adequate oxygenation. Secondary injury to the brain has been shown to occur at a hematocrit (HCT) of 20% or less, which is approximately equivalent to a Hb concentration of 67 g/dL [8]. Hb carries the vast majority of total oxygen (O2) content dissolved in the blood and a reduction in Hb concentration (i.e., anemia) can dramatically reduce O 2-carrying capacity. Impaired O2 delivery to the vital, highly-metabolic brain can lead to irrevocable damage. Thus, it is imperative that Hb levels be maintained especially in the setting of acute blood loss.
2. Methods
This systematic review was prepared according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) standard.
2.1. Sources and Search Strategy The Scopus, Web of Science, and PubMed databases were searched by independent authors (LC and CL) through February 7, 2017. Seven strategic search term combinations were used (Table 1). The search strategy is summarized Figure 1. English, full-text randomized controlled trials, prospective cohorts, and retrospective clinical studies were selected. Titles and abstracts were screened, and relevant full-text articles were reviewed. Bibliographies of the full-texts were surveyed for additional pertinent studies.
2.2. Study Selection Studies investigating transfusion of packed red blood cell (pRBC) products [10-32], including autologous [6, 7], allogenic [7, 33], and salvage RBCs [34, 35], in neurosurgical patients
5
undergoing intracranial surgery and medical management, were included. The primary areas of interest were general neurosurgical practice, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and brain tumor surgery. Studies investigating transfusion of RBC products in the context of craniosynostosis or spine surgery were excluded. Transfusions of prothrombin complex concentrate, fresh frozen plasma, platelets, or other non-RBC products were considered irrelevant and studies describing their use were excluded. The main findings of each study are summarized in Table 2.
3. General Practices
In a normal brain, when Hb concentration falls to < 10 g/dL, compensatory vasodilation occurs to ensure adequate blood supply [36]. Compensatory vasodilation maintains adequate perfusion until brain hypoxia develops, typically at an Hb concentration of < 6 g/dL [37]. However, with impaired cerebrovascular reserve, as in cases of SAH, tissue hypoxia and cell injury may develop at higher Hb levels. Hence, a “transfusion trigger” is defined as the threshold level of Hb in the blood at which transfusion is indicated. Transfusion triggers are defined for restrictive as well as liberal strategies of blood transfusion. An extensive review of clinical trials and literature by a joint taskforce of Eastern Association for Surgery of Trauma (EAST) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM) concluded that while restrictive transfusions occur when the Hb concentration has dropped below 7 g/dL [38]. Hb level of 5 g/dL was associated with significant cognitive changes in normal subjects, with increases in reaction time and impaired immediate and delayed memory. However, these changes were not documented with Hb levels of 7 g/dL.
6
Carson et al. conducted a review of 10 randomized controlled trials over a period of 40 years, involving 1,780 patients between the ages of 47 to 80 years [39]. Of these trials, 5 examined surgical patients undergoing general, cardiac, orthopedic or vascular surgeries, 3 examined patients with acute blood loss or trauma, and the remaining trials involved patients in critical care units (neurosurgical patients were excluded). In each trial, patients were randomized to either conservative or liberal transfusion strategies based on guidelines published by the American Society of Anesthesiologists (ASA) and their own institutional experiences [40]. The authors found that transfusion triggers were most often in the range of 8-9 g/dL. However, an overlap between restrictive triggers, in some trials, with liberal triggers in others prevented a meaningful comparison of outcomes. Each trial defined its own unique range of Hb concentrations according to the patient populations. As a result, the benefits and drawbacks of either strategy could not be determined. The conservative or restricted transfusion trigger did decrease the incidence of blood transfusion and the number of RBC units transfused when compared to a more liberal approach.
The Transfusion Requirements in Critical Care (TRICC) randomized trial, by Hebert et al., examined transfusions in intensive care unit (ICU) patients with Hb concentrations of 9.0 g/dL or less within 72 hours of admission in patients, who were euvolemic after initial treatment [41, 42]. The study compared a liberal RBC transfusion strategy (Hb level at 10-12 g/dL) to a restrictive strategy (Hb level at 7-9 g/dL) in 830 critically ill patients. A total of 26 (6%) of patients with a primary diagnosis of neurologic abnormality were included in the restrictive transfusion group and 13 (3%) in the liberal transfusion group. Overall, neurologic complications were higher in the liberal group versus the restrictive group (7.9% vs 6.0%), but the mortality rate in the
7
restricted group was lower. The latter was particularly evident in patients less than 55 years of age and suggests that critically ill patients should only be transfused if their Hb concentration falls below 7 g/dL. However, these patients had varying diseases and/or traumas that were not controlled for.
The CRIT study was a prospective observational cohort comprised of 4,892 patients from 284 ICUs in 213 hospitals. Investigations were limited to medical, surgical, or medical-surgical ICUs (excluded neurologic ICU). Nevertheless, the study provides a general perspective of transfusion practices in the United States [43]. The mean pre-transfusion Hb of all patients was found to be 8.6 ± 1.7 g/dL and 44% of patients received one or more RBC unit (mean: 4.6 ± 4.9 U) in the ICU. Hb nadir of < 9 g/dL was a predictor of mortality and length of stay.
Several studies have examined Hb levels as transfusion triggers, but other physiological indications for blood transfusions must be considered: tachycardia, hypotension, O2 extraction > 50%, a mixed venous O2 pressure of < 32 mmHg, an increase of lactate, and electrocardiogram changes warrant monitoring. Additionally, patient assessment should also be based on the severity of shock, hemodynamic response to resuscitation, and the amount of blood loss [44]. Although the TRICC and CRIT studies suggest that the use of more restrictive transfusion strategies improves outcomes, restrictive transfusion strategies have not been universally adopted [45]. Furthermore, a study of 3,026 neurosurgical patients at a single institution found that only a small proportion of pre-operative blood orders were actually used [1]. Thus, understanding the indications for blood transfusions in neurosurgery have the potential to improve patient outcomes and reduce healthcare costs.
8
4. Subarachnoid Hemorrhage
4.1. Intra/peri-operative Transfusion In patients undergoing surgery for intracranial aneurysms, RBCT techniques such as preoperative autologous blood donation, intraoperative transfusion, and acute normovolemic hemodilution are not always immediately available after aneurysm rupture [46]. Studies have been undertaken to determine the current practices of perioperative blood transfusion in aneurysmal surgery. The goals are to establish evidence-based guidelines for ordering blood and to conserve limited resources. Couture et al. reported that cerebrovascular surgical procedures (e.g., aneurysm clipping and carotid endarterectomy) demonstrated a relatively low incidence of intraoperative transfusion, with some studies reporting an incidence as low as 10% [47].
In another study by Le Roux et al., 547 patients who underwent intracranial aneurysm surgery were followed over a 10-year period to evaluate factors possibly associated with allogeneic blood use [46]. Of those studied, 134 patients (22.5%) received an average of 2 U (range: 1-17 U) of intraoperative blood transfusions. Those having experienced intraoperative aneurysm ruptures received an average of 3.6 ± 0.35 U, whereas those who did not, received an average of 1.9 ± 0.12 U. Postoperatively, 244 patients (44.5%) received an average of 2 U of blood with 77 patients having received intraoperative RBCTs.
Risk factors for intraoperative RBCT have been described: baseline Hb < 11.7 g/dL and patient age > 52 years [10, 13]. Lower baseline Hb is associated with larger rises in Hb after RBCT [19].
9
Increased use of intraoperative RBCT has also been significantly associated with lower HCT on admission, larger aneurysm size, ruptured aneurysm, intracerebral hemorrhage, and severe intraventricular hemorrhage. Patients with anterior communicating artery aneurysms were more likely to receive intraoperative RBCT versus other locations. Internal carotid artery aneurysms were least prone to require intraoperative RBCTs. Multiple aneurysm obliteration and intracerebral hematoma evacuation were also associated with increased frequency of RBCTs. The authors of that study recommended that patients undergoing aneurysmal surgery be crossmatched and typed for 2 U of blood. RBCT has also been independently associated with adverse events including, but not limited to, deep-incision/organ/space surgical site infection, wound disruption, pneumonia, pulmonary embolism, acute renal failure, cardiovascular accident, and coma [11, 14]. Of note, the age of packed RBCs has not been associated with adverse events or outcomes [16].
4.2. Medical Management In aneurysmal SAH, approximately 50% of patients suffer subsequent cerebral vasospasm [21]. Cerebral ischemia and infarction are known causes of mortality in these patients. However, not every angiographically-confirmed vasospasm becomes symptomatic. Symptomatic vasospasm is defined as a neurological deficit without other potential causes such as seizure, hyponatremia, or intracerebral hematoma. Triple-H therapy consists of induced hypertension, hypervolemia, and active or passive hemodilution and is often employed in the setting of symptomatic vasospasm as a means to achieve a balance between blood viscosity and preserved O2 carrying capacity [48]. However, the utility of hemodilution in this strategy remains unclear [49, 50].
10
In a study by Ekelund et al. the effects of isovolemic and hypervolemic hemodilution were studied on 8 patients aged 19 to 56 years, with Doppler verified vasospasm after SAH [50]. During isovolemic hemodilution, mean HCT decreased from 0.36 ± 0.04 to 0.28 ± 0.03 and Hb decreased from 119 ± 9 g/dL to 92 ± 8 g/dL. During hypervolemic hemodilution, carried out by autotransfusion and using additional dextran–albumin solution, HCT increased from 0.29 ± 0.02 to 0.31 ± 0.03 and Hb increased from 97 ± 6 g/dL to 103 ± 7 g/dL. Global CBF and global cerebral delivery rate of O2 (CDRO2) were measured before and after hemodilution. CBF increased after isovolemic hemodilution but remained unchanged from iso- to hypervolemic hemodilution. CDRO2 decreased after isovolemia hemodilution and continued to be low after hypervolemia hemodilution. This study highlights the physiologic endpoints of isovolemic hemodilution: (1) improved global CBF and (2) increased the volume of cerebral ischemia.
Contrary to triple-H therapy, hypervolemic hemodilution to an HCT of 0.28 had no beneficial effect on ischemic areas. Alternatively, RBCT can be used to increase the O2-carrying capacity of erythrocytes, O2 delivery, and brain tissue oxygenation [12, 15]. In a study of 611 patients with spontaneous aneurysmal SAH, Naidech et al. assessed outcomes based on the modified Rankin scale, a global disability/handicap scale with scores ranging from 0 (no symptoms) to 6 (death) with a score from 4 to 6 considered a measure of poor outcomes [51]. The authors suggested that a higher Hb concentration was likely to result in better outcomes and this was confirmed in a later prospective, randomized trial [52].
