- Email: [email protected]
Nonsurviving Patients with Severe Traumatic Brain Injury Have Maintained High Serum sCD40L Levels
Original Article
Nonsurviving Patients with Severe Traumatic Brain Injury Have Maintained High Serum sCD40L Levels Leonardo Lorente1, Marı´a M. Martı´n6, Agustı´n F. Gonza´lez-Rivero2, Luis Ramos7, Mo´nica Argueso8, Juan J. Ca´ceres9, Jordi Sole´-Viola´n10, Alejandro Jime´nez3, Juan M. Borreguero-Leo´n4, Victor Garcı´a-Marı´n5
BACKGROUND: Soluble cluster of differentiation 40 ligand (sCD40L) is a member of the tumor necrosis factor family with proinflamatory and procoagulant effects. A previous study found higher serum sCD40L levels at day 1 of traumatic brain injury (TBI) in nonsurviving than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and to determine whether it could be used as a mortality predictor biomarker.
first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.
METHODS: In this multicenter study severe TBI patients (with Glasgow Coma Scale score <9) with an Injury Severity Score in noncranial item <9 were included. Serum sCD40L concentrations at days 1, 4, and 8 of TBI were determined. We performed receiver operating characteristic analyses to determine the capacity of 30-day TBI mortality prediction by serum sCD40L levels at days 1, 4, and 8 of TBI.
any deaths, disabilities, and consumption of resources are due to traumatic brain injury (TBI).1 In TBI, besides the primary brain injury at the moment of impact by the physical forces suffered to the brain, a secondary brain injury also appears during the hours or days after TBI due to neuroinflammation.2,3 Cluster of differentiation 40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) family that is expressed by activated platelets.4-7 CD40L and its soluble form (sCD40L) are proteins with proinflammatory8,9 and procoagulant10-15 effects when binding to CD40, their cell surface receptor.4,7 Circulating sCD40L levels have barely been studied in patients with TBI. In a previous study higher serum sCD40L levels at day 1 of TBI were found in nonsurviving than surviving patients.16 However, there are no data about whether nonsurviving TBI patients exhibit maintained higher-circulating sCD40L levels than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and determine whether it could be used as a mortality predictor biomarker.
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RESULTS: We found that nonsurviving (n [ 34) patients in comparison with surviving (n [ 90) patients had higher sCD40L levels on days 1 (P < 0.001), 4 (P [ 0.004), and 8 (P < 0.001) of TBI. We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P < 0.001), 72% (P [ 0.01) and 83% (P < 0.001), respectively.
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CONCLUSIONS: The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the
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INTRODUCTION
M
Key words - Brain trauma - Injury - Mortality - Patients - sCD40L
Laguna, and 6Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife; 7Intensive Care Unit, Hospital General La Palma, Breña Alta, La Palma; 8Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda, Valencia; 9 Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria; and 10Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Las Palmas de Gran Canaria, Spain
Abbreviations and Acronyms ICU: Intensive care unit sCD40L: Soluble cluster of differentiation 40 ligand SOFA: Sepsis-related Organ Failure Assessment TNF: Tumor necrosis factor
Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.03.179
To whom correspondence should be addressed: Leonardo Lorente, M.D., Ph.D. [E-mail: [email protected]]
Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
From the 1Intensive Care Unit, 2Laboratory Department, 3Research Unit, 4Laboratory Department, and 5Department of Neurosurgery, Hospital Universitario de Canarias, La
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ORIGINAL ARTICLE LEONARDO LORENTE ET AL.
