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BACKGROUND Many penetrating trauma patients in severe hemorrhagic shock receive positive pressure ventilation (PPV) upon transport to definitive care, either by intubation (INT) or bag-valve mask (BVM). Using a swine hemorrhagic shock model that simulates penetrating trauma, we proposed that severely injured patients may have better outcomes with "permissive hypoventilation," where manual breaths are not given and oxygen is administrated passively via face mask (FM). We hypothesized that PPV has harmful physiologic effects in severe low-flow states and that permissive hypoventilation would result in better outcomes. METHODS The carotid arteries of Yorkshire pigs were cannulated with a 14-gauge catheter. One group of animals (n = 6) was intubated and manually ventilated, a second received PPV via BVM (n = 7), and a third group received 100% oxygen via FM (n = 6). After placement of a Swan-Ganz catheter, the carotid catheters were opened, and the animals were exsanguinated. The primary end point was time until death. Secondary end points included central venous pressure, cardiac output, lactate levels, serum creatinine, CO2 levels, and pH measured in 10-minute intervals. RESULTS Average survival time in the FM group (50.0 minutes) was not different from the INT (51.1 minutes) and BVM groups (48.5 minutes) (p = 0.84). Central venous pressure was higher in the FM group as compared with the INT 10 minutes into the shock phase (8.3 mm Hg vs. 5.2 mm Hg, p = 0.04). Drop in cardiac output (p < 0.001) and increase in lactate (p < 0.05) was worse in both PPV groups throughout the shock phase. Creatinine levels were higher in both PPV groups (p = 0.04). The FM group was more hypercarbic and acidotic than the two PPV groups during the shock phase (p < 0.001). CONCLUSION Although permissive hypoventilation leads to respiratory acidosis, it results in less hemodynamic suppression and better perfusion of vital organs. In severely injured penetrating trauma patients, consideration should be given to immediate transportation without PPV.

BACKGROUND Prehospital intubation does not result in a survival advantage in patients experiencing penetrating trauma, yet resistance to immediate transportation to facilitate access to definitive care remains. An animal model was developed to determine whether intubation provides a survival advantage during severe hemorrhagic shock. We hypothesized that intubation would not provide a survival advantage in potentially lethal hemorrhage. METHODS After starting a propofol drip, Yorkshire pigs were intubated (n = 6) or given bag-valve mask ventilation (n = 7) using 100% oxygen. The carotid artery was cannulated with a 14-gauge catheter, and a Swan-Ganz catheter was placed under fluoroscopy using a central venous introducer. After obtaining baseline hemodynamic and laboratory data, the animals were exsanguinated through the carotid line until death. The primary end point was time until death, while secondary end points included volume of blood shed, temperature, cardiac index, mean arterial pressure, lactic acid, base excess, and creatinine levels measured in 10-minute intervals. RESULTS There was no difference in time until death between the two groups (51.1 [2.5] minutes vs. 48.5 [2.4] minutes, p = 0.52). Intubated animals had greater volume of blood shed at 30 minutes (33.6 [4.4] mL/kg vs. 28.5 [4.3] mL/kg, p = 0.03), 40 minutes (41.7 [4.7] mL/kg vs. 34.9 [3.8] mL/kg, p = 0.04), and 50 minutes (49.2 [8.6] mL/kg vs. 40.2 [1.0] mL/kg, p = 0.001). In addition, the intubated animals were more hypothermic at 40 minutes (35.5°C [0.4°C] vs. 36.7°C [0.2°C], p = 0.01) and had higher lactate levels (2.4 [0.1] mmol/L vs. 1.8 [0.4] mmol/L, p = 0.04) at 10 minutes. Cardiac index (p = 0.66), mean arterial pressure (p = 0.69), base excess (p = 0.14), and creatinine levels (p = 0.37) were not different throughout the shock phase. CONCLUSION Intubation does not convey a survival advantage in this model of severe hemorrhagic shock. Furthermore, intubation in the setting of severe hemorrhagic shock may result in a more profuse hemorrhage, worse hypothermia, and higher lactate when compared with bag-valve mask ventilation.

Objective— Laminin is a major component of the vascular basal lamina, implying that laminin receptors, such as α6β1 and α6β4 integrins, may regulate vascular remodeling and homeostasis. Previous studies in the central nervous system have shown that β4 integrin is expressed by only a fraction of cerebral vessels, but defining the vessel type and cellular source of β4 integrin has proved controversial. The goal of this study was to define the class of vessel and cell type expressing β4 integrin in cerebral vessels and to examine its potential role in vascular remodeling. Approach and Results— Dual-immunofluorescence showed that β4 integrin is expressed predominantly in arterioles, both in the central nervous system and in peripheral organs. Cell-specific knockouts of β4 integrin revealed that β4 integrin expression in cerebral vessels is derived from endothelial cells, not astrocytes or smooth muscle cells. Lack of endothelial β4 integrin had no effect on vascular development, integrity, or endothelial proliferation, but in the hypoxic central nervous system, its absence led to defective arteriolar remodeling and associated transforming growth factor–β signaling. Conclusions— These results define high levels of β4 integrin in arteriolar endothelial cells and demonstrate a novel link among β4 integrin, transforming growth factor–β signaling, and arteriolar remodeling in cerebral vessels.

