Persistently High Serum Substance P Levels and Early Mortality in Patients with Severe Traumatic Brain Injury

doi:10.1016/j.wneu.2019.08.064

World Neurosurgery

Volume 132, December 2019, Pages e613-e617

https://doi.org/10.1016/j.wneu.2019.08.064 Get rights and content

Background

Substance P is a neuropeptide belonging to the tachykinin family and is involved in neuroinflammation. In a previous study by our team, we found higher serum substance P levels on day 1 of traumatic brain injury (TBI) in nonsurviving than in surviving patients. Thus, the objective of this study was to determine whether serum substance P levels during the first week of TBI could predict early mortality.

Methods

This was a multicenter, observational, and prospective study. We included patients with an isolated severe TBI, defining isolated as <9 points in non-cranial aspects of Injury Severity Score and severe as <9 points of Glasgow Coma Scale. We determined serum substance P concentrations at days 1, 4, and 8 of TBI. We performed receiver operating characteristic analyses to determine the capacity of serum substance P levels at day 1, 4, and 8 of TBI to predict 30-day mortality.

Results

Nonsurviving (n = 34) compared with surviving patients (n = 90) had greater serum substance P levels on day 1 (P < 0.001), 4 (P < 0.001), and 8 (P < 0.001) of TBI. The areas under curve of serum substance P concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality were 76% (P < 0.001), 87% (P < 0.001), and 89% (P < 0.001), respectively.

Conclusions

The new finding of our study is that the presence of elevated serum substance P levels during the first week of TBI is associated with increased mortality.

Introduction

Traumatic brain injury (TBI) is the cause of many financial costs, disabilities, and deaths.¹ In TBI, besides the primary brain injury due to the physical forces applied to the brain at the moment of impact, a secondary brain injury also appears due to the neuroinflammatory response and other mechanisms during the hours or days after the trauma.2, 3

Substance P is a neuropeptide belonging to the tachykinin family and is widely distributed in the central and peripheral nervous systems, as well as the gut, the respiratory and urinary systems, and in blood vessels.4, 5, 6 Substance P exhibits proinflammatory effects when binding with its receptor and is involved in several biological processes such as airway contraction, inflammation, vasodilation, vascular extravasation, smooth muscle contraction, transmission of nociceptive responses, and salivary secretion.4, 5, 6 Substance P has been implicated in different diseases such as asthma, inflammatory bowel disease, and central and peripheral nervous systems diseases.4, 5, 6 Specifically, substance P has been implicated in neuroinflammation after TBI.7, 8, 9, 10, 11, 12, 13, 14, 15

Data are scarce about substance P in patients with TBI.16, 17 In a study that compared postmortem brain samples from patients with TBI having neuropathologic abnormalities and from patients with a history of epilepsy having no neuropathologic abnormalities, greater substance P perivascular was found in samples of patients with TBI.¹⁶ In a previous study by our team, we found greater serum substance P levels at day 1 of TBI in nonsurviving than in surviving patients.¹⁷ Thus, the objectives of this study were to compare serum substance P levels during the first week of TBI between surviving and nonsurviving patients, and to determine whether serum substance P levels during the first week of TBI could predict early mortality.

Section snippets

Design and Subjects

Six intensive care units from Spanish hospitals participated in this observational and prospective study. The institutional review boards of the 6 hospitals approved the study before the beginning: H. Clínico Universitario de Valencia, H. Insular de Las Palmas de Gran Canaria, H. Universitario Nuestra Señora de Candelaria of Santa Cruz de Tenerife, H. General de La Palma, H. Universitario Dr. Negrín of Las Palmas de Gran Canaria, and H. Universitario de Canarias of La Laguna. We obtained

Results

Surviving (n = 90) and nonsurviving patients (n = 34) at 30 days of severe TBI showed significant differences in CT findings on admission (P = 0.01), and surviving compared with nonsurviving patients showed greater GCS (P < 0.001), lower female ratio (P = 0.02), lower APACHE II score (P < 0.001), and younger age (P < 0.001) (Table 1). The causes of death were brain death in 25 patients, cardiac arrest in 5 patients, and nosocomial pneumonia in 4 patients.

Surviving compared with nonsurviving

Discussion

Previously, we found greater serum substance P levels on day 1 of severe TBI in nonsurviving than in surviving patients.¹⁷ Thus, the new findings of our current study were that nonsurviving patients with severe TBI showed greater serum substance P levels during the first week than surviving patients, and that those levels at different moments of the first week of TBI could be used as biomarkers for the prediction of 30-day mortality.

