Gianluca Villa

Glycocalyx and sepsis-induced alterations in vascular permeability

Endothelial cells line the inner portion of the heart, blood vessels, and lymphatic vessels; a basal membrane of extracellular matrix lines the extraluminal side of endothelial cells. The apical side of endothelial cells is the site for the glycocalyx, which is a complex network of macromolecules, including cell-bound proteoglycans and sialoproteins. Sepsis-associated alterations of this structure may compromise endothelial permeability with associated interstitial fluid shift and generalized edema. Indeed, in sepsis, the glycocalyx acts as a target for inflammatory mediators and leukocytes, and its ubiquitous nature explains the damage of tissues that occurs distant from the original site of infection. Inflammatory-mediated injury to glycocalyx can be responsible for a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and hepatic dysfunction. Moreover, some markers of glycocalyx degradation, such as circulating levels of syndecan or selectins, may be used as markers of endothelial dysfunction and sepsis severity. Although a great deal of experimental evidence shows that alteration of glycocalyx is widely involved in endothelial damage caused by sepsis, therapeutic strategies aiming at preserving its integrity did not significantly improve the outcome of these patients.

Postoperative Atrial Fibrillation

Postoperative atrial fibrillation (POAF) is common among surgical patients and associated with a worse outcome. Pathophysiology of POAF is not fully disclosed, and several perioperative factors could be involved. Direct cardiac stimulation from perioperative use of catecholamines or increased sympathetic outflow from volume loss/anaemia/pain may play a role. Metabolic alterations, such as hypo-/hyperglycaemia and electrolyte disturbances, may also contribute to POAF. Moreover, inflammation, both systemic and local, may play a role in its pathogenesis. Strategies to prevent POAF aim at reducing its incidence and ameliorate global outcome of surgical patients. Nonpharmacological prophylaxis includes an adequate control of postoperative pain, the use of thoracic epidural analgesia, optimization of perioperative oxygen delivery, and, possibly, modulation of surgery-associated inflammatory response with immunonutrition and antioxidants. Perioperative potassium and magnesium depletion should be corrected. The impact of those interventions on patients outcome needs to be further investigated.

Nomenclature for renal replacement therapy in acute kidney injury: Basic principles

This article reports the conclusions of a consensus expert conference on the basic principles and nomenclature of renal replacement therapy (RRT) currently utilized to manage acute kidney injury (AKI). This multidisciplinary consensus conference discusses common definitions, components, techniques, and operations of the machines and platforms used to deliver extracorporeal therapies, utilizing a “machine-centric” rather than a “patient-centric” approach. We provide a detailed description of the performance characteristics of membranes, filters, transmembrane transport of solutes and fluid, flows, and methods of measurement of delivered treatment, focusing on continuous renal replacement therapies (CRRT) which are utilized in the management of critically ill patients with AKI. This is a consensus report on nomenclature harmonization for principles of extracorporeal renal replacement therapies. Devices and operations are classified and defined in detail to serve as guidelines for future use of terminology in papers and research.

Accuracy of invasive arterial pressure monitoring in cardiovascular patients: an observational study

IntroductionCritically ill patients and patients undergoing high-risk and major surgery, are instrumented with intra-arterial catheters and invasive blood pressure is considered the “gold standard” for arterial pressure monitoring. Nonetheless, artifacts due to inappropriate dynamic response of the fluid-filled monitoring systems may lead to clinically relevant differences between actual and displayed pressure values. We sought to analyze the incidence and causes of resonance/underdamping phenomena in patients undergoing major vascular and cardiac surgery.MethodsArterial pressures were measured invasively and, according to the fast-flush Gardner’s test, each patient was attributed to one of two groups depending on the presence (R-group) or absence (NR-group) of resonance/underdamping. Invasive pressure values were then compared with the non-invasive ones.ResultsA total of 11,610 pulses and 1,200 non-invasive blood pressure measurements were analyzed in 300 patients. Ninety-two out of 300 (30.7%) underdamping/resonance arterial signals were found. In these cases (R-group) systolic invasive blood pressure (IBP) average overestimation of non-invasive blood pressure (NIBP) was 28.5 (15.9) mmHg (P <0.0001) while in the NR-group the overestimation was 4.1(5.3) mmHg (P <0.0001). The mean IBP-NIBP difference in diastolic pressure in the R-group was −2.2 (10.6) mmHg and, in the NR-group −1.1 (5.8) mmHg. The mean arterial pressure difference was 7.4 (11.2) mmHg in the R-group and 2.3 (6.4) mmHg in the NR-group. A multivariate logistic regression identified five parameters independently associated with underdamping/resonance: polydistrectual arteriopathy (P =0.0023; OR = 2.82), history of arterial hypertension (P =0.0214; OR = 2.09), chronic obstructive pulmonary disease (P =0.198; OR = 2.61), arterial catheter diameter (20 vs. 18 gauge) (P <0.0001; OR = 0.35) and sedation (P =0.0131; OR = 0.5). The ROC curve for the maximal pressure–time ratio, showed an optimum selected cut-off point of 1.67 mmHg/msec with a specificity of 97% (95% CI: 95.13 to 99.47%) and a sensitivity of 77% (95% CI: 67.25 to 85.28%) and an area under the ROC curve by extended trapezoidal rule of 0.88.ConclusionPhysicians should be aware of the possibility that IBP can be inaccurate in a consistent number of patients due to underdamping/resonance phenomena. NIBP measurement may help to confirm/exclude the presence of this artifact avoiding inappropriate treatments.

Cytokine removal with high cut-off membrane: review of literature.