Background Prehospital intubation does not appear to result in a survival advantage for patients experiencing penetrating trauma; yet, there is still resistance to the practice of "scoop and run" to speed access to advanced care. An animal model was used to determine whether intubation provides a survival advantage during potentially lethal hemorrhage. Methods The carotid arteries of Sprague-Dawley rats were cannulated, and mean arterial pressure (MAP) was measured. One group of animals (n = 10) was intubated and placed on a ventilator, whereas the other (n = 9) was administered with 100% oxygen via nose cone. Rats were exsanguinated to a MAP of 40 mm Hg and then bled periodically to maintain a MAP between 40 mm Hg and 45 mm Hg. The primary end-point was time until death. Secondary end-points included lactic acid and base excess levels measured in blood collected at 30-minute intervals after inducing shock. Results There was no significant difference in time until death between the intubated and nose cone groups (85.5 vs. 93.3 minutes, p = 0.60). Intubated animals had higher lactic acid levels at 90 minutes (6.1 vs. 3.5 mmol/L; p = 0.02) and 120 minutes (7.7 vs. 2.6 mmol/L, p = 0.03) after the initiation of shock. In addition, intubated animals had worse base excess at 90 minutes (-13.5 vs. -7.9 mmol/L, p = 0.04). Conclusion Intubation does not result in a survival advantage in this rat model of hemorrhagic shock. Positive pressure ventilation may cause decreased venous return and accentuate end-organ hypoperfusion. Large animal studies are needed to further investigate these findings.

Objective Platelet-rich concentrate (PRC) is in routine use for orthopaedic and maxilofacial surgery and is frequently combined with bone graft materials to fill bony defects and enhance healing. Numerous studies have been performed investigating the efficacy of PRC to enhance bone healing in which a variety of graft materials have been combined with varying degrees of success. Here, we sought to determine the effect of combining PRC with different graft materials on human bone marrow stromal cell (hBMSC) proliferation, osteoblastic differentiation, and bone formation. Methods Our central hypothesis is that PRC is not a true osteogenic agent but rather is osteopromotive, with cell fate determination being dependent on additional signals derived from the microenvironment. Experiments were performed with low passage (maximum 3) hBMSCs that were maintained in the presence of ascorbic acid-2-phosphate and beta-glycerol phosphate. Dexamethasone was excluded from these studies. PRC and graft materials were retained within well inserts and clotted by addition of bovine thrombin. Cell proliferation was determined by DNA content, osteoblastic commitment, and differentiation by alkaline phosphatase activity and matrix mineralization. Results Combining PRC with the graft materials increased proliferation above that seen with the graft materials alone; however, only demineralized bone matrix (DBM) and allograft were capable of increasing proliferation above that seen with PRC alone. The increased proliferation observed in the presence of PRC coincided with decreased normalized alkaline phosphatase activity, suggesting decreased osteoblastic differentiation. However, at later time points, PRC increased mineralization compared with DBM, collagen, or beta tricalcium phosphate alone. When compared with PRC alone, addition of DBM or allograft decreased mineralization. Collagen gave rise to a small increase in mineralization, whereas beta tricalcium phosphate yielded the same level of mineralization as PRC alone. Conclusions The data obtained from these in vitro investigations demonstrate that the cellular responses induced by PRC and bone graft materials in hBMSC can be significantly (positively or negatively) modified by adding the agents in combination. These in vitro data highlight the need to consider the potential interaction between biologic agents when added in combination.

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro–MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.

Objective: Vascular remodeling involves a highly coordinated break-down and build-up of the vascular basal lamina and inter-endothelial tight junction proteins. The goal of this study was to examine the role of matrix metalloproteinase-9 (MMP-9) in remodeling of cerebral blood vessels, both in hypoxia-induced angiogenesis and in the vascular pruning that accompanies the switch from hypoxia back to normoxia. Approach and Results: In a chronic mild hypoxia model of cerebrovascular remodeling, gel zymography revealed that MMP-9 levels were increased, both in the hypoxic angiogenic response and in the post-hypoxic pruning response. Compared to wild-type mice, MMP-9 KO mice showed no alteration in hypoxic-induced angiogenesis, but did show marked delay in post-hypoxic vascular pruning. In wild-type mice, vascular pruning was associated with fragmentation of vascular laminin and the tight junction protein claudin-5, while this process was markedly attenuated in MMP-9 KO mice. In vitro experiments showed that hypoxia stimulated MMP-9 expression in brain endothelial cells (BECs) but not pericytes. While immunofluorescent and flow cytometry analyses showed that hypoxia led to reduced expression of laminin and claudin-5 in wild-type BECs, this decrease was absent in MMP-9 KO BECs. Conclusions: These results show that while MMP-9 is not essential for hypoxic-induced cerebral angiogenesis, it plays an important role in post-hypoxic vascular pruning by degrading laminin and claudin-5. Our data support the concept that MMP-9 inhibition might provide therapeutic benefit in the treatment of ischemic stroke, by preventing post-hypoxic vascular pruning, thereby optimizing vascular density and integrity.

Background Stress management programs improve efficacy in aviation, military, and professional sports; however, similar educational strategies have not been adopted in surgical training. We have evaluated the effectiveness of a stress management program for surgical residents. Methods From 2011 to 2016, 137 surgical residents participated in a prospective, blinded study. The intervention group (n = 65) underwent training in self-awareness, focus, relaxation, positive self-talk, visualization, and team building. All participants subsequently completed a high-stress trauma simulation, requiring diagnosis and management of a life-threatening problem. Study endpoints included measures of procedural efficiency, and physiologic and subjective measurements of anxiety. Results Residents with stress training came to an accurate diagnosis 21% faster than controls (mean diagnosis time: 2.2 vs. 2.8 min; p = 0.04), and performed with greater technical accuracy (mean OSAT scores: 9.4 vs. 8.9; p = 0.03). Both cohorts exhibited similar physiologic and subjective anxiety metrics after simulation. Conclusions Stress management education may enhance technical performance in surgical trainees during simulation. This underscores the need for early, comprehensive stress training in surgical residency.