Substance P is involved in neurogenic inflammation

Conclusions

The new finding of our study is that the presence of elevated serum substance P levels during the first week of TBI is associated with increased mortality.

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Role of substance P in cerebral edema and association with an estimated specific gravity of the brain and an outcome prediction in post-traumatic cerebral edema
2024, World Neurosurgery: X
The study aims to evaluate the role of substance P in cerebral edema and outcomes associated with acute TBI.
Patients with acute TBI who presented within 6 h and a CT scan showed predominantly cerebral edema were included in the study. Substance P level was assessed from a serum sample collected within 6 h of trauma. We also evaluated the brain-specific gravity using the Brain View software.
A total of 160 (128 male) patients were recruited. The median serum substance P concentration was 167.89 (IQR: 101.09–238.2). Substance P concentration was high in the early hours after trauma (p = 0.001). The median specific gravity of the entire brain was 1.04. Patients with a low Glasgow coma scale (GCS) at admission had a high concentration of the substance P. In the univariate analysis, low GCS, elevated serum concentrations of substance P level, high Rotterdam grade, high cerebral edema grade, a high international normalized ratio value, and high blood sugar levels were associated with poor outcomes at six months. In logistic regression analysis, low GCS at admission, high cerebral edema grade, and elevated blood sugar level were strongly associated with poor outcomes at six months. The area under the receiver operating characteristic curve was 0.884 (0.826–0.941).
Serum substance P is strongly associated with the severity of cerebral edema after TBI. However, brain-specific gravity does not directly correlate with posttraumatic cerebral edema severity. Serum substance P does not influence the clinical outcome of traumatic brain injury.
Neurokinin-1 Receptor as a potential drug target for COVID-19 treatment
2021, Biomedicine and Pharmacotherapy
Citation Excerpt :
SP was found to be raised in serum samples of non/surviving patients of traumatic brain injury (TBI) as compared to surviving on Day 1. It was also found, that elevated SP levels during the first week of TBI was a predictor of increased mortality [50]. SIDS and cancer studies also support SP as a predictor of poor prognosis and mortality [51–53].
Novel Coronavirus infection (COVID-19) has become a pandemic in these days. It is an acute respiratory and infectious disease with no known etiology and treatment. It is continuously causing losses of precious lives and economy at a global scale on daily basis. It is the need of the hour to find more treatment strategies by either developing a drug or to boost the immune system. This opinion article aims to provide Substance P (SP) as a possible cause of the initiation of cytokine storm developed in COVID-19 infection and to suggest Neurokinin-1 Receptor (NK-1R) antagonist, Aprepitant, as a drug to be used for its treatment. This perspective will provide directions to the Biomedical scientists to explore SP and NK-1R and prepare a drug to alleviate the symptoms and cure the disease. It is very important to work on this perspective at earliest to reach to some conclusion regarding the therapeutic intervention. Clinical studies may also be conducted if proven successful. SP is a neurotransmitter and neuromodulator, released from the trigeminal nerve of brainstem as a result of nociception. It is directly related to the respiratory illness as in COVID-19 infection. It is responsible for the increased inflammation and the signature symptoms associated with this disease. It is the main switch that needs to be switched off by administering Aprepitant along with glucocorticosteroid, dexamethasone.
Elevated lead levels in relation to low serum neuropeptide Y and adverse behavioral effects in preschool children with e-waste exposure
2021, Chemosphere
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What is more, NPY neurons have been shown to interact with behavioral brain pathways and dopaminergic reward in the amygdala and nucleus accumbens, respectively (Dalgleish, 2004; Heilig, 2004; Morales-Medina et al., 2010). Substance P is highly expressed in hypothalamus, amygdaloid nucleus, and the periaqueductal gray, regulating emotion (Datar et al., 2004; Herpfer et al., 2007; Lorente et al., 2019). Elevated substance P levels are associated with increased inner tension and anxiety (Ebner and Singewald, 2006; Herpfer et al., 2007; Iftikhar et al., 2020).
