Cerebrospinal Fluid Markers of Brain Injury, Inflammation, and Blood-Brain Barrier Dysfunction in Cardiac Surgery

Reinsfelt, Björn; Ricksten, Sven‐Erik; Zetterberg, Henrik; Blennow, Kaj; Fredén-Lindqvist, Johan; Westerlind, A.

doi:10.1016/j.athoracsur.2012.04.044

Cited by 100 publications

(96 citation statements)

References 33 publications

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“…The time course is not surprising, given that the vast majority ([ 80%) of measurable microemboli are generated at the point of aortic cross-clamp release. 42 Although we did not observe a difference in activated platelets between the placebo and lidocaine groups in our current study, we did observe a significant difference in platelet-monocyte conjugate levels. P-selectin is a platelet marker that is rapidly expressed but is also rapidly internalized, accounting for its transient expression on activated platelets.…”

Section: Discussioncontrasting

confidence: 40%

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial

Klinger

Cooter

Berger

et al. 2016

Can J Anesth/J Can Anesth

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Purpose Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates. Methods We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized doubleblinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus ? 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and plateletleukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration. Results Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates. Conclusion While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964). RésuméObjectif Le dysfonctionnement cognitif postopératoire (DCPO) constitue une complication fréquente après une A list of all members of the Neurologic Outcome Research Group is given in the Appendix.

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Section: Discussioncontrasting

confidence: 40%

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial

Klinger

Cooter

Berger

et al. 2016

Can J Anesth/J Can Anesth

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“…[9][10][11][12] In patients, inflammatory molecules such as TNF-a and interleukins appear in CSF within 12 hours after major surgery. 4,[13][14][15] Although such clinical observations are in line with a series of experimental studies, 2,3,8 the time course pattern beyond the immediate postsurgery phase of immune activation within the human CNS is unknown, and how the systemic pro-and anti-inflammatory response [16][17][18] is associated with cognitive performance is largely unexplored.…”

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confidence: 78%

The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and longterm impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [ 11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [ 11 C]PBR28 binding of 26 6 26% (mean 6 standard deviation) at 3 to 4 days postoperatively compared to baseline (p 5 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 6 39%) on the 3rd to 4th postoperative day, corresponding to changes in [ 11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [ 11 C]PBR28 binding (p 5 0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. ANN NEUROL 2017;81:572-582 A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that ultimately reaches and activates the intrinsic immune system of the brain. [1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning,...

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“…In patients undergoing aortic valve replacement, S100B and GFAP increased, possibly because cardiac surgery with cardiopulmonary bypass may cause cerebral inflammation, glial cell injury, and blood-brain barrier (BBB) dysfunction without biochemical signs of neuronal damage. 30 Children with sickle cell disease (SCD) had higher plasma GFAP than did healthy pediatric controls, and GFAP among children with SCD may be associated with subclinical brain injury. 31 NSE and S100B can be released into serum during operations by extracranial sources, and although assessment of neurocognitive decline after surgery has been hampered by heterogeneous testing techniques, GFAP may be a sensitive marker whose extracranial sources are antigenically different from the brain-derived form.…”

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confidence: 99%

GFAP-BDP as an Acute Diagnostic Marker in Traumatic Brain Injury: Results from the Prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study

Okonkwo

Yue

Puccio

et al. 2013

Journal of Neurotrauma

184

120

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Reliable diagnosis of traumatic brain injury (TBI) is a major public health need. Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system, and breakdown products (GFAP-BDP) are released following parenchymal brain injury. Here, we evaluate the diagnostic accuracy of elevated levels of plasma GFAP-BDP in TBI. Participants were identified as part of the prospective Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. Acute plasma samples (< 24 h post-injury) were collected from patients presenting with brain injury who had CT imaging. The ability of GFAP-BDP level to discriminate patients with demonstrable traumatic lesions on CT, and with failure to return to pre-injury baseline at 6 months, was evaluated by the area under the receiver operating characteristic curve (AUC). Of the 215 patients included for analysis, 83% had mild, 4% had moderate, and 13% had severe TBI; 54% had acute traumatic lesions on CT. The ability of GFAP-BDP level to discriminate patients with traumatic lesions on CT as evaluated by AUC was 0.88 (95% confidence interval [CI], 0.84-0.93). The optimal cutoff of 0.68 ng/mL for plasma GFAP-BDP level was associated with a 21.61 odds ratio for traumatic findings on head CT. Discriminatory ability of unfavorable 6 month outcome was lower, AUC 0.65 (95% CI, 0.55-0.74), with a 2.07 odds ratio. GFAP-BDP levels reliably distinguish the presence and severity of CT scan findings in TBI patients. Although these findings confirm and extend prior studies, a larger prospective trial is still needed to validate the use of GFAP-BDP as a routine diagnostic biomarker for patient care and clinical research. The term ''mild'' continues to be a misnomer for this patient population, and underscores the need for evolving classification strategies for TBI targeted therapy. (ClinicalTrials.gov number NCT01565551; NIH Grant 1RC2 NS069409)

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Cerebrospinal Fluid Markers of Brain Injury, Inflammation, and Blood-Brain Barrier Dysfunction in Cardiac Surgery

Cited by 100 publications

References 33 publications

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial

The immune response of the human brain to abdominal surgery

GFAP-BDP as an Acute Diagnostic Marker in Traumatic Brain Injury: Results from the Prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study

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