In a different study, Oddo et al. specified that a Hb concentration of 9.0 g/dL and an HCT of 0.27 was optimal and that lower levels were associated with cerebral hypoxia when invasive
11
monitoring was undertaken [53]. However, there are no randomized controlled studies comparing restrictive and liberal transfusion strategies for SAH patients. A prospective study by Springer et al. suggested that anemia or blood transfusion within the acute period of SAH, when vasospasm is a major concern, could exacerbate neurological injury within the first two weeks [54]. Anemia is found to be the second most common medical complication of SAH (35%) and is typically treated with RBCT [51, 55].
In cases of aneurysmal SAH, vasospasm can be due to the depletion of nitric oxide, an endogenous vasodilator [21]. In addition to the local production by the endothelium, nitric oxide is stored and transported within the RBC cytoplasm, where it is then transferred to the vessel surface, passing through hypoxic areas. However, physiologic RBC-function may be impaired after transfusion, which may worsen the vasospasm. SAH patients who receive RBCTs also have a higher risk of death or disability 6 months after hemorrhage onset as compared to those who do not receive blood transfusions [21, 51, 54, 55].
Similarly, a retrospective study by the Mayo Clinic in acute SAH patients reported that the risk of in-hospital death is 3 times greater for those who were transfused than those who were not [56]. Recovery after SAH is often complicated by long-term cognitive dysfunction, perhaps related to reduced O2 delivery to ischemic tissues, transfusion-related inflammatory mediators and/or microcirculatory dysfunction [21, 54]. Furthermore, the timing of RBCT has also been shown to influence outcomes in SAH patients [21]. In a retrospective analysis of 441 patients with SAH, patients receiving intraoperative blood transfusions were more likely to have poorer
12
outcomes, while patients receiving post-operative blood transfusions were at a higher risk of vasospasms [21].
In a retrospective study of 421 patients with SAH, Levine et al. investigated the relationship between a liberal transfusion strategy (transfusion threshold of 10 g/dL) and medical complications [17]. A total of 214 patients received RBCT during their ICU stay and 156 patients developed at least one extra-cranial medical complication. Patients who received RBCTs (46%) were more likely to develop a complication than those who had not (29.8%; p < 0.01). RBCT was found to be significantly associated with the development of any medical complication (OR: 1.6; 95% CI: 1.1-2.5).
In 183 patients with culture-confirmed non-central nervous system infections, blood transfusions were significantly associated with an increased likelihood of infections (OR: 2.4; 95% CI: 1.63.7), pneumonia (OR: 2.3; 95% CI, 1.4-3.8) and septicemia (OR: 2.6; 95% CI: 1.2-5.8). Central nervous system infections such as meningitis, brain abscess, or cranial flap wound occurred in 15 patients (3.6%) and were significantly correlated with the utilization of RBCT (p = 0.03). However, the units of blood transfused were not associated with these infections. A total of 259 patients were mechanically ventilated during their ICU stay; a significant association between ventilator use and blood transfusions was reported (OR: 2.9; 95% CI: 1.7-5.0). The ICU length of stay and total hospital stay were significantly longer and associated with RBCT.
Based on those findings, the authors inferred that extra-cerebral complications and infections seemed to be associated with RBCT in patients with SAH; however, whether transfusions
13
affected outcomes or were just an indication of disease severity is unclear [17]. Broessner et al. evaluated the influence of RBCT on mortality and outcomes in 292 SAH patients and failed to identify any significant associations between RBCT and in-hospital mortality or unfavorable outcomes [18]. Contrastingly, Kramer et al. found that RBCT predicted mortality (among other things) in SAH patients receiving RBCT [20].
5. Traumatic Brain Injury
After a traumatic brain injury (TBI), compensatory vasodilation, which ensures adequate blood supply to the brain, may be impaired. Thus, the natural treatment strategy is to increase blood O2-carrying capacity by raising Hb concentration. Studies have reported higher RBCT requirements in the setting of iron deficiency and worse outcomes in patients with anemia [25, 57-60]. However, variables definitions of anemia, including its treatment and threshold for transfusion, have made it difficult to reach a consensus [26, 28]. Some articles report an association between blood transfusions and poor outcomes in TBI patients, but these papers generally had not adjusted for confounding factors such as disease severity or units of blood transfused [3, 58, 60, 61]. The previously described TRICC trial failed to identify major clinical variances when Hb was maintained at either low (7-9 g/dL) or high levels (10.0-12.0 g/dL), but later studies demonstrated an apparent improvement in cerebral well-being with packed RBCT based on neurophysiologic monitoring [62, 63]. However, Sekhon et al. found that RBCT in severe TBI patients resulted in worsened cerebral autoregulation, as measured by pressure reactivity indices [27].
14
The controversy surrounding transfusion thresholds has been evaluated in a prior survey study conducted among physicians at level I trauma centers and revealed that neurosurgeons favored blood transfusions at higher Hb thresholds than trauma surgeons, or non-surgeon intensivists in patients with TBI, regardless of whether the intracranial pressure was normal or elevated [64]. Higher RBCT thresholds of 10 g/dL have been observed to increase the risk of severe progressive hemorrhagic injury and thromboembolic events after TBI [22, 24]. Moreover, a recent study by Almeida et al. demonstrated a significant association between RBCT and inhospital mortality [23].
In examining outcomes of liberal versus conservative transfusion triggers, George et al. reviewed two nearby level I urban trauma centers with similar numbers of TBI patients, and a similar treatment strategy based on guidelines from the Brain Trauma Foundation (BTF) that included management of intracranial and cerebral perfusion pressures [65]. However, the two hospitals had different transfusion thresholds, with one institution transfusing liberally (Hb < 10 g/dL) and the other transfusing conservatively (Hb < 7 g/dL). Approximately 500 patients with TBI were admitted with 20% having Glasgow Coma Scale scores less than 8. Although RBCT was marginally correlated with mortality in these patients, the statistically significant results led the authors to conclude that RBCT was unnecessary in patients with Hb nadir recorded at 10 g/dL.
Similarly, Al-Dorzi et al. reported a significant correlation between mortality and anemia in ICU patients with isolated TBI, though the relationship was not significant by multivariable analysis [66]. TBI is known to be frequently associated with coagulopathy, due to the release of tissue factor present in the brain parenchyma, and may lead to disseminated intravascular coagulation.
15
Hypoperfusion may also contribute to coagulopathy [67-70]. Blood products like plasma, platelets, and cryoprecipitate may be used for replacement of the depleted coagulation factors. Recent transfusion studies in trauma patients have emphasized the use of an increased ratio of plasma and platelets to RBCs for improved outcomes [71]. Peiniger et al. found that fresh frozen plasma to packed RBC ratios > 1:2 were associated with lower mortality rates in TBI patients compared to ratios < 1:2 [30].
Blood transfusions have been found to increase brain tissue oxygenation (PTio 2) in patients with head injury irrespective of their cerebral perfusion pressures, especially in those who were anemic with a low baseline PTio 2 [72]. PTio2 of 15 mmHg is associated with increased risk of stroke and mortality in neuro-trauma patients. However, the extent of brain injury cannot be quantified based on PTio2. Microdialysis has made it possible to assess brain injury and changes in brain metabolism by monitoring neurotransmitters and other neurochemical markers present in the extracellular space [73]. The benefits of these novel methods of monitoring have yet to be fully elucidated. Another area in need of further investigation is RBCT in neurosurgical pediatric patients. The single pediatric study identified in our review investigated the role of RBCT in the setting of TBI [29]. Most pediatric studies focused on blood loss during craniosynostosis repair.
6. Brain Tumor Resection Surgery
Complex brain tumor resections are often associated with significant amounts of blood loss due to increased vascularity and inherent hemostatic challenges [74]. Moreover, skull base surgery can be complicated by cerebral vasospasm. Similar to vasospasm following SAH, vasospasm in
16
brain tumor surgery is initially managed with triple-H therapy [75]. Wei et al. reported that postoperative fibrinogen deficiency was closely associated with poorer clinical outcomes and increased need for blood transfusions [76]. The literature describing blood transfusions in brain tumor surgeries is particularly scarce.
Risk factors for intraoperative allogenic RBCT during oncologic neurosurgery have been described and include patient age less than 4 years, pre-operative Hb less than 12.2 g/dL, and surgery duration greater than 270 minutes [33]. Recent studies have also reported that tranexamic acid and noninvasive Hb monitoring have the potential to reduce RBCT rates [31, 32]. However, further studies are needed to investigate the role of these adjuncts to RBCT. Lastly, Kudo et al. demonstrated the presence of tumor cells (glioma and meningioma cells) in salvage RBCs reinfused through the cell saver [35]. The probability of migration was lower in meningioma cells compared to glioma cells. Thus, the authors concluded that salvaged RBCs should not be reinfused in patients with glioblastoma.
7. Conclusion
Neurosurgical procedures can be complicated by significant blood losses requiring RBCTs However, evidence-based practices concerning transfusion thresholds and indications among the variety of neurosurgical diseases are limited. The complications of blood transfusions should be considered along with the cerebral outcomes of each disease state. Although blood transfusions are a safe and effective method of increasing Hb concentration, few studies have investigated RBCTs with other blood components such as platelets, fresh frozen plasma or cryoprecipitate in
17
neurosurgical patients. In addition, the outcomes of most large studies are not controlled for the disease pathology of individual patients. Therefore, further research is needed to better understand the optimal utilization of RBCTs to improve neurosurgical outcomes and to standardize patient care. DISCLOSURE OF FUNDING Lawrance K. Chung is supported by an AMA foundation Seed Grant and an AΩA Carolyn L. Kuckein Student Research Fellowship. Carlito Lagman is supported by a Gurtin Skull Base Research Fellowship. Isaac Yang is partially supported by a Visionary Fund Grant, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Jason Dessel Memorial Seed Grant, the UCLA Honberger Endowment Brain Tumor Research Seed Grant and the Stop Cancer (US) Research Career Development Award. The remaining authors have no disclosures or conflicts of interest.
Acknowledgement None
References [1] S. Linsler, Red blood transfusion in neurosurgery, Acta Neurochir (2012). [2] A. Kramer, Anemia and red blood cell transfusion in neurocritical care, Crit Care (2009).