TRAUMATIC BRAIN INJURY AND MAINTAINED HIGH SERUM SCD40L LEVELS
METHODS
Laguna), and Hospital Universitario Dr. Negrín (Las Palmas de Gran Canaria). Legal patients’ guardians granted a written informed consent for their participation in the study. We included severe TBI patients (scored lower than 9 points on the Glasgow Coma Scale [GCS]17) and scored below 9 points in noncranial aspects in the Injury Severity Score (ISS).18 Patients with inflammatory or malignant disease, pregnancy, or age younger than 18 years were excluded. Previously, we determined serum sCD40L at day 1 of TBI in some of those patients.16 The objective of our research was to
Design, Patients, and Variables Recorded This observational and prospective study was performed in 6 Spanish intensive care units. The study was carried out after approval from Institutional Review Boards at all hospitals participating: Hospital Clínico Universitario de Valencia, Hospital Insular de Las Palmas de Gran Canaria, Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife), Hospital General de La Palma, Hospital Universitario de Canarias (La
Table 1. Characteristics of 30-Day Surviving and Nonsurviving Traumatic Brain Injury Patients Nonsurviving (n [ 34)
Surviving (n [ 90)
P Value
PaO2 (mm Hg)—median (IQR)
142 (97e195)
148 (110e242)
0.45
PaO2/FIO2 ratio—median (IQR)
294 (167e395)
336 (246e400)
0.11
Glycemia (g/dL)—median (IQR)
160 (125e191)
139 (121e167)
0.11
2.30 (1.25e4.58)
1.75 (1.10e2.50)
0.08
141 (136e147)
140 (138e143)
0.41
0.80 (0.70e1.10)
0.80 (0.70e1.00)
0.50
Lactic acid (mmol/L) median (IQR) Sodium (mEq/L)—median (IQR) Creatinine (mg/dL)—median (IQR) Bilirubin (mg/dL)—median (IQR)
0.70 (0.53e1.05)
0.60 (0.40e0.80)
0.06
Temperature ( C)—median (IQR)
36.0 (35.0e37.0)
37.0 (36.0e37.3)
0.07
Platelets—median*103/mm3 (IQR)
172 (125e232)
182 (135e238)
0.49
Leukocytes—median*103/mm3 (IQR)
14.9 (9.7e21.6)
13.9 (10.1e19.0)
0.47
Hemoglobin (g/dL)—median (IQR)
11.9 (10.0e13.7)
11.2 (10.0e13.0)
0.73
Fibrinogen (mg/dL)—median (IQR)
348 (300e475)
371 (286e471)
0.70
29 (25e37)
28 (25e31)
0.25
aPTT (seconds)—median (IQR) INR—median (IQR)
1.12 (1.03e1.48)
1.11 (1.00e1.24)
0.19
APACHE-II score—median (IQR)
25 (23e28)
18 (14e22)
<0.001
ISS—median (IQR)
25 (25e25)
25 (25e34)
0.28
4 (3e7)
7 (5e8)
<0.001
ICP (mm Hg)—median (IQR)
25 (11e30)
15 (14e20)
0.36
CPP (mm Hg)—median (IQR)
61 (52e70)
68 (57e70)
0.60
GCS—median (IQR)
Computed tomography classification—number (%)
0.01
Type 1
0
0
Type 2
5 (14.7)
25 (27.8)
Type 3
6 (17.6)
15 (16.7)
Type 4
9 (26.5)
13 (14.4)
Type 5
6 (17.6)
32 (35.6)
Type 6
8 (23.5)
5 (5.6)
Gender female—number (%) Age (years)—median (IQR) sCD40L (ng/mL)—median (IQR)
13 (38.2)
15 (16.7)
0.02
65 (55e75)
46 (28e62)
<0.001
4.00 (2.74e5.09)
1.76 (0.77e2.56)
<0.001
PaO2, pressure of arterial oxygen/fraction inspired oxygen; IQR, interquartile range; FIO2, pressure of arterial oxygen/fraction inspired oxygen; aPTT, activated partial thromboplastin time; INR, international normalized ratio; APACHE II, Acute Physiology and Chronic Health Evaluation; ISS, Injury Severity Score; GCS, Glasgow Coma Scale; ICP, intracranial pressure; CPP, cerebral perfusion pressure.
