The role of the endothelium as a mediator of critical illness
Endothelium was once thought to be an inert organ. However, it plays an important role in multiple functions. These include coagulation, inflammation and determination of vascular permeability. He then gives a brief overview of the endothelial arrangement, function of the glycocalyx layer and how an injury causing a loss of the protective layer results in holes in the endothelium. The inflammatory cells enter via these holes and causes oedema in the affected organs leading to multiple pathologies. Danny then explains the role of endothelium in controlling cell barrier function. Activation of cortactin protein and the myosin light-chain kinase (MLCK) enzymes activate stress fibres resulting in pulling of endothelial cells thereby increasing its permeability. Danny discusses the role of endothelial dysfunction in acute respiratory distress syndrome (ARDS) at macrovascular, microvascular and molecular levels. Macrovascular thrombosis is related to an increase in severity of ARDS, pulmonary hypertension, and mortality. At a microvascular level there is a loss of vascularity and increased blood vessel thickness. At a microscopic level, endothelial cells appear swollen and damaged in ARDS. Endothelial dysfunction drives organ dysfunction and mortality. Changes in various endothelial markers like increased von Willebrand factor (vWF), decreased protein C and increased pulmonary dead space correlate with increased mortality. Studies show that endothelial dysfunction is a more specific and sensitive method to predict mortality of critically ill patients when compared to SOFA score, SAPS 2 score and WCC. Danny discusses ventilator strategies for endothelial cells in ARDS patients. Lowering the tidal volume of ventilators and employing recruitment manoeuvres are such strategies. Both of these cause a decrease in oedema by reducing endothelial permeability. He then shares the various potential pharmacological treatments for treating endothelial damage. These include statins and spingosine-1-phosphate (S1P). Different studies on the effect of statins in ARDS show contradicting result. However, targeted therapies can be designed by studying the phenotypes and molecular basis of ARDS in each patient. The role of the endothelium as a mediator of critical illness by Danny McAuley Finally, for more like this, head to our podcast page. #CodaPodcast
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (20)
Similar to The role of the endothelium as a mediator of critical illness
Similar to The role of the endothelium as a mediator of critical illness (20)
More from SMACC Conference
More from SMACC Conference (20)
Recently uploaded
Recently uploaded (20)
The role of the endothelium as a mediator of critical illness
- 1. What you need to know about the endothelium (and why is it important for my patient?) Danny McAuley @dfmcauley Royal Victoria Hospital and Queen’s University of Belfast SMACC Dublin June 2016
- 2. • Endothelial injury and the pathogenesis of ARDS • Improving endothelial function What you need to know about the endothelium
- 3. Giving a talk on the endothelium at SMACC #Ilovetheendothelium
- 4. Giving a talk on the endothelium at SMACC
- 5. Giving a talk on the endothelium at SMACC
- 6. Giving a talk on the endothelium at SMACC
- 7. Giving a talk on the endothelium at SMACC
- 8. Cecilia O’Kane Endothelial dysfunction and ARDS Gap A B Endothelial Paracellular Gap Formation In Vivo Scanning EM Alveolar oedema Respiratory failure Endothelium Epithelium Vessel lumen Alveoli LPS LPS vWF/Ang-2 RAGE SP-D Cytokines Proteases Glycocalyx
- 9. Actin/Myosin contraction Barrier dysfunction Barrier integrity Cellular adhesion αβ Integrin Adherens junction Cadherin Focal adhesion assembly/ disassembly αβ Integrin Occludin ZO-1 β/γcatenin α−catenin Ca2+Actin stress fibers Myosin MLCKMLCK Cortactin Rho Kinase Regulation of lung endothelial cell barrier function Thrombin MLC phosphatase X RacRho MLCK P60src GIT1 PAX FAK Talin Vinculin Jacobson et al. AJRCMB 2004;30:662 Barrier disruption Barrier protection
- 10. Macrovascular obstruction in ARDS: detection with pulmonary angiography Green et al ARRD 1982
- 11. Microvascular obstruction and remodeling in ARDS Normal human lung capillaries Lung capillaries day 14 ARDS Zapol et al Chest, 1977; Snow et al ARRD 1982
- 12. ARDS - lung endothelial injury Bachofen and Weibel ARRD 1977
- 13. Increased plasma vWF is an independent predictor of mortality in ARDS N = 193366 DiedSurvived 800 600 400 200 0 * p < 0.0001 Baseline vWF (% control) Ware et al. AJRCCM 2004;170:766
- 14. Decreased plasma protein C is a predictor of mortality in ARDS * Protein C (% control) Survived 506 Died 272 * P < 0.0001 Wilcoxon Test 30 60 90 N = Ware et al. CCM 2007;35:1821-28