18
[3] A. Carlson, Retrospective evaluation of anemia and transfusion in traumatic brain injury, J Trauma (2006). [4] L. McIntyre, Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury., Neurocrit Care (2006). [5] A. Shander, What is really dangerous: anaemia or transfusion?, Br J Anaesth (2011). [6] A. McGirr, K. Pavenski, B. Sharma, M.D. Cusimano, Blood conservation in neurosurgery: erythropoietin and autologous donation, Can J Neurol Sci 41(5) (2014) 583-9. [7] S. Cataldi, N. Bruder, H. Dufour, P. Lefevre, F. Grisoli, G. Francois, Intraoperative autologous blood transfusion in intracranial surgery, Neurosurgery 40(4) (1997) 765-71; discussion 771-2. [8] J. Bellapart, Physiopathology of anemia and transfusion thresholds in isolated head injury, J Trauma Acute Care Surg (2012). [9] N. Shimada, Ischemic flow threshold for extracellular glutamate increase in cat cortex., J Cereb Blood Flow Metab (1989). [10] J.N. Yee, A. Koht, R.J. McCarthy, J.F. Bebawy, Factors associated with blood transfusion during intracranial aneurysm surgery, J Clin Ane 36 (2017) 164-167. [11] A. Seicean, N. Alan, S. Seicean, D. Neuhauser, W.R. Selman, N.C. Bambadikis, Risks associated with preoperative anemia and perioperative blood transfusion in open surgery for intracranial aneurysms, J Neurosurg 123(1) (2015) 91-100. [12] P. Kurtz, R. Helbok, J. Claassen, J.M. Schmidt, L. Fernandez, R.M. Stuart, E.S. Connolly, K. Lee, S.A. Mayer, N. Badjatia, The Effect of Packed Red Blood Cell Transfusion on Cerebral Oxygenation and Metabolism After Subarachnoid Hemorrhage, Neurocrit Care 24(1) (2016) 118-21.
19
[13] T. Luostarinen, H. Lehto, M.B. Skrifvars, R. Kivisaari, M. Niemela, J. Hernesniemi, T. Randell, T. Niemi, Transfusion Frequency of Red Blood Cells, Fresh Frozen Plasma, and Platelets During Ruptured Cerebral Aneurysm Surgery, World Neurosurg 84(2) (2015) 446-50. [14] M.A. Kumar, T.A. Boland, M. Baiou, M. Moussouttas, J.H. Herman, R.D. Bell, R.H. Rosenwasser, S.E. Kasner, V.E. Dechant, Red blood cell transfusion increases the risk of thrombotic events in patients with subarachnoid hemorrhage, Neurocrit Care 20(1) (2014) 84-90. [15] R. Dhar, M.T. Scalfani, A.R. Zazulia, T.O. Videen, C.P. Derdeyn, M.N. Diringer, Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage, J Neurosurg 116(3) (2012) 648-56. [16] A.M. Naidech, S.M. Liebling, I.M. Duran, M.L. Ault, Packed red blood cell age does not impact adverse events or outcomes after subarachnoid haemorrhage, Transfus Med 21(2) (2011) 130-3. [17] J. Levine, Red blood cell transfusion is associated with infection and extracerebral complications after subarachnoid hemorrhage., Neurosurgery (2010). [18] G. Broessner, P. Lackner, C. Hoefer, R. Beer, R. Helbok, C. Grabmer, H. Ulmer, B. Pfausler, C. Brenneis, E. Schmutzhard, Influence of red blood cell transfusion on mortality and long-term functional outcome in 292 patients with spontaneous subarachnoid hemorrhage, Crit Care Med 37(6) (2009) 1886-1892. [19] A.M. Naidech, M.J. Kahn, W. Soong, D. Green, H.H. Batjer, T.P. Bleck, Packed red blood cell transfusion causes greater hemoglobin rise at a lower starting hemoglobin in patients with subarachnoid hemorrhage, Neurocrit Care 9(2) (2008) 198-203.
20
[20] A.H. Kramer, M.J. Gurka, B. Nathan, A.S. Dumont, N.F. Kassell, T.P. Bleck, Complications associated with anemia and blood transfusion in patients with aneurysmal subarachnoid hemorrhage, Crit Care Med 36(7) (2008) 2070-5. [21] M. Smith, Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage., J Neurosurg (2004). [22] A. Vedantam, J.M. Yamal, M.L. Rubin, C.S. Robertson, S.P. Gopinath, Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds, Journal of Neurosurgery 125(5) (2016) 1229-1234. [23] K.J. Almeida, A.B. Rodrigues, L.E.A.S. Lemos, M.C.S. de Oliveira, B.F. Gandara, R.D. Lopes, D.R.E.S. Modesto, I.K.P. Rego, Hemotransfusion and mechanical ventilation time are associated with intra-hospital mortality in patients with traumatic brain injury admitted to intensive care unit, Arq Neuro-Psiquiat 74(8) (2016) 644-649. [24] C. Lelubre, F.S. Taccone, Transfusion strategies in patients with traumatic brain injury: which is the optimal hemoglobin target?, Minerva Anestesiol 82(1) (2016) 112-116. [25] M.A. Durak, M.S. Aydogan, S. Gurbuz, The effects of iron deficiency on blood transfusion requirements in traumatic brain injury, Biomed Res-India 27(3) (2016) 849-853. [26] J.M. Yamal, J.S. Benoit, P. Doshi, M.L. Rubin, B.C. Tilley, H.J. Hannay, C.S. Robertson, Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury, J Trauma Acute Care 79(5) (2015) 843-849. [27] M.S. Sekhon, D.E. Griesdale, M. Czosnyka, J. Donnelly, X. Liu, M.J. Aries, C. Robba, A. Lavinio, D.K. Menon, P. Smielewski, A.K. Gupta, The Effect of Red Blood Cell Transfusion on
21
Cerebral Autoregulation in Patients with Severe Traumatic Brain Injury, Neurocritical Care 23(2) (2015) 210-216. [28] C.S. Robertson, H.J. Hannay, J.M. Yamal, S. Gopinath, J.C. Goodman, B.C. Tilley, E.S.T.T. Investigators, Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury A Randomized Clinical Trial, Jama-J Am Med Assoc 312(1) (2014) 36-47. [29] S.N. Acker, D.A. Partrick, J.T. Ross, N.A. Nadlonek, M. Bronsert, D.D. Bensard, Blood component transfusion increases the risk of death in children with traumatic brain injury, J Trauma Acute Care 76(4) (2014) 1082-1088. [30] S. Peiniger, U. Nienaber, R. Lefering, M. Braun, A. Wafaisade, S. Wutzler, M. Borgmann, P.C. Spinella, M. Maegele, Tr-Dgu, Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury, Crit Care 15(1) (2011). [31] D. Mebel, R. Akagami, A.M. Flexman, Use of Tranexamic Acid Is Associated with Reduced Blood Product Transfusion in Complex Skull Base Neurosurgical Procedures: A Retrospective Cohort Study, Anesth Analg 122(2) (2016) 503-508. [32] W.N. Awada, M.F. Mohmoued, T.M. Radwan, G.Z. Hussien, H.W. Elkady, Continuous and noninvasive hemoglobin monitoring reduces red blood cell transfusion during neurosurgery: a prospective cohort study, J Clin Monit Comput 29(6) (2015) 733-40. [33] O. Vassal, F.P. Desgranges, S. Tosetti, S. Burgal, F. Dailler, E. Javouhey, C. Mottolese, D. Chassard, Risk factors for intraoperative allogeneic blood transfusion during craniotomy for brain tumor removal in children, Paediatr Anaesth 26(2) (2016) 199-206. [34] H. Liang, Y. Zhao, D. Wang, B. Wang, Evaluation of the quality of processed blood salvaged during craniotomy, Surg Neurol 71(1) (2009) 74-80.
22
[35] H. Kudo, H. Fujita, Y. Hanada, H. Hayami, T. Kondoh, E. Kohmura, Cytological and bacteriological studies of intraoperative autologous blood in neurosurgery, Surg Neurol 62(3) (2004) 195-9; discussion 199-200. [36] L. Borgstrom, The influence of acute normovolemic anemia on cerebral blood flow and oxygen consumption of anesthetized rats, Acta Physiol Scand (1975). [37] A. McLaren, Increased expression of hif-1alpha, nnos, and vegf in the cerebral cortex of anemic rats, Am J Physiol Regul Integr Comp Physiol (2007). [38] L.M. Napolitano, Clinical practice guideline: Red blood cell transfusion in adult trauma and critical care, Crit Care Med (2009). [39] J.L. Carson, Transfusion Triggers: A Systematic Review of the Literature, Transfusion Medicine Reviews (2002). [40] American Society of Anesthesiologists, Practice guidelines for Blood Component Therapy. A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy, Anesthesiology (1996). [41] M. Blajchman, Red blood cell transfusion strategies, Transfus Clin Biol (2001). [42] P.C. Hebert, A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care, The New England Journal of Medicine (1999). [43] H.L. Corwin, A. Gettinger, R.G. Pearl, M.P. Fink, M.M. Levy, E. Abraham, N.R. MacIntyre, M.M. Shabot, M.S. Duh, M.J. Shapiro, The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States, Crit Care Med 32(1) (2004) 39-52. [44] K. Kleinert, Alternative Procedures for Reducing Allogenic Blood Transfusion in Elective Orthopedic Surgery, HSSJ (2009).
23
[45] L.M. Napolitano, Current status of blood component therapy in surgical critical care, Curr Opin Crit Care 10(5) (2004) 311-7. [46] P. Le Roux, Blood Transfusion during Aneurysm Surgery, Neurosurgery (2001). [47] D. Couture, Blood use in cerebrovascular neurosurgery, Stroke (2002). [48] J. McEwen, Transfusion practice in neuroanesthesia., Curr Opin Anethesiol (2009). [49] M. Treggiari, Which H is the most important in triple-H therapy for cerebral vasospasm?, Curr Opin Crit Care (2009). [50] A. Ekelund, Effects of iso- and hypervolemic hemodilution on regional cerebral blood flow and oxygen delivery for patients with vasospasm after aneurysmal subarachnoid hemorrhage., Acta Neurochir (Wien) (2002). [51] A. Niadech, Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage., Crit Care Med (2007). [52] A.M. Naidech, A. Shaibani, R.K. Garg, I.M. Duran, S.M. Liebling, S.L. Bassin, B.R. Bendok, R.A. Bernstein, H.H. Batjer, M.J. Alberts, Prospective, randomized trial of higher goal hemoglobin after subarachnoid hemorrhage, Neurocrit Care 13(3) (2010) 313-20. [53] M. Oddo, Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage., Stroke (2009). [54] M. Springer, Predictors of global cognitive impairment 1 year after subarachnoid Hemorrhage, Neurosurgery (2009). [55] K. Wartenberg, Impact of medical complications on outcome after subarachnoid hemorrhage, Crit Care Med (2006). [56] E. Festic, Blood Transfusion is an Important Predictor of Hospital Mortality Among Patients with Aneurysmal Subarachnoid Hemorrhage, Neurocrit Care (2013).