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TRAUMATIC BRAIN INJURY AND MAINTAINED HIGH SERUM SCD40L LEVELS
determine serum sCD40L concentrations at days 1, 4, and 8 of TBI. We recollected the following variables in patients included in the study: pressure of arterial oxygen/fraction inspired oxygen (PaO2), pressure of arterial oxygen/fraction inspired oxygen (FIO2), lactic acid, sodium, creatinine, body temperature, glycemia, bilirubin, platelets, leukocytes, hemoglobin, fibrinogen, activated partial thromboplastin time (aPTT), international normalized ratio (INR), ISS, GCS, Acute Physiology and Chronic Health Evaluation II (APACHE II) score,19 intracranial pressure (ICP), cerebral perfusion pressure (CPP), age, sex, and brain lesions using the classification of Marshall computed tomography (CT).20 This CT classification included the following lesion classes: I (not visible pathology); II (cisterns present, midline shift <5 mm, and no lesion >25 mL); III (cisterns compressed, midline shift <5 mm, and no lesion >25 mL); IV (midline shift >5 mm, and no lesion >25 mL); V (evacuated lesion); and VI (lesion >25 mL no evacuated). We considered as the endpoint study the 30-day mortality. Blood Samples and Determinations At days 1, 4, and 8 of TBI we obtained blood samples and placed them in separator gel tubes. We then left them at room temperature for 10 minutes to coagulate. Later, the serum from samples was obtained by centrifugation for 15 minutes at 1000 g. Finally, we aliquoted the samples and froze them at 80 C until determination. The Laboratory Department of the Hospital Universitario de Canarias (Tenerife, Spain) carried out the determination of serum sCD40L levels by specific ELISA kit (Bender MedSystems GmbH, Vienna, Austria). The intra-assay coefficient of variation, interassay coefficient of variation, and detection limit for the assay were 4%, 7%, and 0.06 ng/mL, respectively.
surviving compared to surviving TBI patients were older, had higher APACHE-II score and female rate, and lower GCS. In addition, we found different CT findings in non-surviving compared to surviving TBI patients. Besides, we found higher serum sCD40L concentrations at days 1 (P<0.001), 4 (P¼0.004), and 8 (P<0.001) of TBI in non-surviving in comparison to surviving patients (Figure 1). We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P<0.001), 72% (P¼0.01) and 83% (P<0.001) respectively (Table 2). DISCUSSION We found higher serum sCD40L levels on day 1 of TBI in nonsurviving than in surviving patients and that serum sCD40L levels at day 1 of TBI could be used as a mortality predictor biomarker. Those findings are in consonance with that association that previously was found between high sCD40L circulating levels and worst prognosis in patients with acute coronary artery syndrome,22,23 sepsis,24-27 brain infarction28-30 and TBI.16 However, novel aspects of our study were that we found higher serum sCD40L levels during the first week of TBI in non-surviving than in surviving patients, and that serum sCD40L levels during the first week of TBI could be used as mortality predictor biomarker. Preincubation of cerebral vascular endothelial cells with statins has been found to inhibit CD40 expression induced by TNF-alpha.31 In addition, patients receiving statins showed lower circulating levels of sCD40L.32-34 Besides, the administration of statins in patients on an acute phase of ischemic stroke has been associated with improved outcome and lower risk of death in a meta-analysis.35 Finally, the use of statins in rat models of TBI have been associated with decreased intravascular thrombosis and cerebral
Statistical Methods Continuous variables are presented as medians and interquartile ranges, and we compared them between patient groups (surviving and nonsurviving) by Wilcoxon-Mann-Whitney test. Categorical variables are presented as frequencies and percentages. We compared them between patient groups (surviving and nonsurviving) by chi-square test. We carried out receiver operating characteristic curve analyses to determine the goodness of serum sCD40L levels at days 1, 4, and 8 of TBI to predict 30-day mortality. Prognostic capability of serum sCD40L levels at days 1, 4, and 8 of TBI was estimated using sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predicted value, negative predicted value, and its 95% confidence interval. Jouden Index was used to select the cut-offs of serum sCD40L levels at days 1, 4, and 8 of TBI with the maximum prognostic capability.21 P values <0.05 were considered statistically significant. The statistical analysis were performed using the SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA); NCSS 2000 (Kaysville, Utah, USA); and LogXact 4.1 (Cytel Co., Cambridge, Massachusetts, USA) programs. RESULTS Characteristics of 30-day surviving (n¼90) and non-surviving (n¼34) TBI patients are showed in Table 1. We found that non-
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Figure 1. Serum sCD40L levels at days 1, 4, and 8 of traumatic brain injury in 30-day surviving and nonsurviving patients.
