Neurocrit Care DOI 10.1007/s12028-015-0220-z
ORIGINAL ARTICLE
Effects of Red Blood Cell Transfusion on Long-Term Disability of Patients with Traumatic Brain Injury ´ ngela Mun˜oz-Serrano2 • Victoria Arellano-Orden1 • Santiago R. Leal-Noval1 • A 3 • Aurelio Cayuela Manuel Mun˜oz-Go´mez4 • Antonio Recio5 • Antonio Alca´ntara1 Rosario Amaya-Villar1 • Manuel Casado-Me´ndez1 • Francisco Murillo-Cabezas1
•
Ó Springer Science+Business Media New York 2015
Abstract Background This 3-year prospective study examined the association between red blood cell transfusion (RBCT) and 1-year neurocognitive and disability levels in 309 patients with traumatic brain injury (TBI) admitted to the neurological intensive care unit (NICU). Methods Using a telephone interview-based survey, functional outcomes were assessed by the Glasgow Outcome Scale (GOS), Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS) and dichotomized as favorable and unfavorable (dependent variable). The adjusted influence of RBCT on unfavorable results was assessed by
Registered on: https://www.fundacionmapfre.org/fundacion/es_es/ images/fallo-ayudas-2008_tcm164-27583.pdf.
Electronic supplementary material The online version of this article (doi:10.1007/s12028-015-0220-z) contains supplementary material, which is available to authorized users. & Santiago R. Leal-Noval [email protected] 1
Critical Care Division, Instituto de Biomedicina IBIS, Hospital Universitario ‘‘Virgen del Rocı´o’’, Avda/Manuel Siurot, s/n, 41013 Seville, Spain
2
Neuropsychology Division, Instituto de Biomedicina IBIS, Hospital Universitario ‘‘Virgen del Rocı´o’’, Seville, Spain
3
Statistics and Design Division, Hospital de Valme, Seville, Spain
4
Perioperative Transfusion Medicine, University of Ma´laga, Ma´laga, Spain
5
Transfusion Service, Hospital Universitario ‘‘Virgen del Rocı´o’’, Seville, Spain
conventional logistic regression, controlling for illness severity and propensity score (introduced as a continuous variable and by propensity score-matched patients). Results Overall, 164 (53 %) patients received C1 unit of RBCT during their NICU stay. One year postinjury, transfused patients exhibited significantly higher unfavorable GOS (46.0 vs. 22.0 %), RLCFS (37.4 vs. 15.4 %), and DRS (39.6 vs. 18.7 %) scores than nontransfused patients. Although transfused patients were more severely ill upon admission, their adjusted odds ratios (95 % confidence intervals) for unfavorable GOS, RLCFS, and DRS scores were 2.5 (1.2–5.1), 3.0 (1.4–6.3), and 2.3 (1.1–4.8), respectively. These odds ratios remained largely unmodified when the calculated propensity score was incorporated as an independent continuous variable into the multivariate analysis. Furthermore, in 76 pairs of propensity scorematched patients, the rate of an unfavorable RLCFS score at the 1-year (but not 6-month) follow-up was significantly higher in transfused than nontransfused patients [3.0 (1.1–8.2)]. Conclusion Our results strongly suggest an independent association between RBCT and unfavorable long-term functional outcomes of patients with TBI. Keywords Anemia Disability Hemoglobin Neurological Transfusion Traumatic brain injury Abbreviations CTS Computed tomographic scan GCS Glasgow Coma Scale GOS Glasgow Outcome Scale Hb Hemoglobin IMPACT International Mission for Prognosis and Analysis of Clinical Trial
123
Neurocrit Care
IQR RLCFS DRS TBI NICU RBCT
Interquartile range Rancho Level of Cognitive Functioning Scale Disability Rating Scale Traumatic brain injury Neurological intensive care unit Red blood cell transfusion
Introduction Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, with large direct and indirect costs to society. In the United States, more than 1.7 million persons sustain a TBI annually [1], and the annual burden of TBI has been estimated at more than $76 billion [2]. Mortality rates of approximately 40 % were reported in a review of unselected observational studies [3], but permanent disability is also prevalent, affecting 80,000–90,000 patients annually in the United States alone [4]. The prevalence of anemia in patients with TBI ranges from 30 to 40 % [5, 6]. Because reduced hemoglobin (Hb) concentrations can decrease cerebral oxygen delivery and contribute to brain hypoxia, nearly 50 % of