Role of Adiponectin Receptor 1 in Promoting Nitric Oxide-Mediated Flow-Induced Dilation in the Human Microvasculature.

Chronic administration of exogenous adiponectin restores nitric oxide (NO) as the mediator of flow-induced dilation (FID) in arterioles collected from patients with coronary artery disease (CAD). Here we hypothesize that this effect as well as NO signaling during flow during health relies on activation of Adiponectin Receptor 1 (AdipoR1). We further posit that osmotin, a plant-derived protein and AdipoR1 activator, is capable of eliciting similar effects as adiponectin. Human arterioles (80-200 µm) collected from discarded surgical adipose specimens were cannulated, pressurized, and pre-constricted with endothelin-1 (ET-1). Changes in vessel internal diameters were measured during flow using videomicroscopy. Immunofluorescence was utilized to compare expression of AdipoR1 during both health and disease. Administration of exogenous adiponectin failed to restore NO-mediated FID in CAD arterioles treated with siRNA against AdipoR1 (siAdipoR1), compared to vessels treated with negative control siRNA. Osmotin treatment of arterioles from patients with CAD resulted in a partial restoration of NO as the mediator of FID, which was inhibited in arterioles with decreased expression of AdipoR1. Together these data highlight the critical role of AdipoR1 in adiponectin-induced NO signaling during shear. Further, osmotin may serve as a potential therapy to prevent microvascular endothelial dysfunction as well as restore endothelial homeostasis in patients with cardiovascular disease.

Left Anterior Thoracotomy Minimally Invasive Aortic Valve Replacement Following Left Pneumonectomy.

We report the case of a 59-year-old man referred for aortic valve replacement for severe, symptomatic aortic insufficiency who underwent a minimally invasive left anterior thoracotomy aortic valve replacement. This approach was facilitated by his history of a left pneumonectomy for lung cancer 7 years prior to presentation, which resulted in a significant left mediastinal shift. The cannulation strategy and exposure were analogous to what would be expected from a standard right anterior thoracotomy minimally invasive aortic valve replacement. The minimally invasive approach allowed for early extubation and mobilization in a patient with moderate baseline pulmonary dysfunction.

Cardiac Surgery and Postoperative Renal Allograft Failure.

BACKGROUND: Although cardiac surgery among renal allograft recipients is relatively safe, less is known about the impact of cardiac surgery on the functioning renal allograft. This study assessed postoperative renal failure among renal transplant recipients undergoing cardiac surgery. METHODS: The study population was identified by matching medical record numbers from the United Network for Organ Sharing Kidney Transplant Database to a cardiovascular surgery database and The Society of Thoracic Surgeons Adult Cardiac Surgery Database for the authors' institution from January 1992 through August 2018. RESULTS: One hundred seventy-nine renal transplant recipients with a functioning allograft underwent cardiac surgery a mean of 6.4 ± 5.6 years after renal transplantation. Thirty (17.6%) of the 170 patients either died or had allograft failure during the first postoperative year. Receiver-operating characteristics curve analysis using Cox regression demonstrated an optimal cutoff point for preoperative serum creatinine predicting postoperative allograft loss is 1.9 mg/dL (hazard ratio 3; 95% confidence interval, 1.5 to 6.9) with a model C statistic of 0.642. CONCLUSIONS: The current study affirms findings in the literature that cardiac surgery in renal transplant recipients carries acceptable perioperative morbidity and mortality. Renal transplant recipients who underwent cardiac surgery had a constant hazard of renal allograft loss similar to that of the general transplant population. A preoperative serum creatinine value greater than 1.9 mg/dL increases the risk for long-term renal allograft loss after cardiac surgery.

Compartment syndrome performance improvement project is associated with increased combat casualty survival.