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Table 2. Receiver Operation Characteristic Analysis Using Serum sCD40L Levels at Days 1, 4, and 8 of Trauma Brain Injury as Predictor of Mortality at 30 Days Day 1
Day 4
Day 8
Cutoff of sCD40L (ng/mL)
>2.11
>2.38
>2.31
AUC, 95% CI, and P value
0.82 (0.74e0.89) P < 0.001
0.72 (0.63e0.80) P ¼ 0.01
0.83 (0.75e0.90) P < 0.001
Sensitivity and 95% CI
91 (76e98)
71 (44e90)
84 (55e98)
Specificity and 95% CI
67 (56e76)
86 (77e92)
90 (82e95)
Positive likelihood ratio and 95% CI
2.74 (2.00e3.70)
4.89 (2.70e8.80)
8.46 (4.40e16.40)
Negative likelihood ratio and 95% CI
0.13 (0.04e0.40)
0.34 (0.20e0.70)
0.17 (0.05e0.60)
Positive predictive value and 95% CI
51 (43e59)
48 (34e63)
55 (39e70)
Negative predictive value and 95% CI
95 (87e98)
94 (88e97)
98 (92e99)
AUC, area under curve; CI, confidence interval.
edema, and with decreased impairment of motor and cognitive functions.36 Thus all those findings could motivate the interest for researching to modulate CD40 system in TBI patients. We believed that the higher mortality rate in patients with high serum sCD40L levels could be explained by a higher proinflammatory and procoagulant states of those patients due to the proinflamatory8,9 and procoagulant10-15 effects of sCD40L. The CD40L stored in a-granules of unstimulated platelets translocates to platelet surface when they are activated, and afterwards CD40L is cleaved and appears in blood as sCD40L. The sCD40L binds to CD40 on endothelial cell surfaces with the subsequent up regulation of proinflammatory and prothrombotic mediators, such as interleukin (IL)-1, IL-6, IL-12, TNF-alpha, tissue factor. That higher proinflamatory and procoagulant state in non-surviving TBI patients could contribute in the development of cerebral edema, vascular thrombosis, cerebral ischemia, and death. We must recognize some limitations in our study. First, we have not found statistically significant differences between nonsurviving and surviving patients in some variable related to inflammation and coagulation (such as leukocytes count fibrinogen, aPTT, INR, or platelet count), and we have not reported data about blood levels of proinflamatory and procoagulant factors. However, we have found statistically significant differences between non-surviving and surviving patients in some variable
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previously associated with mortality in those patients such as APACHE-II, GCS, CT findings, age and sex.37-45 Second, there has been reported differences between serum and plasma concentrations of sCD40L46 and we have only determined serum levels. Three, we have not assessed infectious complications. According to the results of the receiver operating characteristic curve analyses, serum sCD40L on days 1, 4, and 8 of TBI could be used for 30-day mortality prediction of TBI patients. The negative predictive value of serum sCD40L concentrations on days 1, 4, and 8 was higher than 90%; thus the probability that patients did not die in the following 30 days of TBI with serum sCD40L levels <2.11 ng/mL at day 1 of TBI, 2.38 ng/mL at day 4, and 2.31 ng/mL at day 8 was >90%. We think that the findings of our study could motivate the interest to research the role of serum sCD40L levels for the mortality prediction of patients with TBI and to research the modulation of circulating sCD40L levels to reduce the risk of death of those patients. CONCLUSIONS The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.
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elevation myocardial infarction. Thromb Res. 2007; 121:293-299. 24. Lorente L, Martín MM, Varo N, et al. Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis. Crit Care. 2011;15:R97. 25. Martínez de Lizarrondo S, Roncal C, Calvayrac O, et al. Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2012;32: 1477-1487. 26. Lorente L, Martín MM, Pérez-Cejas A, et al. Nonsurvivor septic patients have persistently higher serum sCD40L levels than survivors. J Crit Care. 2017;41:177-182. 27. Nolan A, Weiden M, Kelly A, et al. CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. Am J Respir Crit Care Med. 2008;177:301-308. 28. Lorente L, Martín MM, González-Rivero AF, et al. Association between serum soluble cd154 levels and mortality in patients with malignant middle cerebral artery infarction. Int J Mol Sci. 2015;16: 12147-12158. 29. Tsai NW, Chang WN, Shaw CF, et al. Levels and value of platelet activation markers in different subtypes of acute non-cardio-embolic ischemic stroke. Thromb Res. 2009;124:213-218. 30. Lukasik M, Dworacki G, Kufel-Grabowska J, Watala C, Kozubski W. Upregulation of CD40 ligand and enhanced monocyte-platelet aggregate formation are associated with worse clinical outcome after ischaemic stroke. Thromb Haemost. 2012;107:346-355. 31. Lin R, Liu J, Peng N, et al. Lovastatin reduces apoptosis and downregulates the CD40 expression induced by TNF-alpha in cerebral vascular endothelial cells. Curr Neurovasc Res. 2006;3:41-47. 32. Li J, Zhao SP, Peng DQ, Xu ZM, Zhou HN. Early effect of pravastatin on serum soluble CD40L, matrix metalloproteinase-9, and C-reactive protein in patients with acute myocardial infarction. Clin Chem. 2004;50:1696-1699. 33. Hamdan R1, Hajj F, Kadry Z, et al. Benefit and tolerability of the coadministration of ezetimibe and atorvastatin in acute coronary syndrome patients. J Med Liban. 2011;59:65-69. 34. Han SH1, Koh KK, Quon MJ, Lee Y, Shin EK. The effects of simvastatin, losartan, and combined therapy on soluble CD40 ligand in hypercholesterolemic, hypertensive patients. Atherosclerosis. 2007;190:205-211. 35. Ní Chróinín D, Asplund K, Åsberg S, et al. Statin therapy and outcome after ischemic stroke:
