Christian Shults

Reproducibility of an Animal Model Simulating Complex Combat-Related Injury in a Multiple-Institution Format

We developed a complex combat-relevant model of abdominal and extremity trauma, hemorrhagic shock, hypothermia, and acidosis. We then simulated injury, preoperative, and operative phases. We hypothesized that this model is reproducible and useful for randomized multicenter preclinical trials. Yorkshire swine were anesthetized, intubated, and instrumented. They then underwent femur fracture, 60% total blood volume hemorrhage, a 30-min shock period, induced hypothermia to 33°C, and hemorrhage volume replacement with 3:1 isotonic sodium chloride solution (NS) at each of three centers. Hemodynamic parameters were measured continuously. Thromboelastography, arterial blood gas, and laboratory values were collected at baseline, after the shock period, and after NS replacement. Thirty-seven animals were used for model development. Eight (21%) died before completion of the study period. Twenty-nine survivors were included in the analysis. MAP (±SEM) after the shock period was 32 ± 2 mmHg and was similar between centers (P = 0.4). Mean pH, base deficit, and lactate levels were 7.29 ± 0.02, 8.20 ± 0.65 mmol/L, and 5.29 ± 0.44 mmol/L, respectively, after NS replacement. These were similar between centers (P > 0.05). Prothrombin time values increased significantly over time at all centers, reflecting a progressive coagulopathy (P < 0.02). Thromboelastography maximum amplitude values were similar among centers (P > 0.05) and demonstrated progressively weakened platelet interaction over time (P < 0.03). Hematocrit was similar after controlled hemorrhage (P = 0.15) and dilution (P = 0.9). The pH, lactate, base deficit, and coagulation tests reflect a severely injured state. A complex porcine model of polytrauma and shock canbe used for multi-institutional study with excellent reproducibility. A consistent severe injury profile was achieved, afterwhich experimental interventions can be applied. This is the first report of a reproducible multicenter trauma and resuscitation-related animal model.

Cell protective mechanism of valproic acid in lethal hemorrhagic shock

BACKGROUND We have demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve animal survival after hemorrhagic shock and protect neurons from hypoxia-induced apoptosis. This study investigated whether VPA treatment works through the beta-catenin survival pathways. METHODS Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss) followed by treatment with or without VPA (300 mg/kg). Brains were harvested after 1, 6, and 24 hours and analyzed for acetylated histone-H3 at lysine-9 (Ac-H3K9), acetylated and total beta-catenin, and Bcl-2 by Western blot. In addition, primary neurons dissociated from E18 rat embryos were exposed to hypoxia (0.5% O(2)) for 16 hours with or without VPA (1 mmol/L) and analyzed using confocal microscopy. RESULTS After treatment of hemorrhaged animals with VPA, acetylated beta-catenin was found in both the cytosol and nucleus, along with Ac-H3K9. Bcl-2 transcript increased after 1 hour followed by an increase in Bcl-2 protein at 6 hours. Confocal imaging demonstrated that after VPA treatment, beta-catenin translocated into the nucleus and colocalized with Ac-H3K9. CONCLUSION VPA treatment acetylates H3K9 and beta-catenin and enhances translocation of beta-catenin into the nucleus, where it colocalizes with Ac-H3K9 and stimulates the transcription of survival gene bcl-2. This finding suggests that VPA protects cells after severe insult through the beta-catenin survival pathway.

Putting life on hold-for how long? Profound hypothermic cardiopulmonary bypass in a Swine model of complex vascular injuries.

