Igor Voskresensky

Early prediction of massive transfusion in trauma: Simple as ABC (Assessment of Blood Consumption)?

BACKGROUND Massive transfusion (MT) occurs in about 3% of civilian and 8% of military trauma patients. Although many centers have implemented MT protocols, most do not have a standardized initiation policy. The purpose of this study was to validate previously described MT scoring systems and compare these to a simplified nonlaboratory dependent scoring system (Assessment of Blood Consumption [ABC] score). METHODS Retrospective cohort of all level I adult trauma patients transported directly from the scene (July 2005 to June 2006). Trauma-Associated Severe Hemorrhage (TASH) and McLaughlin scores calculated according to published methods. ABC score was assigned based on four nonweighted parameters: penetrating mechanism, positive focused assessment sonography for trauma, arrival systolic blood pressure of 90 mm Hg or less, and arrival heart rate > or = 120 bpm. Area under the receiver operating characteristic curve (AUROC) used to compare scoring systems. RESULTS Five hundred ninety-six patients were available for analysis; and the overall MT rate of 12.4%. Patients receiving MT had higher TASH (median, 6 vs. 13; p < 0.001), McLaughlin (median, 2.4 vs. 3.4; p < 0.001) and ABC (median, 1 vs. 2; p < 0.001) scores. TASH (AUROC = 0.842), McLaughlin (AUROC = 0.846), and ABC (AUROC = 0.842) scores were all good predictors of MT, and the difference between the scores was not statistically significant. ABC score of 2 or greater was 75% sensitive and 86% specific for predicting MT (correctly classified 85%). CONCLUSIONS The ABC score, which uses nonlaboratory, nonweighted parameters, is a simple and accurate in identifying patients who will require MT as compared with those previously published scores.

TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer.

Purpose: Activation of the epidermal growth factor receptor (EGFR) requires cell surface cleavage of EGFR ligands, uptake of soluble ligand by the receptor, and initiation of EGFR tyrosine kinase activity. We define these collective events as the EGFR axis. Transforming growth factor-α (TGF-α) and amphiregulin are two EGFR ligands that are delivered preferentially to the basolateral surface of polarized epithelial cells where the EGFR resides. TACE/ADAM-17 (tumor necrosis factor-α converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-α and amphiregulin. Experimental Design: Using a human polarizing colorectal cancer (CRC) cell line, HCA-7, and a tissue array of normal colonic mucosa and primary and metastatic CRC, we determined the intracellular localization of TACE and the effects of EGFR axis inhibition in CRC. Results: Herein, we show that TACE is localized to the basolateral plasma membrane of polarized HCA-7 cells. TACE is overexpressed in primary and metastatic CRC tumors compared with normal colonic mucosa; the intensity of its immunoreactivity is inversely correlated with that of TGF-α and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selective TACE inhibitor results in concentration-dependent decreases in cell proliferation and active, phosphorylated mitogen-activated protein kinase. Combining suboptimal concentrations of these agents results in cooperative growth inhibition, increased apoptosis, and reduced mitogen-activated protein kinase pathway activation. Furthermore, an EGFR tyrosine kinase–resistant clone of HCA-7 cells is growth-inhibited by combined monoclonal antibody and TACE inhibition. Conclusion: These results implicate TACE as a promising target of EGFR axis inhibition in CRC.

MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia

Nanopolyplexes formulated from a pH-responsive, endosomolytic polymer with a peptide inhibitor of MAPKAP kinase 2 block inflammatory and migratory signaling in vascular smooth muscle cells and prevent intimal hyperplasia in human saphenous vein grafts. Nano keeps MK2 inhibitor intact, on-target A peptide, currently in clinical trials, that can penetrate cells and block the activity of MAPKAP kinase 2 (MK2) may be able to stop inflammation and fibrosis after vein grafting, but it has low bioavailability and is degraded easily once inside the cell. To more effectively translate this inhibitory peptide, called MK2i, Evans et al. formulated it in electrostatically complexed nanoparticles—nanopolyplexes—for delivery to vascular cells and tissues. The MK2i nanopolyplexes were taken up readily by vascular smooth muscle cells and endothelial cells in human saphenous veins and significantly inhibited neointima formation ex vivo. In rabbit vein grafts, treatment with the MK2 nanopolyplexes prevented intimal hyperplasia for 1 month after transplant; by contrast, free MK2i peptide had no effect. Thus, complexing the MK2 inhibitor peptide with an endosomolytic polymer could improve long-term graft patency. Both treatments were able to block macrophage recruitment and/or signaling in vivo, possibly leading to less inflammation. In human saphenous veins, the MK2i nanopolyplexes similarly reduced proinflammatory cytokines and were also shown to reduce vascular smooth muscle cell migration. Such new insights into the effects of MK2i on intimal hyperplasia could open doors to new therapeutic options in this multifactorial disease. Furthermore, this nanoencapsulation approach could be broadly applied to other therapeutic cell-penetrating peptides to prolong bioavailability and enhance stability in vivo. Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)–activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3′,5′-monophosphate) element–binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i–treated grafts. The decrease in IH in MK2i-NP–treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.