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Conflict of interest statement: This study was supported by a grant (OA18/011) from Fundación DISA a la Investigación Médica 2017 (Santa Cruz de Tenerife. Spain). Received 30 November 2018; accepted 18 March 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.03.179 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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Nonsurviving Patients with Severe Traumatic Brain Injury Have Maintained High Serum sCD40L Levels Leonardo Lorente1, Marı´a M. Martı´n6, Agustı´n F. Gonza´lez-Rivero2, Luis Ramos7, Mo´nica Argueso8, Juan J. Ca´ceres9, Jordi Sole´-Viola´n10, Alejandro Jime´nez3, Juan M. Borreguero-Leo´n4, Victor Garcı´a-Marı´n5
BACKGROUND: Soluble cluster of differentiation 40 ligand (sCD40L) is a member of the tumor necrosis factor family with proinflamatory and procoagulant effects. A previous study found higher serum sCD40L levels at day 1 of traumatic brain injury (TBI) in nonsurviving than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and to determine whether it could be used as a mortality predictor biomarker.
first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.
METHODS: In this multicenter study severe TBI patients (with Glasgow Coma Scale score <9) with an Injury Severity Score in noncranial item <9 were included. Serum sCD40L concentrations at days 1, 4, and 8 of TBI were determined. We performed receiver operating characteristic analyses to determine the capacity of 30-day TBI mortality prediction by serum sCD40L levels at days 1, 4, and 8 of TBI.
any deaths, disabilities, and consumption of resources are due to traumatic brain injury (TBI).1 In TBI, besides the primary brain injury at the moment of impact by the physical forces suffered to the brain, a secondary brain injury also appears during the hours or days after TBI due to neuroinflammation.2,3 Cluster of differentiation 40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) family that is expressed by activated platelets.4-7 CD40L and its soluble form (sCD40L) are proteins with proinflammatory8,9 and procoagulant10-15 effects when binding to CD40, their cell surface receptor.4,7 Circulating sCD40L levels have barely been studied in patients with TBI. In a previous study higher serum sCD40L levels at day 1 of TBI were found in nonsurviving than surviving patients.16 However, there are no data about whether nonsurviving TBI patients exhibit maintained higher-circulating sCD40L levels than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and determine whether it could be used as a mortality predictor biomarker.
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RESULTS: We found that nonsurviving (n [ 34) patients in comparison with surviving (n [ 90) patients had higher sCD40L levels on days 1 (P < 0.001), 4 (P [ 0.004), and 8 (P < 0.001) of TBI. We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P < 0.001), 72% (P [ 0.01) and 83% (P < 0.001), respectively.
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CONCLUSIONS: The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the
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INTRODUCTION
M
Key words - Brain trauma - Injury - Mortality - Patients - sCD40L
Laguna, and 6Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife; 7Intensive Care Unit, Hospital General La Palma, Breña Alta, La Palma; 8Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda, Valencia; 9 Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria; and 10Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Las Palmas de Gran Canaria, Spain
Abbreviations and Acronyms ICU: Intensive care unit sCD40L: Soluble cluster of differentiation 40 ligand SOFA: Sepsis-related Organ Failure Assessment TNF: Tumor necrosis factor
Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.03.179
To whom correspondence should be addressed: Leonardo Lorente, M.D., Ph.D. [E-mail: [email protected]]
Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
From the 1Intensive Care Unit, 2Laboratory Department, 3Research Unit, 4Laboratory Department, and 5Department of Neurosurgery, Hospital Universitario de Canarias, La
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ORIGINAL ARTICLE LEONARDO LORENTE ET AL.