24
[57] J. Van Beek, Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study., J Neurotrauma (2007). [58] A. Salim, Role of Anemia in Traumatic Brain Injury, J Am Coll Surg (2008). [59] G. Utter, Anemia in the setting of traumatic brain injury: the arguments for and against liberal transfusion., Journal of Neurotrauma (2010). [60] T. Duane, The effect of anemia and blood transfusions on mortality in closed head injury patients, J Surg Res (2008). [61] M. Warner, Transfusions and long-term functional outcomes in traumatic brain injury., J Neurosurg (2010). [62] S. Leal-Noval, Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: a preliminary study., Intensive Care Med (2006). [63] D. Zygun, The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury., Crit Care Med (2009). [64] M. Sena, Transfusion practices for acute traumatic brain injury: a survey of physicians at US trauma centers., Intensive Care Med (2009). [65] M. George, Aggressive Red Blood Cell Transfusion: No Association with Improved Outcomes for Victims of Isolated Traumatic Brain Injury, Neurocrit Care (2008). [66] H.M. Al-Dorzi, W. Al-Humaid, H.M. Tamim, S. Haddad, A. Aljabbary, A. Arifi, Y.M. Arabi, Anemia and Blood Transfusion in Patients with Isolated Traumatic Brain Injury, Crit Care Res Pract 2015 (2015) 672639. [67] V. Saggar, Haemostatic abnormalities in patients with closed head injuries and their role in predicting early mortality, J Neurotrauma (2009).
25
[68] P. Talving, Coagulopathy in severe traumatic brain injury: a prospective study, J Trauma (2009). [69] J. Pasternak, Disseminated intravascular coagulation after craniotomy., J Neurosurg Anesthesiol (2008). [70] M. Cohen, Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway., J Trauma (2007). [71] J. Holcomb, Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients., Ann Surg (2008). [72] A. Johnston, Advanced monitoring in the neurology intensive care unit: microdialysis, Curr Opin Crit Care (2002). [73] S. Peerdeman, Cerebral microdialysis as a new tool for neurometabolic monitoring., Intensive Care Med (2000). [74] I. Nagash, Evaluation of Acute Normovolemic Hemodilution and Autotransfusion in Neurosurgical Patients undergoing Excision of Intracranial Meningioma., J Anaesthesiol Clin Pharmacol (2011). [75] G. Bejjani, Vasospasm after cranial base tumor resection: pathogenesis, diagnosis, therapy, Surg Neurol (1999). [76] N. Wei, Y. Jia, X. Wang, Y. Zhang, G. Yuan, B. Zhao, Y. Wang, K. Zhang, X. Zhang, Y. Pan, J. Zhang, Risk Factors for Postoperative Fibrinogen Deficiency after Surgical Removal of Intracranial Tumors, PLoS One 10(12) (2015) e0144551.
26
Figure Legends Figure 1. Search strategy
27
Table 1. Search term combinations ‘blood’ AND ‘transfusion’ AND ‘neurosurgery’ ‘blood’ AND ‘transfusion’ AND ‘intracranial’ AND ‘aneurysm’ ‘blood’ AND ‘transfusion’ AND ‘subarachnoid’ AND ‘hemorrhage’ AND ‘SAH’ ‘blood’ AND ‘transfusion’ AND ‘transfusion’ AND ‘trauma’ AND ‘brain’ AND ‘injury’ AND ‘TBI’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ AND ‘surgery’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ AND ‘resection’
SAH, subarachnoid hemorrhage; TBI, traumatic brain injury
28
Table 2. Summary of blood transfusion studies Author & year [Ref] Design General neurosurgery McGirr et al., 2014 [6] Retro Cataldi et al., 1997 [7] Retro Intracranial aneurysm Yee et al., 2017 [10] Retro Seicean et al., 2015 [11] Retro Liang et al., 2009 [34] RCT Subarachnoid hemorrhage Kurtz et al., 2016 [12] Prosp Luostarinen et al., 2015 [13] Retro Kumar et al., 2014 [14] Retro Dhar et al., 2012 [15] Prosp Naidech et al., 2011 [16] Prosp Levine et al., 2010 [17] Prosp Naidech et al., 2010 [52] RCT Broessner et al., 2009 [18] Prosp Naidech et al., 2008 [19] Retro/Prosp Kramer et al., 2008 [20] Retro Smith et al., 2004 [21] Retro Traumatic brain injury Vedantam et al., 2016 [22] RCT Almeida et al., 2016 [23] Retro Lelubre et al., 2016 [24] RCT Durak et al., 2016 [25] Prosp Yamal et al., 2015 [26] RCT Sekhon et al., 2015 [27] Prosp Robertson et al., 2014 [28] RCT Acker et al., 2014 [29] Retro Peiniger et al., 2011 [30] Retro Carlson et al., 2006 [3] Retro Brain tumor Vassal et al., 2016 [33] Retro
N
Product
Findings
57 472
auRBC au/alRBC
PAD resulted in anemia and increased RBCT req. auRBC more cost-effective than alRBC
471 668 24
pRBC pRBC sRBC
Risk factors for RBCT: Hb <11.7 g/dL and age >52 yrs RBCT independently associated w/ perioperative complications ZITI-200 and BRAT 2 are comparable
15 488 205 17 119 421 44 292 48/56 245 270
pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC
PbtO2 improved iRBCT associated w/ lower preop. [Hb], higher WFNS class, rupture Increased risk of TE RBCT improved DO2 to tissue at risk for ischemia s/p SAH Age of pRBCs not associated w/ adverse events or outcomes RBCT associated w/ medical complications Higher Hb goal (11.5 vs 10 g/dL) appears safe RBCT not associated w/ mortality or unfavorable outcomes RBCT at lower baseline Hb associated with larger increase in Hb RBCT predicted mortality, disability, infarction, and infections Vasospasm more frequent among pts who received post-op. RBCT
200 87 200 134 200 28 200 178 1,250 169
pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC
Higher RBCT threshold of 10 g/dL increased risk of severe PHI RBCT associated w/in-hospital mortality TE more frequent at higher threshold (10 vs 7 g/dL) Iron deficiency associated with higher RBCT req. No major clinical variance between RBCT thresholds (<7 vs 10 g/dL) Worsened cerebral autoregulation, measured by PRx Threshold 10 g/dl associated with higher incidence of adverse events Pediatric pts who received RBCT had worse outcomes (vs no RBCT) High FFP:pRBC (>1:2) associated with lower mortality (vs low <1:2) RBCT threshold should not differ from critical care pts
110
alRBC
Risks for iRBCT: <4 yrs, <12.2 g/dL (pre-op), >270 min surgery
29
Mebel et al., 2016 [31] Awada et al., 2015 [32] Kudo et al., 2004 [35]
Retro Prosp Prosp
245 106 50
pRBC pRBC sRBC
Tranexamic acid associated with reduced RBCT rates SpHb decreased blood utilization, and facilitated early RBCT sRBC should NOT be reinfused in pts with GBM or TSS
N, sample size; Retro, retrospective; RCT, randomized-controlled trial; Prosp, prospective; auRBC, autologous red blood cell; alRBC, allogenic red blood cell; pRBC, packed red blood cell; sRBC, salvage red blood cell; PAD, preoperative autologous donation; ZITI-200 and BRAT 2, autotransfusion devices; PbtO2, brain tissue oxygen; iRBCT, intraoperative red blood cell transfusion; Hb, hemoglobin; WFNS, World Federation of Neurological Societies; DO2, oxygen delivery; TE, thromboembolic event; SAH, subarachnoid hemorrhage; PHI, progressive hemorrhagic injury; PRx, pressure reactivity index; SpHb, noninvasive Hb monitoring
30
S0303-8467(17)30035-5 http://dx.doi.org/doi:10.1016/j.clineuro.2017.02.006 CLINEU 4621
To appear in:
Clinical Neurology and Neurosurgery
Received date: Revised date: Accepted date:
20-1-2017 7-2-2017 12-2-2017
Please cite this article as: Bagwe Shefali, Chung Lawrance K, Lagman Carlito, Voth Brittany L, Barnette Natalie E, Elhajjmoussa Lekaa, Yang Isaac.Blood Transfusion Indications in Neurosurgical Patients: A Systematic Review.Clinical Neurology and Neurosurgery http://dx.doi.org/10.1016/j.clineuro.2017.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Blood Transfusion Indications in Neurosurgical Patients: A Systematic Review
Shefali Bagwe, MD1, Lawrance K. Chung, BS1, Carlito Lagman, MD1, Brittany L. Voth, MPH1, Natalie E. Barnette1, Lekaa Elhajjmoussa1, Isaac Yang, MD1,2,3,4
1
Departments of Neurosurgery, 2Radiation Oncology, 3Head and Neck Surgery, and 4Jonsson
Comprehensive Cancer Center, University of California, Los Angeles
Corresponding Author Isaac Yang, MD Associate Professor Department of Neurosurgery University of California, Los Angeles 300 Stein Plaza, Suite 562 5th Floor Wasserman Building Los Angeles, California 90095-6901 Phone: (310) 267-2621 Fax: (310) 825-9385 E-mail: [email protected]
1
Highlights
Blood transfusion practices in neurosurgery vary across institutions
Evidence-based outcomes for transfusion thresholds and indications are limited
Most studies favor a conservative blood transfusion threshold of hemoglobin 7 g/dl
Abstract
Neurosurgical procedures can be complicated by significant blood losses that have the potential to decrease tissue perfusion to critical brain tissue. Red blood cell transfusion is used in a variety of capacities both inside, and outside, of the operating room to prevent untoward neurologic damage. However, evidence-based guidelines concerning thresholds and indications for transfusion in neurosurgery remain limited. Consequently, transfusion practices in neurosurgical patients are highly variable and based on institutional experiences. Recently, a paradigm shift has occurred in neurocritical intensive care units, whereby restrictive transfusion is increasingly favored over liberal transfusion but the ideal strategy remains in clinical equipoise. The authors of this study perform a systematic review of the literature with the objective of capturing the changing landscape of blood transfusion indications in neurosurgical patients.