anemic patients with TBI receive at least one red blood cell transfusion (RBCT) during their stay at the neurological intensive care unit (NICU) [4–8]. Theoretically, RBCT should increase cerebral oxygen delivery in patients with TBI; however, observational studies have reported that RBCT is associated with increased mortality rates and poorer 6-month functional results [8]. When both anemia and RBCT were introduced into a multivariate analysis, the association with poor outcomes was present only for RBCT [9]. Moreover, in a recent randomized controlled trial in patients with TBI, a liberal RBCT threshold (Hb < 100 g/L) was associated with a higher incidence of adverse events and did not improve 6-month neurological outcomes when compared with a restrictive RBCT threshold (Hb < 70 g/L) [10]. However, systematic reviews have neither refuted nor confirmed a difference in mortality rates between RBCT strategies in patients with TBI [5]. Indeed, the effects of RBCT on mortality following TBI are likely to be small or variable [11], and the assessment of other relevant outcomes, such as long-term neurologic functional status, could be more reliable. Simple estimation of mortality could seriously underestimate the impact of RBCT on TBI outcomes, and any useful risk prediction model should provide estimates of poor neurological outcome other than mortality [5].
123
The functional outcomes of TBI are typically assessed using the five-level Glasgow Outcome Scale (GOS) or the eight-level extended GOS [6, 12, 13]. Other scores assessing long-term neurological disabilities have rarely been investigated despite the potential impact of RBCT on these outcome measures. We hypothesized that RBCT may influence long-term functional results in patients with TBI. Therefore, we investigated the influence of RBCT on the functional status of patients with TBI 1 year after discharge from the NICU as assessed by the GOS, Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS).
Methods Design This was a prospective study of patients with TBI admitted to the NICU. The study was funded in part by an unrestricted grant from the MAPFRE foundation (Mutualidad de la Agrupacio´n de Propietarios de Fincas Ru´sticas de Espan˜a). The study protocol was presented and explained to all NICU physicians in a dedicated session prior to logging data collection. Patients, Data Inclusion, and Setting Data from all adult patients with TBI admitted to the NICU at the public teaching Hospital ‘‘Virgen del Rocı´o’’ (Seville, Spain), a large urban level-I trauma center, from January 2010 to December 2012 were prospectively entered into a database (MAPFRE database of TBI). Patients were excluded if they died at or were discharged from the NICU within 24 h of admission because these patients were likely to die or survive irrespective of their Hb concentration and performance of RBCT. Patients with a history of neurological or psychiatric illness or any preinjury cognitive deficit were also excluded. TBI Management Patients with TBI were managed with a protocol that conformed to the Brain Trauma Foundation Guidelines and utilized institutional treatment algorithms, as described elsewhere [14]. Our NICU has a 24-h fully dedicated team of specialists in critical care (note that critical care is a specialty in Spain), ensuring homogenous care of patients thorough their entire NICU stay. Institutional guidelines for blood component transfusions, which are based on national guidelines [15], are available at the hospital intranet and may be consulted at
Neurocrit Care
any time. Neurocritical patients usually receive RBCT with an Hb transfusion trigger of 8 g/dL to maintain a target Hb concentration close to 10 g/dL. However, for each particular patient, the decisions regarding transfusion indications and target Hb concentrations were made by the attending physician and were independent of the purposes of this study. All transfused patients received leukoreduced packed RBCs stored in additive solution (saline, adenine, glucose, and mannitol) and anticoagulant preservative (citrate–phosphate–dextrose). Variables Outcome Variables The primary outcome was the long-term neurocognitive functional status as assessed with the GOS, RLCFS, and DRS scores, 6 and 12 