TRAUMATIC BRAIN INJURY AND MAINTAINED HIGH SERUM SCD40L LEVELS
METHODS
Laguna), and Hospital Universitario Dr. Negrín (Las Palmas de Gran Canaria). Legal patients’ guardians granted a written informed consent for their participation in the study. We included severe TBI patients (scored lower than 9 points on the Glasgow Coma Scale [GCS]17) and scored below 9 points in noncranial aspects in the Injury Severity Score (ISS).18 Patients with inflammatory or malignant disease, pregnancy, or age younger than 18 years were excluded. Previously, we determined serum sCD40L at day 1 of TBI in some of those patients.16 The objective of our research was to
Design, Patients, and Variables Recorded This observational and prospective study was performed in 6 Spanish intensive care units. The study was carried out after approval from Institutional Review Boards at all hospitals participating: Hospital Clínico Universitario de Valencia, Hospital Insular de Las Palmas de Gran Canaria, Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife), Hospital General de La Palma, Hospital Universitario de Canarias (La
Table 1. Characteristics of 30-Day Surviving and Nonsurviving Traumatic Brain Injury Patients Nonsurviving (n [ 34)
Surviving (n [ 90)
P Value
PaO2 (mm Hg)—median (IQR)
142 (97e195)
148 (110e242)
0.45
PaO2/FIO2 ratio—median (IQR)
294 (167e395)
336 (246e400)
0.11
Glycemia (g/dL)—median (IQR)
160 (125e191)
139 (121e167)
0.11
2.30 (1.25e4.58)
1.75 (1.10e2.50)
0.08
141 (136e147)
140 (138e143)
0.41
0.80 (0.70e1.10)
0.80 (0.70e1.00)
0.50
Lactic acid (mmol/L) median (IQR) Sodium (mEq/L)—median (IQR) Creatinine (mg/dL)—median (IQR) Bilirubin (mg/dL)—median (IQR)
0.70 (0.53e1.05)
0.60 (0.40e0.80)
0.06
Temperature ( C)—median (IQR)
36.0 (35.0e37.0)
37.0 (36.0e37.3)
0.07
Platelets—median*103/mm3 (IQR)
172 (125e232)
182 (135e238)
0.49
Leukocytes—median*103/mm3 (IQR)
14.9 (9.7e21.6)
13.9 (10.1e19.0)
0.47
Hemoglobin (g/dL)—median (IQR)
11.9 (10.0e13.7)
11.2 (10.0e13.0)
0.73
Fibrinogen (mg/dL)—median (IQR)
348 (300e475)
371 (286e471)
0.70
29 (25e37)
28 (25e31)
0.25
aPTT (seconds)—median (IQR) INR—median (IQR)
1.12 (1.03e1.48)
1.11 (1.00e1.24)
0.19
APACHE-II score—median (IQR)
25 (23e28)
18 (14e22)
<0.001
ISS—median (IQR)
25 (25e25)
25 (25e34)
0.28
4 (3e7)
7 (5e8)
<0.001
ICP (mm Hg)—median (IQR)
25 (11e30)
15 (14e20)
0.36
CPP (mm Hg)—median (IQR)
61 (52e70)
68 (57e70)
0.60
GCS—median (IQR)
Computed tomography classification—number (%)
0.01
Type 1
0
0
Type 2
5 (14.7)
25 (27.8)
Type 3
6 (17.6)
15 (16.7)
Type 4
9 (26.5)
13 (14.4)
Type 5
6 (17.6)
32 (35.6)
Type 6
8 (23.5)
5 (5.6)
Gender female—number (%) Age (years)—median (IQR) sCD40L (ng/mL)—median (IQR)
13 (38.2)
15 (16.7)
0.02
65 (55e75)
46 (28e62)
<0.001
4.00 (2.74e5.09)
1.76 (0.77e2.56)
<0.001
PaO2, pressure of arterial oxygen/fraction inspired oxygen; IQR, interquartile range; FIO2, pressure of arterial oxygen/fraction inspired oxygen; aPTT, activated partial thromboplastin time; INR, international normalized ratio; APACHE II, Acute Physiology and Chronic Health Evaluation; ISS, Injury Severity Score; GCS, Glasgow Coma Scale; ICP, intracranial pressure; CPP, cerebral perfusion pressure.
