Nicotinic acetylcholine receptor-mediated protection of the rat heart exposed to ischemia reperfusion.

Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically alpha-7 subtype (α7nAChR) in the myocardium remains unknown which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure, and rates of pressure development without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconatine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion, reduced infarct size by 42% (p<0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p<0.01). Flow cytometry of MitoTracker Red stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21 treated compared to untreated I/R hearts. Intracellular ATP concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p<0.001), but significantly increased to normoxic levels with GTS21 treatment, and this was abrogated by MLA pretreatment. Activation of stress-activated kinases, JNK and p38MAPK, were significantly reduced by GTS21 in I/R. We conclude that targeting myocardial 17nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size.

Chest wall stabilization in a patient with severe TBI: A case report.

INTRODUCTION AND IMPORTANCE: Flail chest is a serious complication that may arise secondary to thoracic trauma and is associated with increased morbidity and mortality. In a flail chest, paradoxical chest movement decreases the functional residual capacity, leading to hypoxia, hypercapnia, and atelectasis. Adequate ventilation, fluid and pain management have classically been the cornerstones to flail chest treatment, with operative fixation being utilized in specific cases. Traumatic brain injury (TBI) has historically been believed to be an absolute contraindication for surgical fixation of rib fractures (SSRF); however, emerging studies have shown a favorable prognosis in select patients who underwent SSRF with severe TBI (Glasgow Coma Scale ≤8). CASE PRESENTATION: A 66-year-old male was brought into the Emergency Department by EMS following a traumatic injury that resulted in multiple rib fractures, spinal fractures, and traumatic brain injury. On hospital day 3, the patient underwent SSRF to repair bilateral flail chest. SSRF stabilized cardiopulmonary physiology, improving this patient's hospital course and avoiding the need for a tracheostomy. Herein, we report the successful use of SSRF in a flail chest patient with severe TBI that improved outcomes without evidence of secondary brain injury. CLINICAL DISCUSSION: TBI is a severe condition that often presents with other injuries. Chest wall injuries (CWI) with concurrent TBI remain a significant challenge for clinicians as one set of injuries may exacerbate the other [10]. Through respiratory physiology and predisposition to pneumonia, CWI may lead to prolonged cerebral hypoxia resulting in secondary brain injury-worsening severe TBI. SSRF improves outcomes in polytrauma patients exhibiting CWI with TBI. CONCLUSION: Surgical management of rib fractures has an essential role in select patients with severe TBI. Further research is warranted to improve our understanding of the complex interplay between the physiology of respiratory mechanics and the neurologic system in the trauma population suffering from TBI.

Surgical Infection Society-Chest Wall Injury Society Recommendations for Management of Surgical Site or Implant-Related Infections After Surgical Stabilization of Traumatic Rib or Sternal Fractures.

Background: Surgical stabilization of rib fractures (SSRF) and surgical stabilization of sternal fractures (SSSF) involves open reduction and internal fixation of fractures with an implantable titanium plate to restore and maintain anatomic alignment. The presence of this foreign, non-absorbable material presents an opportunity for infection. Although surgical site infection (SSI) and implant infection rates after SSRF and SSSF are low, they present a challenging clinical entity. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee and Chest Wall Injury Society's Publication Committee convened to develop recommendations for management of SSIs or implant-related infections after SSRF or SSSF. PubMed, Embase, Web of Science and the Cochrane database were searched for pertinent studies. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: For patients undergoing SSRF or SSSF who develop an SSI or an implant-related infection, there is insufficient evidence to suggest a single optimal management strategy. For patients with an SSI, systemic antibiotic therapy, local wound debridement, and vacuum-assisted closure have been used in isolation or combination. For patients with an implant-related infection, initial implant removal with or without systemic antibiotic therapy, systemic antibiotic therapy with local wound drainage, and systemic antibiotic therapy with local antibiotic therapy have been documented. For patients who do not undergo initial implant removal, 68% ultimately require implant removal to achieve source control. Conclusions: Insufficient evidence precludes the ability to recommend guidelines for the treatment of SSI or implant-related infection following SSRF or SSSF. Further studies should be performed to identify the optimal management strategy in this population.

Surgical Infection Society Guidelines for Total Abdominal Colectomy versus Diverting Loop Ileostomy with Antegrade Intra-Colonic Lavage for the Surgical Management of Severe or Fulminant, Non-Perforated Clostridioides difficile Colitis.

Background: Clostridioides difficile infection (CDI) can result in life-threatening illness requiring surgery. Surgical options for managing severe or fulminant, non-perforated C. difficile colitis include total abdominal colectomy with end ileostomy or creation of a diverting loop ileostomy with antegrade vancomycin lavage. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee convened to develop guidelines for summarizing the current SIS recommendations for total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for severe or fulminant, non-perforated C. difficile colitis. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Severe infection was defined as laboratory diagnosis of C. difficile infection with leukocytosis (white blood cell count of ≥15,000 cells/mL) or elevated creatinine (serum creatinine level >1.5 mg/dL). Fulminant infection was defined as laboratory diagnosis of C. difficile infection with hypotension or shock, ileus, or megacolon. Perforation was defined as complete disruption of the colon wall. Total abdominal colectomy was defined as resection of the ascending, transverse, descending, and sigmoid colon with end ileostomy. For the purpose of the guideline, the terms subtotal colectomy, total abdominal colectomy, and rectal-sparing total colectomy were used interchangeably. Diverting loop ileostomy with antegrade enema was defined as creation of both a diverting loop ileostomy with intra-operative colonic lavage and post-operative antegrade vancomycin unless otherwise specified. Evaluation of the published evidence was performed using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: We recommend that total abdominal colectomy be the procedure of choice for definitive therapy of severe or fulminant, non-perforated C. difficile colitis. In select patients, colon preservation using diverting loop ileostomy with intra-colonic vancomycin may be associated with higher rates of ostomy reversal and restoration of gastrointestinal continuity but may lead to development of recurrent C. difficile colitis. Conclusions: This guideline summarizes the current Surgical Infection Society recommendations regarding use of total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for adults with severe or fulminant, non-perforated C. difficile infection.