months after discharge from the NICU. Telephone-based follow-up interviews were performed by a trained local staff member using structured questionnaires and were scored by the investigator according to a standardized approach. For the purposes of this study, outcome variables were later classified as unfavorable or favorable. A complete description of these tests can be found elsewhere [16]. Briefly, The GOS is a global, admittedly crude instrument that only roughly discriminates different levels of disability. Its disadvantage is that the assessment of physical disability disproportionately exceeds that of cognitive and emotional deficits. However, it remains the most widely used and accepted instrument. For the proposal of this study, the categories of severe disability, vegetative status, and death were considered as unfavorable GOS. Death and a vegetative state were collapsed for the analysis in this study because they were considered to be equally undesirable. The RLCFS was developed to assess recovery after severe TBI. The RLCFS consists of a single eightlevel ordinal item category scale, in which each level corresponds to increasingly complex behaviors ranging from no response to purposeful and appropriate. Higher scores indicate improved functioning. The RLCFS correlates with the DRS. Unfavorable RLCFS scores includes levels V (confused, inappropriate, nonagitated response), IV (confused, agitated response), III (localized response), II (generalized response), I (nonresponse), and death. The DRS is the most versatile outcome measure and was introduced to overcome the poor precision of the GOS. It reliably assesses impairment, disability, and handicap. The scale is intended to accurately measure
changes in general functional over the course of recovery. An unfavorable DRS score indicates severe and extremely severe disabilities, vegetative and extremely vegetative states, and death. Independent Variables The Glasgow Coma Scale (GCS) score obtained after resuscitation at the emergency department or NICU was used for the baseline neurological assessment. Findings in the initial computed tomographic scan were classified using the Marshall scoring system. The Acute Physiology and Chronic Health Evaluation (APACHE) score, Injury Severity Score (ISS), Head Abbreviated Injury Scale (Head AIS) score, and International Mission for Prognosis and Analysis of Clinical Trial (IMPACT) probabilities of a poor GOS score and mortality were also calculated. Each of these scores is related to the severity of injury, and its adjusted influence on the unfavorable long-term neurocognitive outcome was always assessed. In addition to these severity scores, multiple clinical and analytical variables were prospectively collected upon admission for all enrolled patients (Table 1). The laboratory values measured in terminal patients (those who withdrew from active treatment) were omitted from the analyses. Statistical Analysis The sample size was calculated based on previously published IMPACT data [12], which documented an unfavorable outcome (dichotomized GOS score) occurring in nearly 48 % of patients with TBI exhibiting a GCS score of
ORIGINAL ARTICLE
Effects of Red Blood Cell Transfusion on Long-Term Disability of Patients with Traumatic Brain Injury ´ ngela Mun˜oz-Serrano2 • Victoria Arellano-Orden1 • Santiago R. Leal-Noval1 • A 3 • Aurelio Cayuela Manuel Mun˜oz-Go´mez4 • Antonio Recio5 • Antonio Alca´ntara1 Rosario Amaya-Villar1 • Manuel Casado-Me´ndez1 • Francisco Murillo-Cabezas1
•
Ó Springer Science+Business Media New York 2015
Abstract Background This 3-year prospective study examined the association between red blood cell transfusion (RBCT) and 1-year neurocognitive and disability levels in 309 patients with traumatic brain injury (TBI) admitted to the neurological intensive care unit (NICU). Methods Using a telephone interview-based survey, functional outcomes were assessed by the Glasgow Outcome Scale (GOS), Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS) and dichotomized as favorable and unfavorable (dependent variable). The adjusted influence of RBCT on unfavorable results was assessed by
Registered on: https://www.fundacionmapfre.org/fundacion/es_es/ images/fallo-ayudas-2008_tcm164-27583.pdf.