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ORIGINAL ARTICLE LEONARDO LORENTE ET AL.
TRAUMATIC BRAIN INJURY AND MAINTAINED HIGH SERUM SCD40L LEVELS
determine serum sCD40L concentrations at days 1, 4, and 8 of TBI. We recollected the following variables in patients included in the study: pressure of arterial oxygen/fraction inspired oxygen (PaO2), pressure of arterial oxygen/fraction inspired oxygen (FIO2), lactic acid, sodium, creatinine, body temperature, glycemia, bilirubin, platelets, leukocytes, hemoglobin, fibrinogen, activated partial thromboplastin time (aPTT), international normalized ratio (INR), ISS, GCS, Acute Physiology and Chronic Health Evaluation II (APACHE II) score,19 intracranial pressure (ICP), cerebral perfusion pressure (CPP), age, sex, and brain lesions using the classification of Marshall computed tomography (CT).20 This CT classification included the following lesion classes: I (not visible pathology); II (cisterns present, midline shift <5 mm, and no lesion >25 mL); III (cisterns compressed, midline shift <5 mm, and no lesion >25 mL); IV (midline shift >5 mm, and no lesion >25 mL); V (evacuated lesion); and VI (lesion >25 mL no evacuated). We considered as the endpoint study the 30-day mortality. Blood Samples and Determinations At days 1, 4, and 8 of TBI we obtained blood samples and placed them in separator gel tubes. We then left them at room temperature for 10 minutes to coagulate. Later, the serum from samples was obtained by centrifugation for 15 minutes at 1000 g. Finally, we aliquoted the samples and froze them at 80 C until determination. The Laboratory Department of the Hospital Universitario de Canarias (Tenerife, Spain) carried out the determination of serum sCD40L levels by specific ELISA kit (Bender MedSystems GmbH, Vienna, Austria). The intra-assay coefficient of variation, interassay coefficient of variation, and detection limit for the assay were 4%, 7%, and 0.06 ng/mL, respectively.
surviving compared to surviving TBI patients were older, had higher APACHE-II score and female rate, and lower GCS. In addition, we found different CT findings in non-surviving compared to surviving TBI patients. Besides, we found higher serum sCD40L concentrations at days 1 (P<0.001), 4 (P¼0.004), and 8 (P<0.001) of TBI in non-surviving in comparison to surviving patients (Figure 1). We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P<0.001), 72% (P¼0.01) and 83% (P<0.001) respectively (Table 2). DISCUSSION We found higher serum sCD40L levels on day 1 of TBI in nonsurviving than in surviving patients and that serum sCD40L levels at day 1 of TBI could be used as a mortality predictor biomarker. Those findings are in consonance with that association that previously was found between high sCD40L circulating levels and worst prognosis in patients with acute coronary artery syndrome,22,23 sepsis,24-27 brain infarction28-30 and TBI.16 However, novel aspects of our study were that we found higher serum sCD40L levels during the first week of TBI in non-surviving than in surviving patients, and that serum sCD40L levels during the first week of TBI could be used as mortality predictor biomarker. Preincubation of cerebral vascular endothelial cells with statins has been found to inhibit CD40 expression induced by TNF-alpha.31 In addition, patients receiving statins showed lower circulating levels of sCD40L.32-34 Besides, the administration of statins in patients on an acute phase of ischemic stroke has been associated with improved outcome and lower risk of death in a meta-analysis.35 Finally, the use of statins in rat models of TBI have been associated with decreased intravascular thrombosis and cerebral
Statistical Methods Continuous variables are presented as medians and interquartile ranges, and we compared them between patient groups (surviving and nonsurviving) by Wilcoxon-Mann-Whitney test. Categorical variables are presented as frequencies and percentages. We compared them between patient groups (surviving and nonsurviving) by chi-square test. We carried out receiver operating characteristic curve analyses to determine the goodness of serum sCD40L levels at days 1, 4, and 8 of TBI to predict 30-day mortality. Prognostic capability of serum sCD40L levels at days 1, 4, and 8 of TBI was estimated using sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predicted value, negative predicted value, and its 95% confidence interval. Jouden Index was used to select the cut-offs of serum sCD40L levels at days 1, 4, and 8 of TBI with the maximum prognostic capability.21 P values <0.05 were considered statistically significant. The statistical analysis were performed using the SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA); NCSS 2000 (Kaysville, Utah, USA); and LogXact 4.1 (Cytel Co., Cambridge, Massachusetts, USA) programs. RESULTS Characteristics of 30-day surviving (n¼90) and non-surviving (n¼34) TBI patients are showed in Table 1. We found that non-
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Figure 1. Serum sCD40L levels at days 1, 4, and 8 of traumatic brain injury in 30-day surviving and nonsurviving patients.