Right ventricular myocardial energetic model for evaluating right heart function in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) increases right ventricular (RV) workload and decreases myocardial oxygen reserve, eventually leading to poor cardiac output. This study created and assessed a novel model of RV work output based on RV hemodynamics and oxygen supply, allowing new insight into causal mechanisms of RV dysfunction. METHODS: The RV function model was built upon an earlier, left ventricular model and further adjusted for more accurate clinical use. The model assumes that RV total power output (1) is the sum of isovolumic and stroke power and (2) is linearly related to its right coronary artery oxygen supply. Thus, when right coronary artery flow is limited or isovolumic power is elevated, less energy is available for producing cardiac output. The original and adjusted models were validated via data from patients with idiopathic PAH (n = 14) and large animals (n = 6) that underwent acute pulmonary banding with or without hypoxia. RESULTS: Both models demonstrated strong, significant correlations between RV oxygen consumption rate and RV total power output for PAH patients (original model, R2  = 0.66; adjusted model, R2  = 0.78) and sheep (original, R2  = 0.85; adjusted, R2  = 0.86). Furthermore, the models demonstrate a significant inverse relationship between required oxygen consumption and RV efficiency (stroke power/total power) (p < 0.001). Lastly, higher NYHA class was indicative of lower RV efficiency and higher oxygen consumption (p = 0.013). CONCLUSION: Right ventricular total power output can be accurately estimated directly from pulmonary hemodynamics and right coronary perfusion during PAH. This model highlights the increased vulnerability of PAH patients with compromised right coronary flow coupled with high afterload.

Surgical Infection Society: Chest Wall Injury Society Recommendations for Antibiotic Use during Surgical Stabilization of Traumatic Rib or Sternal Fractures to Reduce Risk of Implant Infection.

Background: Surgical stabilization of rib fractures is recommended in patients with flail chest or multiple displaced rib fractures with physiologic compromise. Surgical stabilization of rib fractures (SSRF) and surgical stabilization of sternal fractures (SSSF) involve open reduction and internal fixation of fractures with a plate construct to restore anatomic alignment. Most plate constructs are composed of titanium and presence of this foreign, non-absorbable material presents opportunity for implant infection. Although implant infection rates after SSRF and SSSF are low, they present a challenging clinical entity often requiring prolonged antibiotic therapy, debridement, and potentially implant removal. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee and Chest Wall Injury Society's Publication Committee convened to develop recommendations for antibiotic use during and after surgical stabilization of traumatic rib and sternal fractures. Clinical scenarios included patients with concomitant infectious processes (sepsis, pneumonia, empyema, cellulitis) or sources of contamination (open chest, gross contamination) incurred as a result of their trauma and present at the time of their surgical stabilization. PubMed, Embase, and Cochrane databases were searched for pertinent studies. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: For patients undergoing SSRF or SSSF in the absence of pre-existing infectious process, there is insufficient evidence to suggest existing peri-operative guidelines or recommendations are inadequate. For patients undergoing SSRF or SSSF in the presence of sepsis, pneumonia, or an empyema, there is insufficient evidence to provide recommendations on duration and choice of antibiotic. This decision may be informed by existing guidelines for the concomitant infection. For patients undergoing SSRF or SSSF with an open or contaminated chest there is insufficient evidence to provide specific antibiotic recommendations. Conclusions: This guideline document summarizes the current Surgical Infection Society and Chest Wall Injury Society recommendations regarding antibiotic use during and after surgical stabilization of traumatic rib or sternal fractures. Limited evidence exists in the chest wall surgical stabilization literature and further studies should be performed to delineate risk of implant infection among patients undergoing SSSRF or SSSF with concomitant infectious processes.

In vivo testing of a novel blood pump for short-term extracorporeal life support.

BACKGROUND: Centrifugal pumps are used increasingly for temporary mechanical support for the treatment of cardiogenic shock. However, centrifugal pumps can generate excessive negative pressure and are afterload sensitive. A previously developed modified roller pump mitigates these limitations both in vitro and in preliminary animal experiments. We report the results of intermediate-term testing of our evolving pump technology, known as the BioVAD. METHODS: The BioVAD was implanted in 6 adult male sheep (62.5±3.9 kg), with drainage from the left atrium and reinfusion into the descending aorta. The sheep were monitored for 5 days. Heparin was given during the initial implantation, but no additional anticoagulants were given. Data collected included hemodynamic status, pump flow and pressures, laboratory values to monitor end-organ function and hemolysis, pathologic specimens to evaluate for thromboembolic events and organ ischemia, and explanted pump evaluation results. RESULTS: All animals survived the planned experimental duration and there were no pump malfunctions. Mean BioVAD flow was 3.57±0.30 L/min (57.1 mL/kg/min) and mean inlet pressure was -30.51±4.25 mm Hg. Laboratory values, including plasma free hemoglobin, creatinine, lactate, and bilirubin levels, remained normal. Three animals had small renal cortical infarcts, but there were no additional thromboembolic events or other abnormalities seen on pathologic examination. No thrombus was identified in the BioVAD blood flow path. CONCLUSIONS: The BioVAD performed well for 5 days in this animal model of temporary left ventricular assistance. Its potential advantages over centrifugal pumps may make it applicable for short-term mechanical circulatory support.