S100B as a biomarker of blood-brain barrier disruption after thoracoabdominal aortic aneurysm repair: a secondary analysis from a prospective cohort study.

PURPOSE: The objective of this study was to determine whether the magnitude of the peripheral inflammatory response to cardiovascular surgery is associated with increases in blood-brain barrier (BBB) permeability as reflected by changes in cerebrospinal fluid (CSF)/plasma S100B concentrations. METHODS: We conducted a secondary analysis from a prospective cohort study of 35 patients undergoing elective thoracoabdominal aortic aneurysm repair with (n = 17) or without (n = 18) cardiopulmonary bypass (CPB). Plasma and CSF S100B, interleukin-6 (IL-6), and albumin concentrations were measured at baseline (C0) and serially for up to five days. RESULTS: Following CPB, the median [interquartile range] plasma S100B concentration increased from 58 [32-88] pg·mL-1 at C0 to a maximum concentration (Cmax) of 1,131 [655-1,875] pg·mL-1 over a median time (tmax) of 6.3 [5.9-7.0] hr. In the non-CPB group, the median plasma S100B increased to a lesser extent. There was a delayed increase in CSF S100B to a median Cmax of 436 [406-922] pg·mL-1 in the CPB group at a tmax of 23.7 [18.5-40.2] hr. In the non-CPB group, the CSF concentrations were similar at all time points. In the CPB group, we did not detect significant correlations between plasma and CSF S100B with plasma IL-6 [r = 0.52 (95% confidence interval [CI], -0.061 to 0.84)] and CSF IL-6 [r = 0.53 (95% CI, -0.073 to 0.85)] concentrations, respectively. Correlations of plasma or CSF S100B levels with BBB permeability were not significant. CONCLUSION: The lack of parallel increases in plasma and CSF S100B following CPB indicates that S100B may not be a reliable biomarker for BBB disruption after thoracoabdominal aortic aneurysm repair employing CPB. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00878371); registered 7 April 2009.

RéSUMé: OBJECTIF: L'objectif de cette étude était de déterminer si l'intensité de la réponse inflammatoire périphérique à la chirurgie cardiovasculaire était associée à une augmentation de la perméabilité de la barrière hémato-encéphalique (BHE), telle que reflétée par des changements dans les concentrations de S100B dans le liquide céphalorachidien (LCR) et le plasma. MéTHODE: Nous avons mené une analyse secondaire à partir d'une étude de cohorte prospective portant sur 35 patients bénéficiant d'une réparation élective d'un anévrisme aortique thoraco-abdominal avec (n = 17) ou sans (n = 18) circulation extracorporelle (CEC). Les concentrations plasmatiques et dans le LCR de S100B, d'interleukine-6 (IL-6) et d'albumine ont été mesurées au départ (C0) et en série jusqu'à cinq jours. RéSULTATS: Après la CEC, la concentration médiane [écart interquartile] plasmatique de S100B est passée de 58 [32­88] pg·mL-1 au départ (C0) à une concentration maximale (Cmax) de 1131 [655­1875] pg·mL-1 sur une période médiane (tmax) de 6,3 [5,9­7,0] h. Dans le groupe sans CEC, la concentration plasmatique médiane de S100B a augmenté dans une moindre mesure. Il y a eu une augmentation retardée de S100B dans le LCR à une Cmax médiane de 436 [406­922] pg·mL-1 dans le groupe CEC à une tmax de 23,7 [18,5­40,2] h. Dans le groupe sans CEC, les concentrations dans le LCR étaient similaires à tous les moments. Dans le groupe CEC, nous n'avons pas détecté de corrélations significatives entre la concentration de S100B dans le plasma et le LCR avec les concentrations plasmatiques d'IL-6 [r = 0,52 (intervalle de confiance [IC] à 95 %, -0,061 à 0,84)] et d'IL-6 dans le LCR [r = 0,53 (IC 95 %, -0,073 à 0,85)], respectivement. Les corrélations entre les taux plasmatiques ou dans le LCR de S100B et la perméabilité de la BHE n'étaient pas significatives. CONCLUSION: L'absence d'augmentations parallèles de la concentration de S100B dans le plasma et le LCR après la CEC indique que la S100B pourrait ne pas être un biomarqueur fiable de la perturbation de la BHE après une réparation d'anévrisme aortique thoraco-abdominal sous CEC. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00878371); enregistrée le 7 avril 2009.

Single-stage repair of contaminated hernias using a novel antibiotic-impregnated biologic porcine submucosa tissue matrix.