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Table 2. Receiver Operation Characteristic Analysis Using Serum sCD40L Levels at Days 1, 4, and 8 of Trauma Brain Injury as Predictor of Mortality at 30 Days Day 1
Day 4
Day 8
Cutoff of sCD40L (ng/mL)
>2.11
>2.38
>2.31
AUC, 95% CI, and P value
0.82 (0.74e0.89) P < 0.001
0.72 (0.63e0.80) P ¼ 0.01
0.83 (0.75e0.90) P < 0.001
Sensitivity and 95% CI
91 (76e98)
71 (44e90)
84 (55e98)
Specificity and 95% CI
67 (56e76)
86 (77e92)
90 (82e95)
Positive likelihood ratio and 95% CI
2.74 (2.00e3.70)
4.89 (2.70e8.80)
8.46 (4.40e16.40)
Negative likelihood ratio and 95% CI
0.13 (0.04e0.40)
0.34 (0.20e0.70)
0.17 (0.05e0.60)
Positive predictive value and 95% CI
51 (43e59)
48 (34e63)
55 (39e70)
Negative predictive value and 95% CI
95 (87e98)
94 (88e97)
98 (92e99)
AUC, area under curve; CI, confidence interval.
edema, and with decreased impairment of motor and cognitive functions.36 Thus all those findings could motivate the interest for researching to modulate CD40 system in TBI patients. We believed that the higher mortality rate in patients with high serum sCD40L levels could be explained by a higher proinflammatory and procoagulant states of those patients due to the proinflamatory8,9 and procoagulant10-15 effects of sCD40L. The CD40L stored in a-granules of unstimulated platelets translocates to platelet surface when they are activated, and afterwards CD40L is cleaved and appears in blood as sCD40L. The sCD40L binds to CD40 on endothelial cell surfaces with the subsequent up regulation of proinflammatory and prothrombotic mediators, such as interleukin (IL)-1, IL-6, IL-12, TNF-alpha, tissue factor. That higher proinflamatory and procoagulant state in non-surviving TBI patients could contribute in the development of cerebral edema, vascular thrombosis, cerebral ischemia, and death. We must recognize some limitations in our study. First, we have not found statistically significant differences between nonsurviving and surviving patients in some variable related to inflammation and coagulation (such as leukocytes count fibrinogen, aPTT, INR, or platelet count), and we have not reported data about blood levels of proinflamatory and procoagulant factors. However, we have found statistically significant differences between non-surviving and surviving patients in some variable
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previously associated with mortality in those patients such as APACHE-II, GCS, CT findings, age and sex.37-45 Second, there has been reported differences between serum and plasma concentrations of sCD40L46 and we have only determined serum levels. Three, we have not assessed infectious complications. According to the results of the receiver operating characteristic curve analyses, serum sCD40L on days 1, 4, and 8 of TBI could be used for 30-day mortality prediction of TBI patients. The negative predictive value of serum sCD40L concentrations on days 1, 4, and 8 was higher than 90%; thus the probability that patients did not die in the following 30 days of TBI with serum sCD40L levels <2.11 ng/mL at day 1 of TBI, 2.38 ng/mL at day 4, and 2.31 ng/mL at day 8 was >90%. We think that the findings of our study could motivate the interest to research the role of serum sCD40L levels for the mortality prediction of patients with TBI and to research the modulation of circulating sCD40L levels to reduce the risk of death of those patients. CONCLUSIONS The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.
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Conflict of interest statement: This study was supported by a grant (OA18/011) from Fundación DISA a la Investigación Médica 2017 (Santa Cruz de Tenerife. Spain). Received 30 November 2018; accepted 18 March 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.03.179 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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