BACKGROUND Rapid induction of profound hypothermia for emergency preservation and resuscitation can improve survival from uncontrolled lethal hemorrhage in large animal models. We have previously demonstrated that profound hypothermia (10 degrees C) must be induced rapidly (2 degrees C/min) and reversed gradually (0.5 degrees C/min) for best results. However, the maximum duration of hypothermic arrest in a clinically relevant trauma model remains unknown. METHODS Uncontrolled lethal hemorrhage was induced in 22 swine by creating an iliac artery and vein injury, followed 30 minutes later (simulating transport time) by laceration of the descending thoracic aorta. Through a thoracotomy approach, a catheter was placed in the aorta, and cold organ preservation solution was infused using a roller pump to rapidly induce profound hypothermia (10 degrees C) which was maintained with low-flow cardiopulmonary bypass. Vascular injuries were repaired during the asanguinous hypothermic low flow period. Profound hypothermia was maintained (n = 10-12 per group) for either 60 minutes or 120 minutes. After repair of injuries, animals were rewarmed (0.5 degrees C/min) and resuscitated on cardiopulmonary bypass, and whole blood was infused during this period. Animals were monitored for 4 weeks for neurologic deficits, organ dysfunction, and postoperative complications. RESULTS The 4-week survival rates in 60- and 120-minute groups were 92% and 50%, respectively (p < 0.05). The surviving animals were neurologically intact and had no long-term organ dysfunction, except for one animal in the 120-minute group. The animals subjected to 120 minutes of hypothermia had significantly worse lactic acidosis, displayed markedly slower recovery, and had significantly higher rates of postoperative complications, including late deaths because of infections. CONCLUSION In a model of lethal injuries, rapid induction of profound hypothermia can prevent death. Profound hypothermia decreases but does not abolish metabolism. With current methods, the upper limit of hypothermic arrest in the setting of uncontrolled hemorrhage is 60 minutes.

Impact of Pre-Procedural Serum Albumin Levels on Outcome of Patients Undergoing Transcatheter Aortic Valve Replacement

Risk assessment for transcatheter aortic valve replacement (TAVR) patients is challenging, and surgical scores do not optimally correlate with outcome. The aim of this study was to assess the correlation between serum albumin and survival of patients with symptomatic severe aortic stenosis undergoing TAVR. Patients with severe aortic stenosis who underwent TAVR were categorized into 2 groups according to low and normal preprocedural serum albumin (<3.5 and ≥3.5 g/dl, respectively). The all-cause mortality rates at hospital discharge, at 30-day and 1-year follow-up were compared across the groups. Additionally, a Cox proportional-hazards model was generated to assess the independent effect of serum albumin at 1-year follow-up. Among 567 consecutive patients who underwent TAVR, 476 (84%) had documented preprocedural serum albumin measurements. Of these, 50% had low serum albumin levels, and 50% had normal serum albumin levels. Baseline and procedural characteristics, including age, gender, and transapical access, were similar among the groups. Prevalence of left ventricular ejection fraction<40% was higher in patients with low albumin (29% vs 20%, p=0.02), and risk assessment according to Society of Thoracic Surgeons score tended to be higher in the low-albumin group (10±4.7 vs 9.4±4.4, p=0.09). Patients presenting with low albumin had higher in-hospital mortality (11% vs 5%), as well as at 30-day (12% vs 6%, p=0.01) and 1-year (29% vs 19%, p=0.02) follow-up. Serum albumin was independently associated with 1-year mortality (adjusted hazard ratio per 0.1 g/dl decrease 1.64, 95% confidence interval 2.50 to 1.75, p=0.02), along with body mass index<20 kg/m2 (hazard ratio 1.89, 95% confidence interval 3.33 to 1.75, p=0.03). In conclusion, preprocedural serum albumin level and low body mass index are independently associated with mortality in patients who undergo TAVR. Patients with severe aortic stenosis and low albumin levels should undergo careful evaluation before and after TAVR.

Impact of transfemoral versus transapical access on mortality among patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

OBJECTIVE To compare early and late mortality of transfemoral (TF) and transapical (TA) transcatheter aortic valve replacement (TAVR) patients and assess predictors for mortality. BACKGROUND Studies have shown conflicting results regarding impact of access on outcome in severe aortic stenosis (AS) patients undergoing TAVR. METHODS AS patients undergoing TAVR between May 2007-December 2014 were included. Baseline demographic, clinical, and imaging parameters were compared according to access, and landmark analysis models were generated to assess outcomes and associated factors. RESULTS Among 648 severe AS patients undergoing TAVR, TF was used in 516 and TA in 132. Baseline characteristics between groups demonstrated lower body mass index, higher STS score, and rate of peripheral vascular disease among TA patients. Procedural complications were more common in the TA group, especially major bleeding (15% vs. 6%, p<0.001) and acute kidney injury >1 (8% vs. 1.4%, p<0.001). Landmark analysis demonstrated higher cumulative mortality rates at 30days among TA than TF patients (log-rank p<0.001), with similar mortality after 30days and up to 1-year (13% in both log-rank p=0.64). In a multivariate model, TA was an independent predictor of early mortality (HR=4.55 95% CI [12.5-1.6], p=0.003) along with pulmonary artery systolic pressure>60mmHg (HR=3.08 95% CI [7.37-1.29], p=0.01) and residual aortic regurgitation severity above mild (HR=3.99 95% CI [10.2-1.56], p=0.004). CONCLUSIONS Patients undergoing TAVR via TA have higher adjusted early mortality and similar late mortality rates compared to TF, despite higher risk profile.