Keywords: Blood transfusion Cerebral neoplasm Intracranial aneurysm Neurosurgery Subarachnoid hemorrhage Traumatic brain injury
2
1. Introduction
Neurosurgical procedures can be complicated by significant blood losses requiring red blood cell transfusions (RBCTs). However, the precise level or extent of anemia that is clinically relevant is unclear, as the effect of low tissue perfusion and oxygenation is likely tissue dependent and can vary between patients [1]. Decreased tissue perfusion becomes particularly important in neurosurgical patients due to the possibility of secondary cerebral injury. Still, controversy exists regarding thresholds for transfusion and what types of transfusions are most meaningful in these patients. Evidence-based guidelines concerning blood transfusion in neurosurgery are also relatively scarce. Thus, transfusion medicine within neurosurgical practices are highly variable and often based on institutional preferences. The authors of this study perform a systematic review of the literature with the objective of capturing the changing landscape of blood transfusion practices in neurosurgical patients, specifically those undergoing surgery for intracranial aneurysms, management of subarachnoid hemorrhage (SAH), treatment of traumatic brain injury (TBI), and resection of brain tumors.
Anemia is defined by the World Health Organization (WHO) as a hemoglobin (Hb) level of less than 12 g/dL in women and less than 13 g/dL in men [2]. Some reports suggest that a Hb level of 7-9 g/dL will not cause secondary neuronal injury, but the exact value at which anemia is harmful in neurosurgical patients is unknown [3, 4]. Currently, RBCT is the quickest and most effective way to raise Hb concentration [5]. Blood transfusions typically fall into 2 general categories, with advantages and disadvantages inherent to each:
3
1. Allogeneic blood transfusions require constant availability of blood donors, as well as facilities for blood grouping, cross matching, storage, and transportation; such requirements, make allogeneic transfusions expensive. In addition, transmission of viral diseases such as HIV and Hepatitis-B are associated risks of allogeneic transfusions. 2. Autologous blood transfusions involve donation of red blood cells (RBCs) by the patient, transfusion of the blood products, and hemodilution. Preoperative autologous RBCT results in anemia and an increased frequency of RBCT [6]. However, autologous RBCT is more cost-effective than allogenic RBCT [7].
Oxidative metabolism is the primary means of energy production in the brain. Thus, maintenance of cerebral perfusion pressure is critical for brain function and health. Major factors involved in ischemic brain injury include increased intracellular cytosolic calcium concentration, metabolic acidosis, and production of free radicals [8]. Increased accumulation of excitatory amino acids such as glutamate and aspartate, during ischemia, also contribute to selective neuronal death. In feline experiments, Shimada et al. demonstrated that decreasing cerebral blood flow (CBF) to 20 ml/100 g/min from a baseline CBF of 55 ± 3.3 ml/100 g/min in a control group, led to increased extracellular glutamate release and accumulation, possibly because of impaired uptake of glutamate due to deficient adenosine triphosphate supplies [9].
Increased extracellular glutamate is associated with large calcium influxes coupled with impaired intracellular calcium sequestration mechanisms. The rises in intracellular calcium activate a series of catabolic enzymes that ultimately lead to neuronal death. Hence, the basic principle in neurocritical care is to avoid secondary injury of the already compromised brain parenchyma by
4
ensuring adequate oxygenation. Secondary injury to the brain has been shown to occur at a hematocrit (HCT) of 20% or less, which is approximately equivalent to a Hb concentration of 67 g/dL [8]. Hb carries the vast majority of total oxygen (O2) content dissolved in the blood and a reduction in Hb concentration (i.e., anemia) can dramatically reduce O 2-carrying capacity. Impaired O2 delivery to the vital, highly-metabolic brain can lead to irrevocable damage. Thus, it is imperative that Hb levels be maintained especially in the setting of acute blood loss.
2. Methods
This systematic review was prepared according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) standard.
2.1. Sources and Search Strategy The Scopus, Web of Science, and PubMed databases were searched by independent authors (LC and CL) through February 7, 2017. Seven strategic search term combinations were used (Table 1). The search strategy is summarized Figure 1. English, full-text randomized controlled trials, prospective cohorts, and retrospective clinical studies were selected. Titles and abstracts were screened, and relevant full-text articles were reviewed. Bibliographies of the full-texts were surveyed for additional pertinent studies.
2.2. Study Selection Studies investigating transfusion of packed red blood cell (pRBC) products [10-32], including autologous [6, 7], allogenic [7, 33], and salvage RBCs [34, 35], in neurosurgical patients
5
undergoing intracranial surgery and medical management, were included. The primary areas of interest were general neurosurgical practice, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and brain tumor surgery. Studies investigating transfusion of RBC products in the context of craniosynostosis or spine surgery were excluded. Transfusions of prothrombin complex concentrate, fresh frozen plasma, platelets, or other non-RBC products were considered irrelevant and studies describing their use were excluded. The main findings of each study are summarized in Table 2.
3. General Practices
In a normal brain, when Hb concentration falls to < 10 g/dL, compensatory vasodilation occurs to ensure adequate blood supply [36]. Compensatory vasodilation maintains adequate perfusion until brain hypoxia develops, typically at an Hb concentration of < 6 g/dL [37]. However, with impaired cerebrovascular reserve, as in cases of SAH, tissue hypoxia and cell injury may develop at higher Hb levels. Hence, a “transfusion trigger” is defined as the threshold level of Hb in the blood at which transfusion is indicated. Transfusion triggers are defined for restrictive as well as liberal strategies of blood transfusion. An extensive review of clinical trials and literature by a joint taskforce of Eastern Association for Surgery of Trauma (EAST) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM) concluded that while restrictive transfusions occur when the Hb concentration has dropped below 7 g/dL [38]. Hb level of 5 g/dL was associated with significant cognitive changes in normal subjects, with increases in reaction time and impaired immediate and delayed memory. However, these changes were not documented with Hb levels of 7 g/dL.
6
Carson et al. conducted a review of 10 randomized controlled trials over a period of 40 years, involving 1,780 patients between the ages of 47 to 80 years [39]. Of these trials, 5 examined surgical patients undergoing general, cardiac, orthopedic or vascular surgeries, 3 examined patients with acute blood loss or trauma, and the remaining trials involved patients in critical care units (neurosurgical patients were excluded). In each trial, patients were randomized to either conservative or liberal transfusion strategies based on guidelines published by the American Society of Anesthesiologists (ASA) and their own institutional experiences [40]. The authors found that transfusion triggers were most often in the range of 8-9 g/dL. However, an overlap between restrictive triggers, in some trials, with liberal triggers in others prevented a meaningful comparison of outcomes. Each trial defined its own unique range of Hb concentrations according to the patient populations. As a result, the benefits and drawbacks of either strategy could not be determined. The conservative or restricted transfusion trigger did decrease the incidence of blood transfusion and the number of RBC units transfused when compared to a more liberal approach.
The Transfusion Requirements in Critical Care (TRICC) randomized trial, by Hebert et al., examined transfusions in intensive care unit (ICU) patients with Hb concentrations of 9.0 g/dL or less within 72 hours of admission in patients, who were euvolemic after initial treatment [41, 42]. The study compared a liberal RBC transfusion strategy (Hb level at 10-12 g/dL) to a restrictive strategy (Hb level at 7-9 g/dL) in 830 critically ill patients. A total of 26 (6%) of patients with a primary diagnosis of neurologic abnormality were included in the restrictive transfusion group and 13 (3%) in the liberal transfusion group. Overall, neurologic complications were higher in the liberal group versus the restrictive group (7.9% vs 6.0%), but the mortality rate in the
7
restricted group was lower. The latter was particularly evident in patients less than 55 years of age and suggests that critically ill patients should only be transfused if their Hb concentration falls below 7 g/dL. However, these patients had varying diseases and/or traumas that were not controlled for.
The CRIT study was a prospective observational cohort comprised of 4,892 patients from 284 ICUs in 213 hospitals. Investigations were limited to medical, surgical, or medical-surgical ICUs (excluded neurologic ICU). Nevertheless, the study provides a general perspective of transfusion practices in the United States [43]. The mean pre-transfusion Hb of all patients was found to be 8.6 ± 1.7 g/dL and 44% of patients received one or more RBC unit (mean: 4.6 ± 4.9 U) in the ICU. Hb nadir of < 9 g/dL was a predictor of mortality and length of stay.
Several studies have examined Hb levels as transfusion triggers, but other physiological indications for blood transfusions must be considered: tachycardia, hypotension, O2 extraction > 50%, a mixed venous O2 pressure of < 32 mmHg, an increase of lactate, and electrocardiogram changes warrant monitoring. Additionally, patient assessment should also be based on the severity of shock, hemodynamic response to resuscitation, and the amount of blood loss [44]. Although the TRICC and CRIT studies suggest that the use of more restrictive transfusion strategies improves outcomes, restrictive transfusion strategies have not been universally adopted [45]. Furthermore, a study of 3,026 neurosurgical patients at a single institution found that only a small proportion of pre-operative blood orders were actually used [1]. Thus, understanding the indications for blood transfusions in neurosurgery have the potential to improve patient outcomes and reduce healthcare costs.
8
4. Subarachnoid Hemorrhage
4.1. Intra/peri-operative Transfusion In patients undergoing surgery for intracranial aneurysms, RBCT techniques such as preoperative autologous blood donation, intraoperative transfusion, and acute normovolemic hemodilution are not always immediately available after aneurysm rupture [46]. Studies have been undertaken to determine the current practices of perioperative blood transfusion in aneurysmal surgery. The goals are to establish evidence-based guidelines for ordering blood and to conserve limited resources. Couture et al. reported that cerebrovascular surgical procedures (e.g., aneurysm clipping and carotid endarterectomy) demonstrated a relatively low incidence of intraoperative transfusion, with some studies reporting an incidence as low as 10% [47].
In another study by Le Roux et al., 547 patients who underwent intracranial aneurysm surgery were followed over a 10-year period to evaluate factors possibly associated with allogeneic blood use [46]. Of those studied, 134 patients (22.5%) received an average of 2 U (range: 1-17 U) of intraoperative blood transfusions. Those having experienced intraoperative aneurysm ruptures received an average of 3.6 ± 0.35 U, whereas those who did not, received an average of 1.9 ± 0.12 U. Postoperatively, 244 patients (44.5%) received an average of 2 U of blood with 77 patients having received intraoperative RBCTs.
Risk factors for intraoperative RBCT have been described: baseline Hb < 11.7 g/dL and patient age > 52 years [10, 13]. Lower baseline Hb is associated with larger rises in Hb after RBCT [19].
9
Increased use of intraoperative RBCT has also been significantly associated with lower HCT on admission, larger aneurysm size, ruptured aneurysm, intracerebral hemorrhage, and severe intraventricular hemorrhage. Patients with anterior communicating artery aneurysms were more likely to receive intraoperative RBCT versus other locations. Internal carotid artery aneurysms were least prone to require intraoperative RBCTs. Multiple aneurysm obliteration and intracerebral hematoma evacuation were also associated with increased frequency of RBCTs. The authors of that study recommended that patients undergoing aneurysmal surgery be crossmatched and typed for 2 U of blood. RBCT has also been independently associated with adverse events including, but not limited to, deep-incision/organ/space surgical site infection, wound disruption, pneumonia, pulmonary embolism, acute renal failure, cardiovascular accident, and coma [11, 14]. Of note, the age of packed RBCs has not been associated with adverse events or outcomes [16].
