Unlocking the Untapped Potential of Endothelial Kinase and Phosphatase Involvement in Sepsis for Drug Treatment Design

Sepsis is a devastating clinical condition that can lead to multiple organ failure and death. Despite advancements in our understanding of molecular mechanisms underlying sepsis and sepsis-associated multiple organ failure, no effective therapeutic treatment to directly counteract it has yet been established. The endothelium is considered to play an important role in sepsis. This review highlights a number of signal transduction pathways involved in endothelial inflammatory activation and dysregulated endothelial barrier function in response to sepsis conditions. Within these pathways – NF-κB, Rac1/RhoA GTPases, AP-1, APC/S1P, Angpt/Tie2, and VEGF/VEGFR2 – we focus on the role of kinases and phosphatases as potential druggable targets for therapeutic intervention. Animal studies and clinical trials that have been conducted for this purpose are discussed, highlighting reasons why they might not have resulted in the expected outcomes, and which lessons can be learned from this. Lastly, opportunities and challenges that sepsis and sepsis-associated multiple organ failure research are currently facing are presented, including recommendations on improved experimental design to increase the translational power of preclinical research to the clinic

Does low angiopoietin-1 predict adverse outcome in sepsis?

Endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multiorgan dysfunction syndrome. The endothelial-specific angiopoietin (Ang)/Tie2 ligand-receptor system has been identified recently as a nonredundant regulator of endothelial responsiveness. Ang-1 is a Tie2 agonist and promotes endothelial stabilization and quiescence, whereas Ang-2 is a Tie2 antagonist and promotes endothelial activation, destabilization, and inflammation. While the mediator function of both Ang-1 and Ang-2 has been well established in preclinical research, only Ang-2 has been identified as a clinically useful biomarker in the critical care arena. In the previous issue of Critical Care, Mankhambo and colleagues report on angiogenic factors in Malawian children with severe bacterial infection. Among those children, diminished levels of the vessel-protective factor Ang-1 remained a significant predictor of outcome after multivariate adjustment. Whether low Ang-1 represents an important risk factor of adverse outcome in critically ill adults remains to be seen

Intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients:A narrative review of past, present, and future steps

BACKGROUND AND OBJECTIVE: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. In this narrative review, we aim to provide a comprehensive overview of current insights into intra-abdominal pressure monitoring, intra-abdominal hypertension, and abdominal compartment syndrome. The focus of this review is on the pathophysiology, risk factors and outcome of intra-abdominal hypertension and abdominal compartment syndrome, and on therapeutic strategies, such as non-operative management, surgical decompression, and management of the open abdomen. Finally, future steps are discussed, including propositions of what a future guideline should focus on. CONCLUSIONS: Pathological intra-abdominal pressure is a continuum ranging from mild intra-abdominal pressure elevation without clinically significant adverse effects to substantial increase in intra-abdominal pressure with serious consequences to all organ systems. Intra-abdominal pressure monitoring should be performed in all patients at risk of intra-abdominal hypertension. Although continuous intra-abdominal pressure monitoring is feasible, this is currently not standard practice. There are a number of effective non-operative medical interventions that may be performed early in the patient's course to reduce intra-abdominal pressure and decrease the need for surgical decompression. Abdominal decompression can be life-saving when abdominal compartment syndrome is refractory to non-operative treatment and should be performed expeditiously. The objectives of open abdomen management are to prevent fistula and to achieve delayed fascial closure at the earliest possible time. There is still a lot to learn and change. The 2013 World Society of Abdominal Compartment Syndrome guidelines should be updated and multicentre studies should evaluate the effect of intra-abdominal hypertension treatment on patient outcome

Immediate sonography and intervention in blunt chest trauma:A case report

Cardiac tamponade is a leading cause of death in blunt thoracic trauma. Ultrasound improved the recognition of cardiac tamponade and therefore has a vital role in acute critical situations in the Emergency Department and in the Intensive Care Unit. Besides recognition of cardiac tamponade, treatment protocols are important. In trauma patients with hemodynamic stable cardiac tamponade, time should be taken for a proper workup for an explorative sternotomy. In hemodynamic unstable trauma patients, the pericardium should be drained, and fluid resuscitation should be performed followed by emergency sternotomy. In this case report we describe a blunt thoracic trauma victim, a 28-year-old male patient without any medical history. He suffered from the unique combination of a tear in the left atrial appendage and a papillary muscle rupture of the right ventricle because of blunt thoracic trauma. Transthoracic echocardiography revealed massive pericardial effusion with diastolic collapse of the right ventricle in our patient. Due to his hemodynamic situation, the patient was brought into the OR for immediate sternotomy and cardiac repair. The patient made a full recovery, was discharged home, and is back to work. This case report emphasizes the relevance of early recognition and treatment of cardiac tamponade in blunt thoracic trauma victims and suggests a multidisciplinary management strategy.</p