Impact of Functional Versus Organic Baseline Mitral Regurgitation on Short- and Long-Term Outcomes After Transcatheter Aortic Valve Replacement

The impact of the specific etiology of mitral regurgitation (MR) on outcomes in the transcatheter aortic valve replacement (TAVR) population is unknown. This study aimed to evaluate the longitudinal changes in functional versus organic MR after TAVR in addition to their impact on survival. Consecutive patients who underwent TAVR from May 2007 to May 2015 who had baseline significant (moderate or greater) MR were included. Transthoracic echocardiography was used to evaluate the cohort at baseline, post-procedure, 30-day, 6-month, and 1-year follow-up. The primary outcomes included mortality at 30 days and 1 year. Longitudinal, mixed-model regression analyses were performed to assess the differences in the magnitude of longitudinal changes of MR, left ventricular (LV) ejection fraction, and New York Heart Association functional class. Seventy patients (44% men, mean 83 years) with moderate or greater MR at baseline (30 functional vs 40 organic) were included, with the functional group having a statistically significant mean younger age and higher rates of previous coronary artery bypass grafting. Kaplan-Meier cumulative mortality rates were similar: 30 days (10% vs 17.5%, unadjusted log-ranked p = 0.413) and 1 year (29.4% vs 23.2%, unadjusted log-ranked p = 0.746) in the functional versus organic MR groups, respectively. There were greater degrees of short- and long-term improvement in MR severity (slope difference p = 0.0008), LV ejection fraction (slope difference p = 0.0009), and New York Heart Association class (slope difference p = 0.0054) in the functional versus organic group. In conclusion, patients with significant functional versus organic MR who underwent TAVR have similar short- and long-term survival; nevertheless, those with a functional origin are more likely to have significant improvements in MR severity, LV-positive remodeling, and functional class. These findings may help strategize therapies for MR in patients with combined aortic and mitral valve disease who are undergoing TAVR.

The versatility of transapical access: Will it lead to a completely new approach to valvular therapy?

Historically, the treatment of aortic stenosis (AS) has been open aortic valve replacement (AVR) utilizing cardiopulmonary bypass (SAVR) via either a median sternotomy or minimally invasive techniques. These techniques have produced durable results with low morbidity and acceptable long-term survival (1). However, at least 30% of patients with severe symptomatic aortic stenosis do not undergo surgical replacement of the aortic valve, due to advanced age, left ventricular dysfunction, or the presence of multiple coexisting conditions (2). In an effort to provide a practical alternative and mitigate risk in this elderly, frail population, transcatheter strategies of aortic valve replacement have been developed. In 2002, Cribier performed the first transcatheter aortic valve replacement (TAVR) through a transvenous, transeptal technique (3). In the subsequent decade, TAVR has evolved and is currently being performed primarily via a retrograde transfemoral (TF), a direct left ventricular transapical (TA), or direct transaortic (TAo) techniques. Most programs have established a femoral-first approach to TAVR, reserving the TA approach for patients with severe, lesion-limiting aortoilliac disease. Transaortic AVR has recently gained traction with more sites utilizing this procedure with either an upper partial mini-median sternotomy or right lateral thoracotomy. However, with the advent of the SAPIEN XT and the Esheath technology (Edwards Lifescience, Irvine, CA), the percentage of patients able to receive TF TAVR will increase. This article will evaluate the role of the transapical approach by evaluating the indications (both before and after the development of the SAPIENXT valve) for and outcomes following TA-TAVR. It will also evaluate the established and theoretical advantages of a TA approach, as well as the unique aspects of the TA access that could facilitate new approaches to valvular therapies even beyond the aortic valve.