- 15. Increased pulmonary dead space fraction predicts pulmonary dysfunction 0 10 20 30 40 No post-op pulmonary complications Post-op pulmonary complications 54 20N = Norris et al. JBJS 2001;83:1162
- 16. Increased pulmonary dead space fraction is associated with mortality in ARDS 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Survivors Non-Survivors DeadSpaceFraction(Vd/Vt) ∗ Nuckton et al. NEJM 2002;346:1281
- 17. Increased pulmonary dead space fraction is associated with mortality in ARDS
- 18. Endothelial dysfunction predicts mortality in the critically ill Endothelium dysfunction SOFA score SAPS 2 score WCC Duffy et al. CCM 2011;39:269-35
- 19. • Tidal volume reduction • Recruitment maneuvres Helping endothelial cells Ventilatory strategy
- 20. Tidal volume reduction NEJM 2000;342:1301
- 21. 50 µm Low tidal volume reduces pulmonary oedema 12 ml/kg 6 ml/kg 3 ml/kg Frank et al. AJRCCM 2002;165:242
- 22. 0 2 4 6 8 * Extravascular Plasma Equivalents (µl/h) 12 ml/kg 6 ml/kg 3 ml/kg 12 ml/kg 6 ml/kg 3 ml/kg Lung Injury No Lung Injury *† * * Low tidal volume reduces endothelial permeability
- 24. Recruitment manoeuvres improve alveolar endothelial function Frank et al. CCM 2005;33:181
- 25. Helping endothelial cells Pharmacological treatment Millar et al. Thorax 2016;71:462-473
- 26. Simvastatin reduces thrombin-induced endothelial injury Jacobson et al. AJRCMB 2004;30:662
- 27. Statins in ARDS McAuley et al. NEJM 2014;371:1695-703 ARDSNet. NEJM 2014;370:3191-200
- 28. LPS Sphingosine-1-phosphate (S1P) reduces LPS-induced canine lung injury LPS + S1P Apex Base 2000 1500 1000 500 0BALprotein(mcg/ml) LPS LPS/S1P Time (min) after LPS 36060 240 ** ** McVerry et al, AJRCCM 2004;170:987
- 29. Conclusions • ARDS and other critical illness characterised by endothelial injury • Severity of endothelial injury correlates with outcome • Tidal volume reduction reduces endothelial injury • Potential novel therapeutic interventions
Editor's Notes
- Focus on ARDS
- Historically endothelial thought to be inert barrier Increasing recognised to be a metabolically active organ, influencing a variety of functions including vascular permeability, inflammation and coagulation
- Filling defects in 19 of 40 patients with ARDS Associated with 1) severity of ARDS 2) PA HTN 3) mortality
- Morphometric analysis: thrombosis, medial thickening, decreased vascular density of pre- and intra-acinar vessels
- Panel D shows a specimen of lung tissue from a patient who died early (four days) after the onset of acute lung injury; there is injury to both the capillary endothelium and the alveolar epithelium. There is an intravascular neutrophil (LC) in the capillary (C). Vacuolization and swelling of the endothelium (EN) are apparent. Loss of alveolar epithelial cells is also apparent, with the formation of hyaline membranes on the epithelial side of the basement membrane (BM*)
- Protein C levels fall in the setting of vascular endothelial dysfunction In patients with non-septic causes of ALI/ARDS (N= 25), lower plasma protein C levels were also associated with worse clinical outcomes In ALI patients without sepsis baseline plasma protein C also lower in non-survivors
- Patients undergoing intramedullary nailing of a femoral shaft fracture, VD/VT measured early (30min) post-operatively. Together these data support the hypothesis indicating vascular endothelial injury is important in the pathogenesis of ALI.
- dead-space fraction was prospectively measured in 179 intubated patients, a mean of 11 hours after ARDS independent risk factor for death: for every 0.05 increase, the odds of death increased by 45 percent
- independent risk factor for death: for every 0.05 increase, the odds of death increased by 45 percent
- 94 critically ill patients within 24 hours of admission Endothelium dysfunction was the only predictor of mortality with an adjusted odds ratio of 26 An endothelium-dependent vasodilatation value of 0.5% or less predicted ICU mortality with high sensitivity and specificity
- Increased endothelial injury associated with pulmonary dead space in acid induced lung injury If pulmonary blood flow due to vascular endothelial dysfunction is compromised to lung regions that remain well-ventilated, this results in an increase in pulmonary dead space.
- 745 patients with sepsis induced ARDS 60-day mortality primary outcome at 60 days – no difference
- Endogenous lipid growth factor sphingosine-1-phosphate (S1P) enhances barrier function through a series of mechanisms S1P and its analogues reduced vascular leakage in small and large animal lung injury models as well as decreased cytokines Clinical application of S1P and its analogues is currently limited by systemic toxicity, most notably immunosuppression prompting the use of FTY720 (an S1P analogue) in multiple sclerosis.