As a neurotoxicant, lead (Pb) primarily affects central nervous system, and particularly impacts developing brain. This study explores the associations of blood Pb level and children’s behavioral health. A total of 213 preschool children aged 3–7 years old were recruited from Guiyu (the e-waste-exposed area) and Haojiang (the reference area). The behavioral health of children was assessed using the ‘behavioral symptoms’ subscale of the Strengths and Difficulties Questionnaire (SDQ). Results showed that there was a significant difference in percent of children categorized as “at risk” between Guiyu (48.2%) and Haojiang (13.9%) (p < 0.001). The blood Pb level of children in Guiyu was significantly higher than those in Haojiang (median: 5.19 μg/dL vs. 3.42 μg/dL, p < 0.001). The serum Neuropeptide Y (NPY) was significantly lower in Guiyu children than those in Haojiang. Spearman correlation analyses demonstrated that blood Pb levels was negatively correlated with NPY (r_s = −0.25, p < 0.001), but positively correlated with behavioral symptom scores; while serum NPY levels were negatively associated with behavioral symptom scores. Behavioral symptom scores were higher in children with blood Pb level ≥5.00 μg/dL (high) than those with blood Pb level < 5.00 μg/dL (low). After adjusting for confounding factors, children with lower NPY levels were at higher risk of having behavioral difficulties. In conclusion, Pb exposure in e-waste-exposed areas may lead to decrease in serum NPY and increase in the risk of children’s behavioral problems. In addition, NPY may mediate the association between Pb exposure and behavioral difficulties.
Serum Substance P Concentration in Children With Traumatic Brain Injury: A First Report
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Citation Excerpt :
It plays a vital role in the nervous system. Some studies have shown that in adult patients with severe TBI, the serum SP concentration is significantly increased, and the persistent high level of serum SP in the week after injury is closely associated with a high mortality rate in the early stage of the injury.3,4 Therefore, this study aimed to study the relationships among the degree of craniocerebral injury, serum SP concentration, and prognosis by detecting the serum SP level in children with different degrees of TBI.
To review the clinic value and severity assessment of serum substance P (SP) concentration in children with different degrees of traumatic brain injury (TBI) through analyzing correlations with outcomes.
One hundred thirty-nine children with TBI who were diagnosed and treated at Nanjing Medical University for longer than 72 hours between June 2017 and 2019 were analyzed. Blood samples were obtained within 24 hours after TBI to measure SP concentration. The endpoint was discharge mortality. Thirty healthy children composed the control group. Comparative analyses of differences in SP concentration were conducted for the different groups. Both the Sequential Organ Failure Assessment (SOFA) scores and Pediatric Clinical Illness Score (PCIS) were measured on admission and used in univariate and multivariate analyses.
The serum SP (89.10 ± 64.32) pmol/L) level in the case group was significantly higher than that in the control group (21.84 ± 2.09) pmol/L (t = 5.71, P < 0.05). The serum SP (182.81 ± 58.39) pmol/L) level in the deceased group was significantly higher than that in the survival group (59.93 ± 27.90) pmol/L (t = 16.52, P < 0.05). A negative correlation existed between serum SP concentration and Glasgow Coma Scale score in the severe, moderate, and mild groups (r = −0.72, P < 0.05). Serum SP concentration was identified as an independent risk factor for mortality (odds ratio >1, 95% confidence interval = 1.04–1.28, P < 0.01). Receiver operating characteristic curve analysis suggested that serum SP concentration had the same calibrating power as SOFA and PCIS in discriminating the risk of death of children.
Serum SP concentration was associated with severity in children with TBI, and extremely high levels indicated a poor prognosis.
Potential role of serum substance P as a favorable biomarker of functional outcome in acute spontaneous intracerebral hemorrhage
2020, Clinica Chimica Acta
Citation Excerpt :
In 2015, a multicenter, observational, prospective study of 100 patients with severe traumatic brain injury showed that serum SP concentrations were associated with injury severity and 30-day mortality [9]. In 2019, another clinical study recruited 124 patients with an isolated severe traumatic brain injury and determined serum SP concentrations at days 1, 4, and 8 after head trauma and subsequently found that elevated serum SP concentrations during the first week of head trauma had a powerful ability for predicting posttraumatic 30-day mortality [10]. In a study regarding ischemic stroke, which included patients with malignant middle cerebral artery infarction and a Glasgow Coma Scale score lower than 9, multiple regression analysis revealed an association between serum concentrations of SP higher than 362 pg/ml and mortality at 30 days after controlling for age and Glasgow Coma Scale score [11].
Substance P (SP) is implicated in brain inflammation. We clarified relationship between serum SP concentrations and functional outcome of acute intracerebral hemorrhage (ICH).
We quantified admission serum SP concentrations in 106 ICH patients. The primary outcome measure was a poor outcome at 90 days (modified Rankin Scale score ≥ 3) after onset.