Transapical Thoracic Endovascular Aortic Repair as a Bridge to Open Repair of an Infected Ascending Aortic Pseudoaneurysm.

Pseudoaneurysms of the ascending aorta pose a significant risk for free rupture during open aortic repair. This report describes the use of a modified thoracic aortic stent graft, delivered through transapical access, as a successful bridge to homograft replacement of the ascending aorta for the treatment of a mycotic ascending aortic pseudoaneurysm.

Use of an ePTFE-covered nitinol self-expanding stent graft for the treatment off pre-closure device failure during transcatheter aortic valve replacement

OBJECTIVES Our aim was to describe our experience with the use of an ePTFE-covered nitinol self-expanding stent graft (GORE® VIABAHN® Endoprosthesis, Gore Medical, USA) placed in the common femoral artery for the treatment of suture-mediated pre-closure device failure following transcatheter aortic valve replacement (TAVR). BACKGROUND Access site-related vascular complications (VC) following sheath removal related to pre-closure device failure during TAVR are common and treatment options may vary. METHODS We performed an observational study on a series of consecutive patients who underwent TAVR between 2013 and 2015. RESULTS Included were 25 patients at a mean (±SD) age of 82±9. Failure of the closure device resulted in overt bleeding in 19 patients, dissection or no flow in 5 patients, and angiographic pseudoaneurysm in 1. Overall 29 stents were deployed with diameters ranging from 8 to 11mm and a length of 50mm (26, 90%). All stent-graft deployments achieved complete hemostasis of the arteriotomy site and resulted in normal flow to the distal vessels. None of the patients required open surgical repair. The mean hemoglobin drop was 2.6±1.3g/dl. Blood transfusions were used in 15 (60%) patients. Acute kidney injury occurred in 4 (16%) patients, none of whom was treated with dialysis. Length of hospital stay was 9±5days. All patients survived during a 30-day follow-up period, and none had VC related to the stented site. CONCLUSIONS The use of an ePTFE-covered Nitinol self-expanding stent graft is a feasible, safe, and effective treatment modality for access site-related VC following TAVR. SUMMARY The use of an ePTFE-covered nitinol self-expanding stent graft placed in the common femoral artery for the treatment of suture-mediated pre-closure device failure following transcatheter aortic valve replacement (TAVR) is described in 25 patients. Its use was found to be feasible, safe, and an effective treatment modality for access site-related vascular complications following TAVR.

Utility of an additive frailty tests index score for mortality risk assessment following transcatheter aortic valve replacement

Background: The impact of frailty assessment on outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) remains unclear. Our aim was to evaluate the individual effect of each frailty test and the utility of an additive frailty index score on short‐ and long‐term survival following TAVR. Methods: Retrospective analysis of consecutive TAVR patients for whom a complete set of frailty tests was obtained: algorithm defined grip strength and 5‐m walking tests, body mass index <20 kg/m2, Katz activities of daily living ≤4/6, serum albumin <3.5 g/dL. Frailty status was defined as having 3 or more positive frailty tests. Included were 498 patients with a mean age of 82 ± 8 years. Results: Frailty status, observed in 266 (53%) patients, was associated with both 30‐day and 1‐year mortality (6% vs. 2%, P = .016; 20% vs. 9%, P < .001; within the respective frailty groups). As compared to 0–2 frailty criteria, a higher frailty index score was associated with increased risk of death at 1 year (OR 2.23; 95% CI 1.14–4.34; P = .019 and OR 3.30; 95% CI 1.36–8.00; P = .008 for 3 and 4–5 frailty criteria met, respectively). In Cox regression analysis, frailty status was correlated with 1‐year mortality (HR = 2.2; 95%CI 1.25–3.96; P = .007), and a higher frailty index was associated with increased mortality risk (HR = 2.0; 95% CI 1.08–3.7; P = .027; and HR = 3.07; 95% CI 1.4–6.7; P = .005; for any 3, and 4–5 frailty criteria, respectively). Conclusions: Frailty status and a higher frailty index score were associated with increased 1‐year mortality risk following TAVR.