BACKGROUND: In 2008, we showed that incomplete or delayed extremity fasciotomies were associated with mortality and muscle necrosis in war casualties with limb injury. Subsequently, we developed an education program focused on surgeon knowledge gaps regarding the diagnosis of compartment syndrome and prophylactic fasciotomy. The program included educational alerts, classroom training, video instruction, and a research publication. We compared casualty data before and after the program implementation to determine whether the education altered outcomes. METHODS: Similar to the previous study, a case series was made from combat casualty medical records. Casualties were US military servicemen with fasciotomies performed in Iraq, Afghanistan, or Germany between two periods (periods 1 and 2). RESULTS: In both periods, casualty demographics were similar. Most fasciotomies were performed to the lower leg and forearm. Period 1 had 336 casualties with 643 fasciotomies, whereas Period 2 had 268 casualties with 1,221 fasciotomies (1.9 vs. 4.6 fasciotomies per casualty, respectively; p < 0.0001). The mortality rate decreased in Period 2 (3%, 8 of 268 casualties) from Period 1 (8%, 26 of 336 casualties; p = 0.0125). Muscle excision and major amputation rates were similar in both periods (p > 0.05). Rates of casualties with revision fasciotomy decreased to 8% in Period 2, (22 of 268 casualties) versus 15% in Period 1 (51 of 336 casualties; p = 0.009). CONCLUSION: Combat casualty care following implementation of a fasciotomy education program was associated with improved survival, higher fasciotomy rates, and fewer revisions. Because delayed fasciotomy rates were unchanged, further effort to educate providers may be indicated. LEVEL OF EVIDENCE: Therapeutic study, level IV.

An experience in the management of the open abdomen in severely injured burn patients.

Few descriptions of temporary abdominal closure for planned relaparotomy have been reported in burned patients. The purpose of this study is to describe our experience and outcomes in the management of burned patients with an open abdomen. The authors performed a retrospective review of all admissions to our burn center from March 2003 to June 2008, identifying patients treated by laparotomy with temporary abdominal closure. The authors collected data on patient demographics, indication for laparotomy, methods of temporary and definitive abdominal closure, and outcomes. Of 2,104 patients admitted, 38 underwent a laparotomy with temporary abdominal closure. Their median TBSA was 55%, and the incidence of inhalation injury was 58%. Abdominal compartment syndrome was the most common indication for laparotomy (82%) followed by abdominal trauma (16%). The in-hospital mortality associated with an open abdomen was 68%. Temporary abdominal closure was performed most commonly using negative pressure wound therapy (90%). Fascial closure was performed in 21 patients but was associated with a 38% rate of failure requiring reexploration. Of 12 survivors, fascial closure was achieved in seven patients and five were managed with a planned ventral hernia. Burned patients who necessitate an open abdomen management strategy have a high morbidity and mortality. Fascial closure was associated with a high rate of failure but was successful in a select group of patients. Definitive abdominal closure with a planned ventral hernia was associated with no increased mortality and remains an option when "tension-free" fascial closure cannot be achieved.

Differential expression of the immunoinflammatory response in trauma patients: burn vs. non-burn.

RATIONALE: Cytokines are central mediators of the immune-inflammatory response to injury and subsequent multiple organ dysfunction syndrome (MODS). Although previous studies evaluated cytokine levels after trauma, differences between patients with burn and non-burn trauma have not been assessed systematically. METHODS: A prospective database of trauma patients admitted between May 2004 and September 2007 to the burn or surgical intensive care units within 24 h of injury with an anticipated stay of at least 72 h was analyzed. Sequential clinical and laboratory parameters were collected in the first week, including multiplex analysis data for plasma levels of inflammatory cytokines (IL-6, and IL-8). Patients with known pre-injury coagulopathy were excluded. A Marshall score of 10 or greater was defined as MODS. RESULTS: A total of 179 patients were enrolled (67 burn and 112 non-burn). Plasma IL-6 and IL-8 levels were markedly elevated in both burn and non-burn patients compared to healthy volunteers. Burn subjects had higher levels of IL-6 and IL-8 than the non-burn on days 1 through 7 after injury. Subjects with burns and at least 30% total body surface area were older and had a lower injury severity score, a higher prevalence of MODS, and correspondingly higher mortality. Multivariate analysis of injury type, MODS, and time did not demonstrate an influence of MODS. CONCLUSIONS: Burns were associated with a greater and more sustained immune-inflammatory response than non-burn trauma as evidenced by elevated plasma IL-6 and IL-8 levels during the first week. There was no association between MODS and plasma cytokine levels.

Impact of improved combat casualty care on combat wounded undergoing exploratory laparotomy and massive transfusion.