Patients with a poor outcome compared with the rest had substantially higher serum SP concentrations. The area under the curve for serum SP concentrations with regard to discriminating a poor outcome was 0.795 (95% CI, 0.706 to 0.867). Serum SP concentrations >449 pg/ml predicted the risk of a poor outcome with 63.0% sensitivity and 78.9% specificity, and were independently associated with a poor outcome (odds ratio, 5.437; 95% CI, 2.156 to 13.715). There were the positive associations between serum SP concentrations, National Institutes of Health Stroke Scale score (r = 0.480), hematoma volume (r = 0.464) and serum C-reactive protein concentrations (r = 0.398).
Higher serum SP concentrations in the acute phase of ICH were intimately associated with aggravated inflammation response, rising severity and increased risk of a poor functional outcome, suggesting that serum SP could be an inflammatory prognostic factor for ICH.
Serum substance P levels and early mortality of spontaneous intracerebral haemorrhage patients
2020, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
To our knowledge, there is no other study reporting serum substance P levels during the evolution of patients with ICH to compare our findings. However, similar findings were found in the studies from our team with traumatic brain injury34 or brain infarction.35 The administration of neurokinin 1 receptor (NK1R) antagonists, therefore antagonists of receptor of substance P, have reduced brain vascular permeability, cerebral edema, intracranial pressure, and functional deficits in animal models of traumatic brain injury27–33 or cerebral ischemia.36–40
Substance P, a neuropeptide of the tachykinin family, is involved in the neuroinflammation of different diseases of the central nervous system. To our knowledge, there is no published data on the level of circulating substance P levels in the prognosis of patients with spontaneous intracerebral hemorrhage (ICH). Therefore, the objectives of this observational and prospective study were to determine whether serum substance P levels in ICH patients were associated with early mortality and whether could be used in the mortality prognostic.
We included patients with severe primary supratentorial ICH (defined as Glasgow Coma Scale < 9) from 6 Intensive Care Units of Spanish hospitals. We determined serum substance P levels at the time of severe ICH diagnosis, at fourth and at eighth day. Thirty-day mortality was considered the end-point study.
Non-surviving (n=53) compared to surviving ICH patients (n=64) showed higher serum substance P levels at day 1 (p<0.001), day 4 (p<0.001) and day 8 (p<0.001). The area under the curve for 30-day mortality prediction by serum substance P levels was of 79% (95% CI = 70–86%; p<0.001). Kaplan–Meier analysis showed a higher 30-day mortality in patients with serum substance P levels>503 pg/mL (Hazard ratio=14.7; 95% CI=6.88–31.55; p<0.001). Multiple logistic regression analysis showed an association between serum substance P levels and 30-day mortality (Odds Ratio=1.006; 95% CI=1.002–1.010; p=0.004) controlling for ICH score, midline shift, glycemia, early evacuation of ICH.
Thus, the novel aspects our study include that serum substance P levels in severe primary ICH patients were higher in non-surviving than in surviving patients, that serum substance P levels were associated with early mortality controlling for other variables, and that serum substance P levels could be used as biomarkers of prognosis.

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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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Original ArticlePersistently High Serum Substance P Levels and Early Mortality in Patients with Severe Traumatic Brain Injury

Background

Methods

Results

Conclusions

Introduction

Section snippets

Design and Subjects

Results

Discussion

Conclusions

Neurotherapeutics

Prog Brain Res

Lancet

Eur J Pharmacol

Neuropeptides

Neuroscience

Int J Biochem Cell Biol

Blood

Blood

Guidelines for the management of severe traumatic brain injury

J Neurotrauma

Cytokine responses in severe traumatic brain injury: where there is smoke, is there fire?

Neurocrit Care

The role of inflammation in CNS injury and disease

Br J Pharmacol

Tachykinins and the cardiovascular system

Curr Drug Targets

Tachykinins and tachykinin receptors: structure and activity relationships

Curr Med Chem

Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors

Curr Drug Targets

Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury

Molecules

The role of tachykinins in central nervous system inflammatory responses

Front Biosci

The role of neurogenic inflammation in blood-brain barrier disruption and development of cerebral oedema following acute central nervous system (CNS) injury

Int J Mol Sci

Original Article
Persistently High Serum Substance P Levels and Early Mortality in Patients with Severe Traumatic Brain Injury