4.2. Medical Management In aneurysmal SAH, approximately 50% of patients suffer subsequent cerebral vasospasm [21]. Cerebral ischemia and infarction are known causes of mortality in these patients. However, not every angiographically-confirmed vasospasm becomes symptomatic. Symptomatic vasospasm is defined as a neurological deficit without other potential causes such as seizure, hyponatremia, or intracerebral hematoma. Triple-H therapy consists of induced hypertension, hypervolemia, and active or passive hemodilution and is often employed in the setting of symptomatic vasospasm as a means to achieve a balance between blood viscosity and preserved O2 carrying capacity [48]. However, the utility of hemodilution in this strategy remains unclear [49, 50].
10
In a study by Ekelund et al. the effects of isovolemic and hypervolemic hemodilution were studied on 8 patients aged 19 to 56 years, with Doppler verified vasospasm after SAH [50]. During isovolemic hemodilution, mean HCT decreased from 0.36 ± 0.04 to 0.28 ± 0.03 and Hb decreased from 119 ± 9 g/dL to 92 ± 8 g/dL. During hypervolemic hemodilution, carried out by autotransfusion and using additional dextran–albumin solution, HCT increased from 0.29 ± 0.02 to 0.31 ± 0.03 and Hb increased from 97 ± 6 g/dL to 103 ± 7 g/dL. Global CBF and global cerebral delivery rate of O2 (CDRO2) were measured before and after hemodilution. CBF increased after isovolemic hemodilution but remained unchanged from iso- to hypervolemic hemodilution. CDRO2 decreased after isovolemia hemodilution and continued to be low after hypervolemia hemodilution. This study highlights the physiologic endpoints of isovolemic hemodilution: (1) improved global CBF and (2) increased the volume of cerebral ischemia.
Contrary to triple-H therapy, hypervolemic hemodilution to an HCT of 0.28 had no beneficial effect on ischemic areas. Alternatively, RBCT can be used to increase the O2-carrying capacity of erythrocytes, O2 delivery, and brain tissue oxygenation [12, 15]. In a study of 611 patients with spontaneous aneurysmal SAH, Naidech et al. assessed outcomes based on the modified Rankin scale, a global disability/handicap scale with scores ranging from 0 (no symptoms) to 6 (death) with a score from 4 to 6 considered a measure of poor outcomes [51]. The authors suggested that a higher Hb concentration was likely to result in better outcomes and this was confirmed in a later prospective, randomized trial [52].
In a different study, Oddo et al. specified that a Hb concentration of 9.0 g/dL and an HCT of 0.27 was optimal and that lower levels were associated with cerebral hypoxia when invasive
11
monitoring was undertaken [53]. However, there are no randomized controlled studies comparing restrictive and liberal transfusion strategies for SAH patients. A prospective study by Springer et al. suggested that anemia or blood transfusion within the acute period of SAH, when vasospasm is a major concern, could exacerbate neurological injury within the first two weeks [54]. Anemia is found to be the second most common medical complication of SAH (35%) and is typically treated with RBCT [51, 55].
In cases of aneurysmal SAH, vasospasm can be due to the depletion of nitric oxide, an endogenous vasodilator [21]. In addition to the local production by the endothelium, nitric oxide is stored and transported within the RBC cytoplasm, where it is then transferred to the vessel surface, passing through hypoxic areas. However, physiologic RBC-function may be impaired after transfusion, which may worsen the vasospasm. SAH patients who receive RBCTs also have a higher risk of death or disability 6 months after hemorrhage onset as compared to those who do not receive blood transfusions [21, 51, 54, 55].
Similarly, a retrospective study by the Mayo Clinic in acute SAH patients reported that the risk of in-hospital death is 3 times greater for those who were transfused than those who were not [56]. Recovery after SAH is often complicated by long-term cognitive dysfunction, perhaps related to reduced O2 delivery to ischemic tissues, transfusion-related inflammatory mediators and/or microcirculatory dysfunction [21, 54]. Furthermore, the timing of RBCT has also been shown to influence outcomes in SAH patients [21]. In a retrospective analysis of 441 patients with SAH, patients receiving intraoperative blood transfusions were more likely to have poorer
12
outcomes, while patients receiving post-operative blood transfusions were at a higher risk of vasospasms [21].
In a retrospective study of 421 patients with SAH, Levine et al. investigated the relationship between a liberal transfusion strategy (transfusion threshold of 10 g/dL) and medical complications [17]. A total of 214 patients received RBCT during their ICU stay and 156 patients developed at least one extra-cranial medical complication. Patients who received RBCTs (46%) were more likely to develop a complication than those who had not (29.8%; p < 0.01). RBCT was found to be significantly associated with the development of any medical complication (OR: 1.6; 95% CI: 1.1-2.5).
In 183 patients with culture-confirmed non-central nervous system infections, blood transfusions were significantly associated with an increased likelihood of infections (OR: 2.4; 95% CI: 1.63.7), pneumonia (OR: 2.3; 95% CI, 1.4-3.8) and septicemia (OR: 2.6; 95% CI: 1.2-5.8). Central nervous system infections such as meningitis, brain abscess, or cranial flap wound occurred in 15 patients (3.6%) and were significantly correlated with the utilization of RBCT (p = 0.03). However, the units of blood transfused were not associated with these infections. A total of 259 patients were mechanically ventilated during their ICU stay; a significant association between ventilator use and blood transfusions was reported (OR: 2.9; 95% CI: 1.7-5.0). The ICU length of stay and total hospital stay were significantly longer and associated with RBCT.
Based on those findings, the authors inferred that extra-cerebral complications and infections seemed to be associated with RBCT in patients with SAH; however, whether transfusions
13
affected outcomes or were just an indication of disease severity is unclear [17]. Broessner et al. evaluated the influence of RBCT on mortality and outcomes in 292 SAH patients and failed to identify any significant associations between RBCT and in-hospital mortality or unfavorable outcomes [18]. Contrastingly, Kramer et al. found that RBCT predicted mortality (among other things) in SAH patients receiving RBCT [20].
5. Traumatic Brain Injury
After a traumatic brain injury (TBI), compensatory vasodilation, which ensures adequate blood supply to the brain, may be impaired. Thus, the natural treatment strategy is to increase blood O2-carrying capacity by raising Hb concentration. Studies have reported higher RBCT requirements in the setting of iron deficiency and worse outcomes in patients with anemia [25, 57-60]. However, variables definitions of anemia, including its treatment and threshold for transfusion, have made it difficult to reach a consensus [26, 28]. Some articles report an association between blood transfusions and poor outcomes in TBI patients, but these papers generally had not adjusted for confounding factors such as disease severity or units of blood transfused [3, 58, 60, 61]. The previously described TRICC trial failed to identify major clinical variances when Hb was maintained at either low (7-9 g/dL) or high levels (10.0-12.0 g/dL), but later studies demonstrated an apparent improvement in cerebral well-being with packed RBCT based on neurophysiologic monitoring [62, 63]. However, Sekhon et al. found that RBCT in severe TBI patients resulted in worsened cerebral autoregulation, as measured by pressure reactivity indices [27].
14
The controversy surrounding transfusion thresholds has been evaluated in a prior survey study conducted among physicians at level I trauma centers and revealed that neurosurgeons favored blood transfusions at higher Hb thresholds than trauma surgeons, or non-surgeon intensivists in patients with TBI, regardless of whether the intracranial pressure was normal or elevated [64]. Higher RBCT thresholds of 10 g/dL have been observed to increase the risk of severe progressive hemorrhagic injury and thromboembolic events after TBI [22, 24]. Moreover, a recent study by Almeida et al. demonstrated a significant association between RBCT and inhospital mortality [23].
In examining outcomes of liberal versus conservative transfusion triggers, George et al. reviewed two nearby level I urban trauma centers with similar numbers of TBI patients, and a similar treatment strategy based on guidelines from the Brain Trauma Foundation (BTF) that included management of intracranial and cerebral perfusion pressures [65]. However, the two hospitals had different transfusion thresholds, with one institution transfusing liberally (Hb < 10 g/dL) and the other transfusing conservatively (Hb < 7 g/dL). Approximately 500 patients with TBI were admitted with 20% having Glasgow Coma Scale scores less than 8. Although RBCT was marginally correlated with mortality in these patients, the statistically significant results led the authors to conclude that RBCT was unnecessary in patients with Hb nadir recorded at 10 g/dL.
Similarly, Al-Dorzi et al. reported a significant correlation between mortality and anemia in ICU patients with isolated TBI, though the relationship was not significant by multivariable analysis [66]. TBI is known to be frequently associated with coagulopathy, due to the release of tissue factor present in the brain parenchyma, and may lead to disseminated intravascular coagulation.
15
Hypoperfusion may also contribute to coagulopathy [67-70]. Blood products like plasma, platelets, and cryoprecipitate may be used for replacement of the depleted coagulation factors. Recent transfusion studies in trauma patients have emphasized the use of an increased ratio of plasma and platelets to RBCs for improved outcomes [71]. Peiniger et al. found that fresh frozen plasma to packed RBC ratios > 1:2 were associated with lower mortality rates in TBI patients compared to ratios < 1:2 [30].
Blood transfusions have been found to increase brain tissue oxygenation (PTio 2) in patients with head injury irrespective of their cerebral perfusion pressures, especially in those who were anemic with a low baseline PTio 2 [72]. PTio2 of 15 mmHg is associated with increased risk of stroke and mortality in neuro-trauma patients. However, the extent of brain injury cannot be quantified based on PTio2. Microdialysis has made it possible to assess brain injury and changes in brain metabolism by monitoring neurotransmitters and other neurochemical markers present in the extracellular space [73]. The benefits of these novel methods of monitoring have yet to be fully elucidated. Another area in need of further investigation is RBCT in neurosurgical pediatric patients. The single pediatric study identified in our review investigated the role of RBCT in the setting of TBI [29]. Most pediatric studies focused on blood loss during craniosynostosis repair.
6. Brain Tumor Resection Surgery
Complex brain tumor resections are often associated with significant amounts of blood loss due to increased vascularity and inherent hemostatic challenges [74]. Moreover, skull base surgery can be complicated by cerebral vasospasm. Similar to vasospasm following SAH, vasospasm in
16
brain tumor surgery is initially managed with triple-H therapy [75]. Wei et al. reported that postoperative fibrinogen deficiency was closely associated with poorer clinical outcomes and increased need for blood transfusions [76]. The literature describing blood transfusions in brain tumor surgeries is particularly scarce.