BACKGROUND: Studies have shown decreased mortality after improvements in combat casualty care, including increased fresh frozen plasma (FFP):red blood cell (RBC) ratios. The objective was to evaluate the evolution and impact of improved combat casualty care at different time periods of combat operations. METHODS: A retrospective review was performed at one combat support hospital in Iraq of patients requiring both massive transfusion (≥ 10 units RBC in 24 hours) and exploratory laparotomy. Patients were divided into two cohorts based on year wounded: C1 between December 2003 and June 2004, and C2 between September 2007 and May 2008. Admission data, amount of blood products and fluid transfused, and 48 hour mortality were compared. Statistical significance was set at p < 0.05. RESULTS: There was decreased mortality in C2 (47% vs. 20%). Patients arrived warmer with higher hemoglobin. They were transfused more RBC and FFP in the emergency department (5 units ± 3 units vs. 2 units ± 2 units; 3 units ± 2 units vs. 0 units ± 1 units, respectively) and received less crystalloid in operating room (3.3 L ± 2.2 L vs. 8.5 L ± 4.9 L). The FFP:RBC ratio was also closer to 1:1 in C2 (0.775 ± 0.32 vs. 0.511 ± 0.21). CONCLUSIONS: The combination of improved prehospital care, trauma systems approach, performance improvement projects, and improved transfusion or resuscitation practices have led to a 50% decrease in mortality for this critically injured population. We are now transfusing blood products in a ratio more consistent with 1 FFP to 1 RBC. Simultaneously, crystalloid use has decreased by 61%, all of which is consistent with hemostatic resuscitation principles.

Clot-inducing minerals versus plasma protein dressing for topical treatment of external bleeding in the presence of coagulopathy.

BACKGROUND: Previous studies identified WoundStat (WS, smectite) and Combat Gauze (CG, kaolin-coated gauze) as the most effective available agents for controlling arterial bleeding with potential utility in casualty care. Tissue sealant properties of WS suggested its potential advantage over clot-promoting CG for treating coagulopathic bleeding. This study compared the efficacy of CG and WS with a fibrinogen-based (FAST) dressing to control bleeding in coagulopathic animals. METHODS: Coagulopathy was induced in pigs (n = 55, 35 kg) by ∼50% isovolemic hemodilution and hypothermia (core temperature, 33°C ± 0.5°C). A 6-mm arteriotomy was made in the femoral artery and free bleeding allowed for 30 seconds. A test agent (n = 13-15 per group) or control product (gauze, GZ, n = 12) was applied to the wounds and compressed with a Kerlix gauze for 2 minutes. Fluid resuscitation was given, titrated to a mean arterial pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Angiography using the computed tomography method was performed on survivors, and local tissues were collected for histology. RESULTS: No differences were seen in baseline measures. Coagulopathy, confirmed by a 31% increase in prothrombin time and a 28% reduction in clotting strength (maximum amplitude, thrombelastography assay), was similar in all groups before injury. The average pretreatment blood loss was 11.9 mL/kg ± 0.4 mL/kg with no difference among groups. Posttreatment blood loss, however, was significantly different (p = 0.015) ranging from 18.2 mL/kg ± 8.8 mL/kg (FAST) to 63.3 mL/kg ± 10.2 mL/kg (GZ controls). Stable hemostasis was achieved in 10 of 13 (FAST), 5 of 15 (CG), 2 of 15 (WS), and 1 of 12 (GZ) animals in each group, resulting in significantly different survival rates (8-77%; p = 0.001). The average survival times were 145 (FAST), 119 (CG), 75 (WS), and 74 (GZ) minutes for different groups (p < 0.002). The outcomes with the FAST dressing were significantly better than with WS or GZ in this coagulopathic bleeding model. Essentially, no difference was found between WS and GZ control. Computed tomography images showed limited blood flow only through the vessels treated with FAST dressings. Histologic observations of the vessels indicated minimal damage with FAST and CG and greater injury with WS with some residues present on the tissues. CONCLUSION: The tissue sealant property of WS is apparently mediated by clot formation in the wound; therefore, it was ineffective under coagulopathic conditions. CG was partially effective in maintaining blood pressure up to 1 hour after application. FAST dressing showed the highest efficacy because of the exogenous delivery of concentrated fibrinogen and thrombin to the wound, which bypasses coagulopathy and secures hemostasis.