During the last decade, blood purification therapies have been proposed as an effective therapy to control the cytokines dysregulation in systemic inflammatory syndromes. Among them, the treatment with high cut-off membranes is characterized by larger pore size and more effective clearance for middle molecular weight molecules (cytokines). In this paper, we performed a thoughtful review of the literature on HCO being used for blood purification indications in all systemic inflammation syndromes. Clinical and experimental studies show that the use of high effluent flows in a pure diffusive treatment effectively removes serum cytokines with a safe profile in albumin clearance. In clinical studies, the removal of these inflammatory mediators is associated with a significant improvement in hemodynamic condition, oxygenation indices, and organ dysfunction.

Optimizing a kidney stress test to evaluate renal functional reserve.

BACKGROUND Renal function reserve (RFR) describes the capacity of the kidney to increase glomerular filtration rate (GFR) in response to physiological or pathological stimuli. The scope of our study was to evaluate the optimal level of stimulation using different doses of protein load (PL) for a standard renal stress test (RST). METHODS 18 young healthy individuals were given sessions of PL with 1 and 2 g/kg body weight. Endogenous creatinine clearance was calculated. Baseline GFR (bGFR) and stress GFR (sGFR) (post-PL) were obtained; RFR is the difference between stress and baseline GFR. A p-value < 0.05 was considered statistically significant. RESULTS Mean bGFR was 107.97 ± 12.33 mL/min/1.73m2. sGFR with 1 and 2 g PL were significantly higher than bGFR in all subjects. The sGFR after 2 g PL (141.75 ± 19.90 mL/min/1.73m2) was not statistically different from the sGFR after 1 g PL (142.37 ± 22.35 mL/min/1.73m2). sGFR and therefore RFR were independent from the value of bGFR. CONCLUSIONS We found no difference between 1 and 2 g/kg body weight PL to elicit sGFR. RST may be useful to predict susceptibility and risk of developing acute kidney injury and/or progression to chronic kidney disease. RST uncovers the possible loss of renal functional mass when this condition is not manifested clinically. Further studies are needed to set this hypothesis.

Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis.

Cardiorenal Syndromes and Sepsis

The cardiorenal syndrome is a clinical and pathophysiological entity defined as the concomitant presence of renal and cardiovascular dysfunction. In patients with severe sepsis and septic shock, acute cardiovascular, and renal derangements are common, that is, the septic cardiorenal syndrome. The aim of this paper is to describe the pathophysiology and clinical features of septic cardiorenal syndrome in light of the actual clinical and experimental evidence. In particular, the importance of systemic and intrarenal endothelial dysfunction, alterations of kidney perfusion, and myocardial function, organ “crosstalk” and ubiquitous inflammatory injury have been extensively reviewed in light of their role in cardiorenal syndrome etiology. Treatment includes early and targeted optimization of hemodynamics to reverse systemic hypotension and restore urinary output. In case of persistent renal impairment, renal replacement therapy may be used to remove cytokines and restore renal function.

Extracorporeal Membrane Oxygenation and the Kidney

Background: Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with reversible cardiac and/or respiratory failure. Acute kidney injury (AKI) often occurs in patients supported with ECMO; it frequently evolves into chronic kidney damage or end-stage renal disease and is associated with a reported 4-fold increase in mortality rate. Although AKI is generally due to the hemodynamic alterations associated with the baseline disease, ECMO itself may contribute to maintaining kidney dysfunction through several mechanisms. Summary: AKI may be related to conditions derived from or associated with extracorporeal therapy, leading to a reduction in renal oxygen delivery and/or to inflammatory damage. In particular, during pathological conditions requiring ECMO, the biological defense mechanisms maintaining central perfusion by a reduction of perfusion to peripheral organs (such as the kidney) have been identified as pretreatment and patient-related risk factors for AKI. Hormonal pathways are also impaired in patients supported with ECMO, leading to failures in mechanisms of renal homeostasis and worsening fluid overload. Finally, inflammatory damage, due to the primary disease, heart and lung crosstalk with the kidney or associated with extracorporeal therapy itself, may further increase the susceptibility to AKI. Renal replacement therapy can be integrated into the main extracorporeal circuit during ECMO to provide for optimal fluid management and removal of inflammatory mediators. Key Messages: AKI is frequently observed in patients supported with ECMO. The pathophysiology of the associated AKI is chiefly related to a reduction in renal oxygen delivery and/or to inflammatory damage. Risk factors for AKI are associated with a patients underlying disease and ECMO-related conditions.

Acute Severe Arterial Hypertension: Therapeutic Options

Arterial hypertension is a very common condition. Cerebral, coronary and renal vessels are mainly affected by the deleterious effect of this condition, and both acute and chronic organ failure may ensue. Exacerbation of underlying pathophysiologic conditions or new precipitating factors can lead to hypertensive crisis, either urgencies or emergencies. During hypertensive emergencies, a quick raise in arterial pressure may lead to acute and significant organ dysfunction, such as aortic dissection, acute myocardial infarction, intracranial bleeding or acute renal failure. Perioperative hypertension often takes the shape of a crisis and it can be related to hypothermia, pain, neuro-hormonal response to surgical trauma or antihypertensive drugs withdrawal. Treatment for hypertensive crisis should achieve a progressive control of blood pressure, avoiding any abrupt decrease in organ blood supply. Therapeutic options are many and different in terms of pharmacokinetics and pharmacodynamic profiles. The best option should be based upon the characteristics of the patient and the pathophysiology of the hypertensive crisis. Of particular interest, some agents are metabolized by blood esterase and have a very short half life (e.g., clevidipine). This allows tight titration of their effect, which is advisable when carefully lowering blood pressure. This is of particular importance when treating hypertensive crisis in surgical patients both intra-operatively or in critical care.