Electronic supplementary material The online version of this article (doi:10.1007/s12028-015-0220-z) contains supplementary material, which is available to authorized users. & Santiago R. Leal-Noval [email protected] 1
Critical Care Division, Instituto de Biomedicina IBIS, Hospital Universitario ‘‘Virgen del Rocı´o’’, Avda/Manuel Siurot, s/n, 41013 Seville, Spain
2
Neuropsychology Division, Instituto de Biomedicina IBIS, Hospital Universitario ‘‘Virgen del Rocı´o’’, Seville, Spain
3
Statistics and Design Division, Hospital de Valme, Seville, Spain
4
Perioperative Transfusion Medicine, University of Ma´laga, Ma´laga, Spain
5
Transfusion Service, Hospital Universitario ‘‘Virgen del Rocı´o’’, Seville, Spain
conventional logistic regression, controlling for illness severity and propensity score (introduced as a continuous variable and by propensity score-matched patients). Results Overall, 164 (53 %) patients received C1 unit of RBCT during their NICU stay. One year postinjury, transfused patients exhibited significantly higher unfavorable GOS (46.0 vs. 22.0 %), RLCFS (37.4 vs. 15.4 %), and DRS (39.6 vs. 18.7 %) scores than nontransfused patients. Although transfused patients were more severely ill upon admission, their adjusted odds ratios (95 % confidence intervals) for unfavorable GOS, RLCFS, and DRS scores were 2.5 (1.2–5.1), 3.0 (1.4–6.3), and 2.3 (1.1–4.8), respectively. These odds ratios remained largely unmodified when the calculated propensity score was incorporated as an independent continuous variable into the multivariate analysis. Furthermore, in 76 pairs of propensity scorematched patients, the rate of an unfavorable RLCFS score at the 1-year (but not 6-month) follow-up was significantly higher in transfused than nontransfused patients [3.0 (1.1–8.2)]. Conclusion Our results strongly suggest an independent association between RBCT and unfavorable long-term functional outcomes of patients with TBI. Keywords Anemia Disability Hemoglobin Neurological Transfusion Traumatic brain injury Abbreviations CTS Computed tomographic scan GCS Glasgow Coma Scale GOS Glasgow Outcome Scale Hb Hemoglobin IMPACT International Mission for Prognosis and Analysis of Clinical Trial
123
Neurocrit Care
IQR RLCFS DRS TBI NICU RBCT
Interquartile range Rancho Level of Cognitive Functioning Scale Disability Rating Scale Traumatic brain injury Neurological intensive care unit Red blood cell transfusion
Introduction Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, with large direct and indirect costs to society. In the United States, more than 1.7 million persons sustain a TBI annually [1], and the annual burden of TBI has been estimated at more than $76 billion [2]. Mortality rates of approximately 40 % were reported in a review of unselected observational studies [3], but permanent disability is also prevalent, affecting 80,000–90,000 patients annually in the United States alone [4]. The prevalence of anemia in patients with TBI ranges from 30 to 40 % [5, 6]. Because reduced hemoglobin (Hb) concentrations can decrease cerebral oxygen delivery and contribute to brain hypoxia, nearly 50 % of anemic patients with TBI receive at least one red blood cell transfusion (RBCT) during their stay at the neurological intensive care unit (NICU) [4–8]. Theoretically, RBCT should increase cerebral oxygen delivery in patients with TBI; however, observational studies have reported that RBCT is associated with increased mortality rates and poorer 6-month functional results [8]. When both anemia and RBCT were introduced into a multivariate analysis, the association with poor outcomes was present only for RBCT [9]. Moreover, in a recent randomized controlled trial in patients with TBI, a liberal RBCT threshold (Hb < 100 g/L) was associated with a higher incidence of adverse events and did not improve 6-month neurological outcomes when compared with a restrictive RBCT threshold (Hb < 70 g/L) [10]. However, systematic reviews have neither refuted nor confirmed a difference in mortality rates between RBCT strategies in patients with TBI [5]. Indeed, the effects of RBCT on mortality following TBI are likely to be small or variable [11], and the assessment of other relevant outcomes, such as long-term neurologic functional status, could be more reliable. Simple estimation of mortality could seriously underestimate the impact of RBCT on TBI outcomes, and any useful risk prediction model should provide estimates of poor neurological outcome other than mortality [5].
123
The functional outcomes of TBI are typically assessed using the five-level Glasgow Outcome Scale (GOS) or the eight-level extended GOS [6, 12, 13]. Other scores assessing long-term neurological disabilities have rarely been investigated despite the potential impact of RBCT on these outcome measures. We hypothesized that RBCT may influence long-term functional results in patients with TBI. Therefore, we investigated the influence of RBCT on the functional status of patients with TBI 1 year after discharge from the NICU as assessed by the GOS, Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS).