Risk factors for intraoperative allogenic RBCT during oncologic neurosurgery have been described and include patient age less than 4 years, pre-operative Hb less than 12.2 g/dL, and surgery duration greater than 270 minutes [33]. Recent studies have also reported that tranexamic acid and noninvasive Hb monitoring have the potential to reduce RBCT rates [31, 32]. However, further studies are needed to investigate the role of these adjuncts to RBCT. Lastly, Kudo et al. demonstrated the presence of tumor cells (glioma and meningioma cells) in salvage RBCs reinfused through the cell saver [35]. The probability of migration was lower in meningioma cells compared to glioma cells. Thus, the authors concluded that salvaged RBCs should not be reinfused in patients with glioblastoma.
7. Conclusion
Neurosurgical procedures can be complicated by significant blood losses requiring RBCTs However, evidence-based practices concerning transfusion thresholds and indications among the variety of neurosurgical diseases are limited. The complications of blood transfusions should be considered along with the cerebral outcomes of each disease state. Although blood transfusions are a safe and effective method of increasing Hb concentration, few studies have investigated RBCTs with other blood components such as platelets, fresh frozen plasma or cryoprecipitate in
17
neurosurgical patients. In addition, the outcomes of most large studies are not controlled for the disease pathology of individual patients. Therefore, further research is needed to better understand the optimal utilization of RBCTs to improve neurosurgical outcomes and to standardize patient care. DISCLOSURE OF FUNDING Lawrance K. Chung is supported by an AMA foundation Seed Grant and an AΩA Carolyn L. Kuckein Student Research Fellowship. Carlito Lagman is supported by a Gurtin Skull Base Research Fellowship. Isaac Yang is partially supported by a Visionary Fund Grant, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Jason Dessel Memorial Seed Grant, the UCLA Honberger Endowment Brain Tumor Research Seed Grant and the Stop Cancer (US) Research Career Development Award. The remaining authors have no disclosures or conflicts of interest.
Acknowledgement None
References [1] S. Linsler, Red blood transfusion in neurosurgery, Acta Neurochir (2012). [2] A. Kramer, Anemia and red blood cell transfusion in neurocritical care, Crit Care (2009).
18
[3] A. Carlson, Retrospective evaluation of anemia and transfusion in traumatic brain injury, J Trauma (2006). [4] L. McIntyre, Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury., Neurocrit Care (2006). [5] A. Shander, What is really dangerous: anaemia or transfusion?, Br J Anaesth (2011). [6] A. McGirr, K. Pavenski, B. Sharma, M.D. Cusimano, Blood conservation in neurosurgery: erythropoietin and autologous donation, Can J Neurol Sci 41(5) (2014) 583-9. [7] S. Cataldi, N. Bruder, H. Dufour, P. Lefevre, F. Grisoli, G. Francois, Intraoperative autologous blood transfusion in intracranial surgery, Neurosurgery 40(4) (1997) 765-71; discussion 771-2. [8] J. Bellapart, Physiopathology of anemia and transfusion thresholds in isolated head injury, J Trauma Acute Care Surg (2012). [9] N. Shimada, Ischemic flow threshold for extracellular glutamate increase in cat cortex., J Cereb Blood Flow Metab (1989). [10] J.N. Yee, A. Koht, R.J. McCarthy, J.F. Bebawy, Factors associated with blood transfusion during intracranial aneurysm surgery, J Clin Ane 36 (2017) 164-167. [11] A. Seicean, N. Alan, S. Seicean, D. Neuhauser, W.R. Selman, N.C. Bambadikis, Risks associated with preoperative anemia and perioperative blood transfusion in open surgery for intracranial aneurysms, J Neurosurg 123(1) (2015) 91-100. [12] P. Kurtz, R. Helbok, J. Claassen, J.M. Schmidt, L. Fernandez, R.M. Stuart, E.S. Connolly, K. Lee, S.A. Mayer, N. Badjatia, The Effect of Packed Red Blood Cell Transfusion on Cerebral Oxygenation and Metabolism After Subarachnoid Hemorrhage, Neurocrit Care 24(1) (2016) 118-21.
19
[13] T. Luostarinen, H. Lehto, M.B. Skrifvars, R. Kivisaari, M. Niemela, J. Hernesniemi, T. Randell, T. Niemi, Transfusion Frequency of Red Blood Cells, Fresh Frozen Plasma, and Platelets During Ruptured Cerebral Aneurysm Surgery, World Neurosurg 84(2) (2015) 446-50. [14] M.A. Kumar, T.A. Boland, M. Baiou, M. Moussouttas, J.H. Herman, R.D. Bell, R.H. Rosenwasser, S.E. Kasner, V.E. Dechant, Red blood cell transfusion increases the risk of thrombotic events in patients with subarachnoid hemorrhage, Neurocrit Care 20(1) (2014) 84-90. [15] R. Dhar, M.T. Scalfani, A.R. Zazulia, T.O. Videen, C.P. Derdeyn, M.N. Diringer, Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage, J Neurosurg 116(3) (2012) 648-56. [16] A.M. Naidech, S.M. Liebling, I.M. Duran, M.L. Ault, Packed red blood cell age does not impact adverse events or outcomes after subarachnoid haemorrhage, Transfus Med 21(2) (2011) 130-3. [17] J. Levine, Red blood cell transfusion is associated with infection and extracerebral complications after subarachnoid hemorrhage., Neurosurgery (2010). [18] G. Broessner, P. Lackner, C. Hoefer, R. Beer, R. Helbok, C. Grabmer, H. Ulmer, B. Pfausler, C. Brenneis, E. Schmutzhard, Influence of red blood cell transfusion on mortality and long-term functional outcome in 292 patients with spontaneous subarachnoid hemorrhage, Crit Care Med 37(6) (2009) 1886-1892. [19] A.M. Naidech, M.J. Kahn, W. Soong, D. Green, H.H. Batjer, T.P. Bleck, Packed red blood cell transfusion causes greater hemoglobin rise at a lower starting hemoglobin in patients with subarachnoid hemorrhage, Neurocrit Care 9(2) (2008) 198-203.
20
[20] A.H. Kramer, M.J. Gurka, B. Nathan, A.S. Dumont, N.F. Kassell, T.P. Bleck, Complications associated with anemia and blood transfusion in patients with aneurysmal subarachnoid hemorrhage, Crit Care Med 36(7) (2008) 2070-5. [21] M. Smith, Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage., J Neurosurg (2004). [22] A. Vedantam, J.M. Yamal, M.L. Rubin, C.S. Robertson, S.P. Gopinath, Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds, Journal of Neurosurgery 125(5) (2016) 1229-1234. [23] K.J. Almeida, A.B. Rodrigues, L.E.A.S. Lemos, M.C.S. de Oliveira, B.F. Gandara, R.D. Lopes, D.R.E.S. Modesto, I.K.P. Rego, Hemotransfusion and mechanical ventilation time are associated with intra-hospital mortality in patients with traumatic brain injury admitted to intensive care unit, Arq Neuro-Psiquiat 74(8) (2016) 644-649. [24] C. Lelubre, F.S. Taccone, Transfusion strategies in patients with traumatic brain injury: which is the optimal hemoglobin target?, Minerva Anestesiol 82(1) (2016) 112-116. [25] M.A. Durak, M.S. Aydogan, S. Gurbuz, The effects of iron deficiency on blood transfusion requirements in traumatic brain injury, Biomed Res-India 27(3) (2016) 849-853. [26] J.M. Yamal, J.S. Benoit, P. Doshi, M.L. Rubin, B.C. Tilley, H.J. Hannay, C.S. Robertson, Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury, J Trauma Acute Care 79(5) (2015) 843-849. [27] M.S. Sekhon, D.E. Griesdale, M. Czosnyka, J. Donnelly, X. Liu, M.J. Aries, C. Robba, A. Lavinio, D.K. Menon, P. Smielewski, A.K. Gupta, The Effect of Red Blood Cell Transfusion on
21
Cerebral Autoregulation in Patients with Severe Traumatic Brain Injury, Neurocritical Care 23(2) (2015) 210-216. [28] C.S. Robertson, H.J. Hannay, J.M. Yamal, S. Gopinath, J.C. Goodman, B.C. Tilley, E.S.T.T. Investigators, Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury A Randomized Clinical Trial, Jama-J Am Med Assoc 312(1) (2014) 36-47. [29] S.N. Acker, D.A. Partrick, J.T. Ross, N.A. Nadlonek, M. Bronsert, D.D. Bensard, Blood component transfusion increases the risk of death in children with traumatic brain injury, J Trauma Acute Care 76(4) (2014) 1082-1088. [30] S. Peiniger, U. Nienaber, R. Lefering, M. Braun, A. Wafaisade, S. Wutzler, M. Borgmann, P.C. Spinella, M. Maegele, Tr-Dgu, Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury, Crit Care 15(1) (2011). [31] D. Mebel, R. Akagami, A.M. Flexman, Use of Tranexamic Acid Is Associated with Reduced Blood Product Transfusion in Complex Skull Base Neurosurgical Procedures: A Retrospective Cohort Study, Anesth Analg 122(2) (2016) 503-508. [32] W.N. Awada, M.F. Mohmoued, T.M. Radwan, G.Z. Hussien, H.W. Elkady, Continuous and noninvasive hemoglobin monitoring reduces red blood cell transfusion during neurosurgery: a prospective cohort study, J Clin Monit Comput 29(6) (2015) 733-40. [33] O. Vassal, F.P. Desgranges, S. Tosetti, S. Burgal, F. Dailler, E. Javouhey, C. Mottolese, D. Chassard, Risk factors for intraoperative allogeneic blood transfusion during craniotomy for brain tumor removal in children, Paediatr Anaesth 26(2) (2016) 199-206. [34] H. Liang, Y. Zhao, D. Wang, B. Wang, Evaluation of the quality of processed blood salvaged during craniotomy, Surg Neurol 71(1) (2009) 74-80.