Impact of policy change on US Army combat transfusion practices.

BACKGROUND: Clinical practice guidelines (CPGs) are used to keep providers up-to-date with the most recent literature and to guide in decision making. Adherence is typically improved although many have a muted impact. In March 2006, the US Army issued a damage control resuscitation CPG, encouraging 1:1 plasma:red blood cell (RBC) transfusions and limiting crystalloid use. The objective of this study was to determine whether the CPG was associated with a change in the transfusion practices in combat-wounded patients. METHODS: All US service members injured in Operation Iraqi Freedom/Operation Enduring Freedom who received massive transfusions (MTs; > or = 10 RBC in 24 hours) were queried from the US Army Institute of Surgical Research transfusion database. Whole blood, when used, was counted as 1 unit of RBC, fresh frozen plasma (FFP), and platelet. Subjects were divided into pre- and post-CPG cohorts. Primary outcomes were ratios of FFP:RBC and crystalloid use. RESULTS: A total of 777 MT patients were identified. The cohorts were similar in age (25 years +/- 6 years vs. 25 years +/- 6 years; p = ns) and injury severity scale score (24 +/- 12 vs. 25 +/- 12; p = ns). The post-CPG cohort was warmer (96.5 degrees F +/- 7.8 degrees F vs. 98.2 degrees F +/- 1.9 degrees F; p < 0.05) and was transfused more RBC, platelets, and plasma but received less crystalloid (17 units +/- 12 units vs. 19 units +/- 11 units, 1 unit +/- 2 units vs. 2 units +/- 3 units, 8 units +/- 8 units vs. 14 units +/- 11 units, 14 L +/- 14 L vs. 9 L +/- 13 L, respectively; p < 0.05). The post-CPG cohort also received a higher ratio transfusion (0.5 +/- 0.31 vs. 0.8 +/- 0.31; p < 0.05) representing a change in practice. Overall mortality was not different between the two groups (24 vs. 19%; p = 0.115). CONCLUSIONS: MT patients are now receiving a higher FFP:RBC ratio and less crystalloid after implementation of the CPG. Additionally, patients are now presenting normothermic and have higher hemoglobin levels. All of these changes are consistent with the principles of damage control resuscitation. Changes in practice were associated with implementation of the CPG, maturity of the battlefield, and increased availability of products.

Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine.

BACKGROUND: In 2007, a potent procoagulant mineral called WoundStat (WS), consisting of smectite granules, received clearance from the Food and Drug Administration for marketing in the United States for temporary treatment of external hemorrhage. Previously, we found that microscopic WS particles remained in the injured vessels that were treated, despite seemingly adequate wound debridement. Thus, we investigated the thromboembolic risk of using WS when compared with kaolin-coated gauze, Combat Gauze (CG); or regular gauze, Kerlix (KX) to treat an external wound with vascular injuries in pigs. METHODS: The right common carotid artery and external jugular vein of pigs were isolated and sharply transected (50%). After 30 seconds of free bleeding, the neck wounds were packed with WS, CG, or KX and compressed until hemostasis was achieved (n = 8 per group). Wounds were debrided after 2 hours, and vascular injuries were primarily repaired with suture. Blood flow was restored after infusing 1 L of crystalloid (no heparin or aspirin) and the wounds were closed. Two hours later, computed tomographic angiography was performed, and the wounds were reopened to harvest the vessels. The brains and lungs were recovered for gross and microscopic examination after euthanasia. RESULTS: No differences were found in baseline measurements. Thrombelastography showed similar hypercoagulability of the final blood samples when compared with baselines in all groups. All vessels treated with KX or CG were patent and had no thrombus or blood clot in their lumen. In contrast, seven of eight carotid arteries and six of eight jugular veins treated with WS developed large occlusive red thrombi and had no flow. Small clots and WS residues were also found in the lungs of two pigs. Histologically, significant endothelial and transmural damage was seen in WS-treated vessels with luminal thrombi and embedded WS residues. CONCLUSION: WS granules caused endothelial injury and significant transmural damage to the vessels that render them nonviable for primary surgical repair. The granules can enter systemic circulation and cause distal thrombosis in vital organs. More relevant in vitro and in vivo safety tests should be required for clearance of new hemostatic agents.