Neonatal carotid repair at ECMO decannulation: patency rates and early neurologic outcomes

PURPOSE Neonates placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) undergo either carotid repair or ligation at decannulation. Study aims were to evaluate carotid patency rates after repair and to compare early neurologic outcomes between repaired and ligated patients. METHODS A retrospective study of all neonates without congenital heart disease (CHD) who had VA-ECMO between 1989 and 2012 was completed using our institutional ECMO Registry. Carotid patency after repair, neuroimaging studies, and auditory brainstem response (ABR) testing at time of discharge were examined. RESULTS 140 neonates were placed on VA-ECMO during the study period. Among survivors, 84% of carotids repaired and imaged remained patent at last study. No significant differences were observed between infants in the repaired and ligated groups regarding diagnosis, ECMO duration, or length of stay. A large proportion (43%) developed a severe brain lesion after VA-ECMO, but few failed their ABR testing. Differences in early neurologic outcomes between the two groups of survivors were not significant. CONCLUSIONS At this single institution, carotid patency is excellent following repair at ECMO decannulation. No increased incidence of severe brain lesions or greater neurosensory impairment in the repair group was observed. Further studies are needed to investigate the effects of ligation on longer-term neurocognitive outcomes.

Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia

BACKGROUND Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. METHODS Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. RESULTS FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. CONCLUSIONS Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV.

Emergency airway management in critically injured patients: A survey of U.S. aero-medical transport programs

OBJECTIVE Pre-hospital airway management represents the intervention most likely to impact outcomes in critically injured patients. As such, airway management issues dominate quality improvement (QI) reviews of aero-medical programs. The purpose of this study was to evaluate current practice patterns of airway management in trauma among U.S. aero-medical service (AMS) programs. METHODS The Association of Air Medical Services (AAMS) Resource Guide from 2005 to 2006 was utilized to identify the e-mail addresses of all directors of U.S. aero-medical transport programs. Program directors from 182 U.S. aero-medical programs were asked to participate in an anonymous, web-based survey of emergency airway management protocols and practices. Non-responders to the initial request were contacted a second time by e-mail. RESULTS 89 programs responded. 98.9% have rapid sequence intubation (RSI) protocols. 90% use succinylcholine, 70% use long-acting neuromuscular blockers (NMB) within their RSI protocol. 77% have protocols for mandatory in-flight sedation but only 13% have similar protocols for maintenance paralytics. 60% administer long-acting NMB immediately after RSI, 13% after confirmation of neurological activity. Given clinical scenarios, however, 97% administer long-acting NMB to patients with scene and in-flight Glasgow Coma Scale (GCS) of 3, even for brief transport times. CONCLUSIONS The majority of AMS programs have well defined RSI and in-flight sedation protocols, while protocols for in-flight NMB are uncommon. Despite this, nearly all programs administer long-acting NMB following RSI, irrespective of GCS or flight time. Given the impact of in-flight NMB on initial assessment, early intervention, and injury severity scoring, a critical appraisal of current AMS airway management practices appears warranted.

Role of the Renin–Angiotensin System in the Pathogenesis of Intimal Hyperplasia: Therapeutic Potential for Prevention of Vein Graft Failure?

The saphenous vein remains the most widely used conduit for peripheral and coronary revascularization despite a high rate of vein graft failure. The most common cause of vein graft failure is intimal hyperplasia. No agents have been proven to be successful for the prevention of intimal hyperplasia in human subjects. The renin-angiotensin system is essential in the regulation of vascular tone and blood pressure in physiologic conditions. However, this system mediates cardiovascular remodeling in pathophysiologic states. Angiotensin II is becoming increasingly recognized as a potential mediator of intimal hyperplasia. Drugs modulating the renin-angiotensin system include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs are powerful inhibitors of atherosclerosis and cardiovascular remodeling, and they are first-line agents for management of several medical conditions based on class I evidence that they delay progression of cardiovascular disease and improve survival. Several experimental models have demonstrated that these agents are capable of inhibiting intimal hyperplasia. However, there are no data supporting their role in prevention of intimal hyperplasia in patients with vein grafts. This review summarizes the physiology of the renin-angiotensin system, the role of angiotensin II in the pathogenesis of cardiovascular remodeling, the medical indications for these agents, and the experimental data supporting an important role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia.

Limiting Injury During Saphenous Vein Graft Preparation For Coronary Arterial Bypass Prevents Metabolic Decompensation

Standard harvest and preparation of human saphenous vein (HSV) for autologous coronary and peripheral arterial bypass procedures is associated with injury and increased oxidative stress that negatively affect graft performance. In this study we investigated the global metabolomic profiles of HSV before (unprepared; UP) and after standard vein graft preparation (AP). AP-HSV showed impaired vasomotor function that was associated with increased oxidative stress, phospholipid hydrolysis and energy depletion that are characteristic of mechanical and chemical injury. A porcine model (PSV) was utilized to validate these metabolomic changes in HSV and to determine the efficacy of an improved preparation technique (OP) using pressure-regulated distension, a non-toxic vein marker, and graft storage in buffered PlasmaLyte solution in limiting metabolic decompensation due to graft preparation. Deficits in vasomotor function and metabolic signature observed in AP-PSV could be largely mitigated with the OP procedure. These findings suggest that simple strategies aimed at reducing injury during graft harvest and preparation represents a straightforward and viable strategy to preserve conduit function and possibly improve graft patency.