22
[35] H. Kudo, H. Fujita, Y. Hanada, H. Hayami, T. Kondoh, E. Kohmura, Cytological and bacteriological studies of intraoperative autologous blood in neurosurgery, Surg Neurol 62(3) (2004) 195-9; discussion 199-200. [36] L. Borgstrom, The influence of acute normovolemic anemia on cerebral blood flow and oxygen consumption of anesthetized rats, Acta Physiol Scand (1975). [37] A. McLaren, Increased expression of hif-1alpha, nnos, and vegf in the cerebral cortex of anemic rats, Am J Physiol Regul Integr Comp Physiol (2007). [38] L.M. Napolitano, Clinical practice guideline: Red blood cell transfusion in adult trauma and critical care, Crit Care Med (2009). [39] J.L. Carson, Transfusion Triggers: A Systematic Review of the Literature, Transfusion Medicine Reviews (2002). [40] American Society of Anesthesiologists, Practice guidelines for Blood Component Therapy. A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy, Anesthesiology (1996). [41] M. Blajchman, Red blood cell transfusion strategies, Transfus Clin Biol (2001). [42] P.C. Hebert, A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care, The New England Journal of Medicine (1999). [43] H.L. Corwin, A. Gettinger, R.G. Pearl, M.P. Fink, M.M. Levy, E. Abraham, N.R. MacIntyre, M.M. Shabot, M.S. Duh, M.J. Shapiro, The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States, Crit Care Med 32(1) (2004) 39-52. [44] K. Kleinert, Alternative Procedures for Reducing Allogenic Blood Transfusion in Elective Orthopedic Surgery, HSSJ (2009).
23
[45] L.M. Napolitano, Current status of blood component therapy in surgical critical care, Curr Opin Crit Care 10(5) (2004) 311-7. [46] P. Le Roux, Blood Transfusion during Aneurysm Surgery, Neurosurgery (2001). [47] D. Couture, Blood use in cerebrovascular neurosurgery, Stroke (2002). [48] J. McEwen, Transfusion practice in neuroanesthesia., Curr Opin Anethesiol (2009). [49] M. Treggiari, Which H is the most important in triple-H therapy for cerebral vasospasm?, Curr Opin Crit Care (2009). [50] A. Ekelund, Effects of iso- and hypervolemic hemodilution on regional cerebral blood flow and oxygen delivery for patients with vasospasm after aneurysmal subarachnoid hemorrhage., Acta Neurochir (Wien) (2002). [51] A. Niadech, Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage., Crit Care Med (2007). [52] A.M. Naidech, A. Shaibani, R.K. Garg, I.M. Duran, S.M. Liebling, S.L. Bassin, B.R. Bendok, R.A. Bernstein, H.H. Batjer, M.J. Alberts, Prospective, randomized trial of higher goal hemoglobin after subarachnoid hemorrhage, Neurocrit Care 13(3) (2010) 313-20. [53] M. Oddo, Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage., Stroke (2009). [54] M. Springer, Predictors of global cognitive impairment 1 year after subarachnoid Hemorrhage, Neurosurgery (2009). [55] K. Wartenberg, Impact of medical complications on outcome after subarachnoid hemorrhage, Crit Care Med (2006). [56] E. Festic, Blood Transfusion is an Important Predictor of Hospital Mortality Among Patients with Aneurysmal Subarachnoid Hemorrhage, Neurocrit Care (2013).
24
[57] J. Van Beek, Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study., J Neurotrauma (2007). [58] A. Salim, Role of Anemia in Traumatic Brain Injury, J Am Coll Surg (2008). [59] G. Utter, Anemia in the setting of traumatic brain injury: the arguments for and against liberal transfusion., Journal of Neurotrauma (2010). [60] T. Duane, The effect of anemia and blood transfusions on mortality in closed head injury patients, J Surg Res (2008). [61] M. Warner, Transfusions and long-term functional outcomes in traumatic brain injury., J Neurosurg (2010). [62] S. Leal-Noval, Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: a preliminary study., Intensive Care Med (2006). [63] D. Zygun, The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury., Crit Care Med (2009). [64] M. Sena, Transfusion practices for acute traumatic brain injury: a survey of physicians at US trauma centers., Intensive Care Med (2009). [65] M. George, Aggressive Red Blood Cell Transfusion: No Association with Improved Outcomes for Victims of Isolated Traumatic Brain Injury, Neurocrit Care (2008). [66] H.M. Al-Dorzi, W. Al-Humaid, H.M. Tamim, S. Haddad, A. Aljabbary, A. Arifi, Y.M. Arabi, Anemia and Blood Transfusion in Patients with Isolated Traumatic Brain Injury, Crit Care Res Pract 2015 (2015) 672639. [67] V. Saggar, Haemostatic abnormalities in patients with closed head injuries and their role in predicting early mortality, J Neurotrauma (2009).
25
[68] P. Talving, Coagulopathy in severe traumatic brain injury: a prospective study, J Trauma (2009). [69] J. Pasternak, Disseminated intravascular coagulation after craniotomy., J Neurosurg Anesthesiol (2008). [70] M. Cohen, Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway., J Trauma (2007). [71] J. Holcomb, Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients., Ann Surg (2008). [72] A. Johnston, Advanced monitoring in the neurology intensive care unit: microdialysis, Curr Opin Crit Care (2002). [73] S. Peerdeman, Cerebral microdialysis as a new tool for neurometabolic monitoring., Intensive Care Med (2000). [74] I. Nagash, Evaluation of Acute Normovolemic Hemodilution and Autotransfusion in Neurosurgical Patients undergoing Excision of Intracranial Meningioma., J Anaesthesiol Clin Pharmacol (2011). [75] G. Bejjani, Vasospasm after cranial base tumor resection: pathogenesis, diagnosis, therapy, Surg Neurol (1999). [76] N. Wei, Y. Jia, X. Wang, Y. Zhang, G. Yuan, B. Zhao, Y. Wang, K. Zhang, X. Zhang, Y. Pan, J. Zhang, Risk Factors for Postoperative Fibrinogen Deficiency after Surgical Removal of Intracranial Tumors, PLoS One 10(12) (2015) e0144551.
26
Figure Legends Figure 1. Search strategy
27
Table 1. Search term combinations ‘blood’ AND ‘transfusion’ AND ‘neurosurgery’ ‘blood’ AND ‘transfusion’ AND ‘intracranial’ AND ‘aneurysm’ ‘blood’ AND ‘transfusion’ AND ‘subarachnoid’ AND ‘hemorrhage’ AND ‘SAH’ ‘blood’ AND ‘transfusion’ AND ‘transfusion’ AND ‘trauma’ AND ‘brain’ AND ‘injury’ AND ‘TBI’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ AND ‘surgery’ ‘blood’ AND ‘transfusion’ AND ‘brain’ AND ‘tumor’ AND ‘resection’
SAH, subarachnoid hemorrhage; TBI, traumatic brain injury
28
Table 2. Summary of blood transfusion studies Author & year [Ref] Design General neurosurgery McGirr et al., 2014 [6] Retro Cataldi et al., 1997 [7] Retro Intracranial aneurysm Yee et al., 2017 [10] Retro Seicean et al., 2015 [11] Retro Liang et al., 2009 [34] RCT Subarachnoid hemorrhage Kurtz et al., 2016 [12] Prosp Luostarinen et al., 2015 [13] Retro Kumar et al., 2014 [14] Retro Dhar et al., 2012 [15] Prosp Naidech et al., 2011 [16] Prosp Levine et al., 2010 [17] Prosp Naidech et al., 2010 [52] RCT Broessner et al., 2009 [18] Prosp Naidech et al., 2008 [19] Retro/Prosp Kramer et al., 2008 [20] Retro Smith et al., 2004 [21] Retro Traumatic brain injury Vedantam et al., 2016 [22] RCT Almeida et al., 2016 [23] Retro Lelubre et al., 2016 [24] RCT Durak et al., 2016 [25] Prosp Yamal et al., 2015 [26] RCT Sekhon et al., 2015 [27] Prosp Robertson et al., 2014 [28] RCT Acker et al., 2014 [29] Retro Peiniger et al., 2011 [30] Retro Carlson et al., 2006 [3] Retro Brain tumor Vassal et al., 2016 [33] Retro
N
Product
Findings
57 472
auRBC au/alRBC
PAD resulted in anemia and increased RBCT req. auRBC more cost-effective than alRBC
471 668 24
pRBC pRBC sRBC
Risk factors for RBCT: Hb <11.7 g/dL and age >52 yrs RBCT independently associated w/ perioperative complications ZITI-200 and BRAT 2 are comparable
15 488 205 17 119 421 44 292 48/56 245 270
pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC
PbtO2 improved iRBCT associated w/ lower preop. [Hb], higher WFNS class, rupture Increased risk of TE RBCT improved DO2 to tissue at risk for ischemia s/p SAH Age of pRBCs not associated w/ adverse events or outcomes RBCT associated w/ medical complications Higher Hb goal (11.5 vs 10 g/dL) appears safe RBCT not associated w/ mortality or unfavorable outcomes RBCT at lower baseline Hb associated with larger increase in Hb RBCT predicted mortality, disability, infarction, and infections Vasospasm more frequent among pts who received post-op. RBCT
200 87 200 134 200 28 200 178 1,250 169
pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC pRBC
Higher RBCT threshold of 10 g/dL increased risk of severe PHI RBCT associated w/in-hospital mortality TE more frequent at higher threshold (10 vs 7 g/dL) Iron deficiency associated with higher RBCT req. No major clinical variance between RBCT thresholds (<7 vs 10 g/dL) Worsened cerebral autoregulation, measured by PRx Threshold 10 g/dl associated with higher incidence of adverse events Pediatric pts who received RBCT had worse outcomes (vs no RBCT) High FFP:pRBC (>1:2) associated with lower mortality (vs low <1:2) RBCT threshold should not differ from critical care pts
110
alRBC
Risks for iRBCT: <4 yrs, <12.2 g/dL (pre-op), >270 min surgery
29
Mebel et al., 2016 [31] Awada et al., 2015 [32] Kudo et al., 2004 [35]
Retro Prosp Prosp
245 106 50
pRBC pRBC sRBC
Tranexamic acid associated with reduced RBCT rates SpHb decreased blood utilization, and facilitated early RBCT sRBC should NOT be reinfused in pts with GBM or TSS
N, sample size; Retro, retrospective; RCT, randomized-controlled trial; Prosp, prospective; auRBC, autologous red blood cell; alRBC, allogenic red blood cell; pRBC, packed red blood cell; sRBC, salvage red blood cell; PAD, preoperative autologous donation; ZITI-200 and BRAT 2, autotransfusion devices; PbtO2, brain tissue oxygen; iRBCT, intraoperative red blood cell transfusion; Hb, hemoglobin; WFNS, World Federation of Neurological Societies; DO2, oxygen delivery; TE, thromboembolic event; SAH, subarachnoid hemorrhage; PHI, progressive hemorrhagic injury; PRx, pressure reactivity index; SpHb, noninvasive Hb monitoring
30