BACKGROUND: Single-stage repair of incisional hernias in contaminated fields has a high rate of surgical site infection (30-42%) when biologic grafts are used for repair. In an attempt to decrease this risk, a novel graft incorporating gentamicin into a biologic extracellular matrix derived from porcine small intestine submucosa was developed. METHODS: This prospective, multicenter, single-arm observational study was designed to determine the incidence of surgical site infection following implantation of the device into surgical fields characterized as CDC Class II, III, or IV. RESULTS: Twenty-four patients were enrolled, with 42% contaminated and 25% dirty surgical fields. After 12 months, 5 patients experienced 6 surgical site infections (21%) with infection involving the graft in 2 patients (8%). No grafts were explanted. CONCLUSIONS: The incorporation of gentamicin into a porcine-derived biologic graft can be achieved with no noted gentamicin toxicity and a low rate of device infection for patients undergoing single-stage repair of ventral hernia in contaminated settings. TRIAL REGISTRATION: The study was registered March 27, 2015 at www.clinicaltrials.gov as NCT02401334.

An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid.

PURPOSE: Morphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function. METHODS: We conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n = 18) or endovascular (n = 15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P < 0.017 indicated a significant correlation. RESULTS: Plasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg·mL-1 vs 29 [16-70] pg·mL-1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL-1 vs 16 [9-80] pg·mL-1, respectively; P = 0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r = -0.009; P = 0.96) or M3G (r = 0.37; P = 0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G. CONCLUSION: Morphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009.

The unrestricted global effort to complete the COOL trial.

BACKGROUND: Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL trial) ( https://clinicaltrials.gov/ct2/show/NCT03163095 ). Initially, the COOL trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of the patients allocated to the intervention (open) arm. In August 2022, the 3 M/Acelity Corporation without consultation but within the terms of the contract canceled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study. METHODS: The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or the use of the OA with an application of an NPPT dressing. Patients are eligible if they have free uncontained intraperitoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer. DISCUSSION: OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of "damage control"; however, improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL trial seeks to expand potential sites and proceed with the evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention. TRIAL REGISTRATION: National Institutes of Health ( https://clinicaltrials.gov/ct2/show/NCT03163095 ).

Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain.

OBJECTIVE: In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury. DESIGN: Observational human pharmacokinetic study. SETTING: Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center. PATIENTS: Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters. INTERVENTIONS: We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin. MEASUREMENTS AND MAIN RESULTS: Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed. CONCLUSIONS: Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.

Time required to initiate outbreak and pandemic observational research.

PURPOSE: Observational research focused upon emerging infectious diseases such as Ebola virus, Middle East respiratory syndrome, and Zika virus has been challenging to quickly initiate. We aimed to determine the duration of start-up procedures and barriers encountered for an observational study focused upon such infectious outbreaks. MATERIALS AND METHODS: At 1 pediatric and 5 adult intensive care units, we measured durations from protocol receipt to a variety of outbreak research milestones, including research ethics board (REB) approval, data sharing agreement (DSA) execution, and patient study screening initiation. RESULTS: The median (interquartile range) time from site receipt of the protocol to REB submission was 73 (30-126) days; to REB approval, 158 (42-188) days; to DSA completion, 276 (186-312) days; and to study screening initiation, 293 (269-391) days. The median time from REB submission to REB approval was 43 (13-85) days. The median time for all start-up procedures was 335 (188-335) days. CONCLUSIONS: There is a lengthy start-up period required for outbreak-focused research. Completing DSAs was the most time-consuming step. A reactive approach to newly emerging threats such as Ebola virus, Middle East respiratory syndrome, and Zika virus will likely not allow sufficient time to initiate research before most outbreaks are advanced.

Research ethics board approval for an international thromboprophylaxis trial.

BACKGROUND: Research ethics board (REB) review of scientific protocols is essential, ensuring participants' dignity, safety, and rights. The objectives of this study were to examine the time from submission to approval, to analyze predictors of approval time, and to describe the scope of conditions from REBs evaluating an international thromboprophylaxis trial. METHODS: We generated survey items through literature review and investigators' discussions, creating 4 domains: respondent and institutional demographics, the REB application process, and alternate consent models. We conducted a document analysis that involved duplicate assessment of themes from REB critique of the protocol and informed consent forms (ICF). RESULTS: Approval was granted from 65 REB institutions, requiring 58 unique applications. We analyzed 44 (75.9%) of 58 documents and surveys. Survey respondents completing the applications had 8 (5-12) years of experience; 77% completed 4 or more REB applications in previous 5 years. Critical care personnel were represented on 54% of REBs. The time to approval was a median (interquartile range) of 75 (42, 150) days, taking longer for sites with national research consortium membership (89.1 vs 31.0 days, P = .03). Document analysis of the application process and ICF yielded 5 themes: methodology, data management, consent procedures, cataloguing, and miscellaneous. Protocol-specific themes focused on trial implementation, external critiques, and budget. The only theme specific to the ICF was risks and benefits. The most frequent comments on the protocol and ICF were about methodology and miscellaneous issues; ICF comments also addressed study risks and benefits. CONCLUSIONS: More studies on methods to enhance efficiency and consistency of the REB approval processes for clinical trials are needed while still maintaining high ethical standards.