Methods Design This was a prospective study of patients with TBI admitted to the NICU. The study was funded in part by an unrestricted grant from the MAPFRE foundation (Mutualidad de la Agrupacio´n de Propietarios de Fincas Ru´sticas de Espan˜a). The study protocol was presented and explained to all NICU physicians in a dedicated session prior to logging data collection. Patients, Data Inclusion, and Setting Data from all adult patients with TBI admitted to the NICU at the public teaching Hospital ‘‘Virgen del Rocı´o’’ (Seville, Spain), a large urban level-I trauma center, from January 2010 to December 2012 were prospectively entered into a database (MAPFRE database of TBI). Patients were excluded if they died at or were discharged from the NICU within 24 h of admission because these patients were likely to die or survive irrespective of their Hb concentration and performance of RBCT. Patients with a history of neurological or psychiatric illness or any preinjury cognitive deficit were also excluded. TBI Management Patients with TBI were managed with a protocol that conformed to the Brain Trauma Foundation Guidelines and utilized institutional treatment algorithms, as described elsewhere [14]. Our NICU has a 24-h fully dedicated team of specialists in critical care (note that critical care is a specialty in Spain), ensuring homogenous care of patients thorough their entire NICU stay. Institutional guidelines for blood component transfusions, which are based on national guidelines [15], are available at the hospital intranet and may be consulted at
Neurocrit Care
any time. Neurocritical patients usually receive RBCT with an Hb transfusion trigger of 8 g/dL to maintain a target Hb concentration close to 10 g/dL. However, for each particular patient, the decisions regarding transfusion indications and target Hb concentrations were made by the attending physician and were independent of the purposes of this study. All transfused patients received leukoreduced packed RBCs stored in additive solution (saline, adenine, glucose, and mannitol) and anticoagulant preservative (citrate–phosphate–dextrose). Variables Outcome Variables The primary outcome was the long-term neurocognitive functional status as assessed with the GOS, RLCFS, and DRS scores, 6 and 12 months after discharge from the NICU. Telephone-based follow-up interviews were performed by a trained local staff member using structured questionnaires and were scored by the investigator according to a standardized approach. For the purposes of this study, outcome variables were later classified as unfavorable or favorable. A complete description of these tests can be found elsewhere [16]. Briefly, The GOS is a global, admittedly crude instrument that only roughly discriminates different levels of disability. Its disadvantage is that the assessment of physical disability disproportionately exceeds that of cognitive and emotional deficits. However, it remains the most widely used and accepted instrument. For the proposal of this study, the categories of severe disability, vegetative status, and death were considered as unfavorable GOS. Death and a vegetative state were collapsed for the analysis in this study because they were considered to be equally undesirable. The RLCFS was developed to assess recovery after severe TBI. The RLCFS consists of a single eightlevel ordinal item category scale, in which each level corresponds to increasingly complex behaviors ranging from no response to purposeful and appropriate. Higher scores indicate improved functioning. The RLCFS correlates with the DRS. Unfavorable RLCFS scores includes levels V (confused, inappropriate, nonagitated response), IV (confused, agitated response), III (localized response), II (generalized response), I (nonresponse), and death. The DRS is the most versatile outcome measure and was introduced to overcome the poor precision of the GOS. It reliably assesses impairment, disability, and handicap. The scale is intended to accurately measure
changes in general functional over the course of recovery. An unfavorable DRS score indicates severe and extremely severe disabilities, vegetative and extremely vegetative states, and death. Independent Variables The Glasgow Coma Scale (GCS) score obtained after resuscitation at the emergency department or NICU was used for the baseline neurological assessment. Findings in the initial computed tomographic scan were classified using the Marshall scoring system. The Acute Physiology and Chronic Health Evaluation (APACHE) score, Injury Severity Score (ISS), Head Abbreviated Injury Scale (Head AIS) score, and International Mission for Prognosis and Analysis of Clinical Trial (IMPACT) probabilities of a poor GOS score and mortality were also calculated. Each of these scores is related to the severity of injury, and its adjusted influence on the unfavorable long-term neurocognitive outcome was always assessed. In addition to these severity scores, multiple clinical and analytical variables were prospectively collected upon admission for all enrolled patients (Table 1). The laboratory values measured in terminal patients (those who withdrew from active treatment) were omitted from the analyses. Statistical Analysis The sample size was calculated based on previously published IMPACT data [12], which documented an unfavorable outcome (dichotomized GOS score) occurring in nearly 48 % of patients with TBI exhibiting a GCS score of
