Cosimo Chelazzi

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.

Pathophysiology of Sepsis in the Elderly : Clinical Impact and Therapeutic Considerations

The aging world population will increase the incidence and mortality of severe sepsis. The aim of the present article is to review the pathophysiological differences in sepsis and its clinical impact on the elderly. The impact of immunosenescence on innate and acquired immunity is associated with relative immunologic depression that may favor the spreading of inflammation. Elderly patients also have enhanced apoptotic pathways that may contribute to the incidence of mortality due to sepsis. The inflammation-coagulation network is activated by age, explaining the success of some specific therapies. The initial clinical picture of sepsis in the elderly may be ambiguous but the specific pathopysiological changes of aging increase the risk of a sudden deterioration to severe sepsis with the development of a serious cardiovascular dysfunction. The reduced stress tolerance characteristic of aged tissues explains the high incidence of multi-organ failure in such patients. The specific pathophysiological and clinical picture of sepsis underlies the increased mortality in such patients and prompts research on therapeutic strategies with particular benefits to elderly septic patients.

Cefazolin bolus and continuous administration for elective cardiac surgery: Improved pharmacokinetic and pharmacodynamic parameters

OBJECTIVE Cefazolin (1-2 g bolus at induction possibly repeated after cardiopulmonary bypass) remains the standard for antibiotic prophylaxis in cardiac surgery. Data indicate, however, that it is underdosed with this dosing schedule. A prospective, randomized study comparing intermittent versus loading dose plus continuous infusion for the same total dose of cefazolin was performed to assess which modality is pharmacokinetically and pharmacodynamically advantageous. METHODS Patients received 2 g cefazolin as a starting dose and then were divided into an intermittent group (receiving another 1 g at 3, 9, and 15 hours after the first dose) and a continuous group (continuous infusion started after the first dose, providing 1 g every 6 hours for 18 hours). Cefazolin levels were measured in blood and atria. RESULTS Mean total and calculated free trough concentrations in blood varied greatly among patients in the intermittent group and were lower than those in the continuous group (P < .05 at 15, 18 and 24 hours). For 9 of 10 (90%) patients in the continuous infusion group, the targeted pharmacokinetic and pharmacodynamic goal (time above minimal inhibitory concentration >90%) was achieved, whereas the goal was met for only 3 of 10 (30%) in the intermittent group (P < .05). The mean atrial tissue concentration was also higher with continuous infusion (P < .05). CONCLUSIONS Administration of cefazolin as bolus plus continuous infusion has pharmacokinetic and pharmacodynamic advantages relative to intermittent administration. It provides more stable serum levels, lower interpatient variability, and higher myocardial tissue penetration.

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.

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.

Organ dysfunction during continuous veno-venous high cut-off hemodialysis in patients with septic acute kidney injury: A prospective observational study

Background Continuous veno-venous hemodialysis with high cut-off membranes (HCO-CVVHD) removes inflammatory mediators involved in organ dysfunction during sepsis. The aim of the present study was to assess the variations in SOFA score and identify early predictors of short-term mortality in a cohort of patients with septic shock, treated with HCO-CVVHD for acute kidney injury (AKI). Methods An observational prospective multicenter cohort study was conducted in four mixed medical-surgical ICUs. Thirty-eight patients with septic shock and AKI (KDIGO stage≥1) treated with HCO-CVVHD have been included in this study. Patients were divided into Survivors and non-Survivors according to mortality observed at 72nd hr of treatment. The variation of SOFA scores and clinical/biochemical parameters were described over time for the entire population and specifically for Survivors and non-Survivors. Similarly, circulating inflammatory mediators (as IL-6, TNF-a and IL-10) were described over time. A logistic regression analysis was used to identify the baseline clinical and biochemical parameters associated with 72 hrs-ICU mortality. Results Overall, the mean SOFA score was 12±3 at baseline, 10.9±3 at 6hrs, 9.8±3 at 12hrs, 8.9±3.3 at 24 hrs, and 8±3.5 at 48 hrs after HCO-CVVHD initiation; and 6.5±2.7 at 24 hrs and 6.6±3 at 48 hrs after HCO-CVVHD discontinuation. In the multivariate regression analysis, baseline serum lactate levels and AKI stage independently correlated with short-term mortality during HCO-CVVHD. A significant reduction was observed in circulating levels of TNFα and IL-6 among Survivors. Conclusions SOFA score significantly decreased early after initiation of HCO-CVVHD in patients with septic AKI. Baseline lactate levels and the AKI stage resulted to be associated to 72 hrs-ICU-mortality.

Is procalcitonin a reliable marker of sepsis in critically ill septic patients undergoing continuous veno-venous hemodiafiltration with “high cut-off” membranes (HCO-CVVHDF)?

*Corresponding author: Dr. Anna Caldini, General Laboratory, Clinical Chemistry Laboratory, Laboratory Diagnostics Department, Careggi University Hospital, Largo Brambilla, 3, 50134 Florence, Italy, Phone: +39 055-7949452, Fax: +39 055-7949416, E-mail: caldinia@aou-careggi.toscana.it Cosimo Chelazzi, Claudia Giannoni, Gianluca Villa and Angelo R. De Gaudio: Department of Health Sciences, Section of Anesthesiology and Intensive Care, University of Florence, Florence, Italy Alessandro Terreni, Tiziana Biagioli and Gianni Messeri: Clinical Chemistry Laboratory, Laboratory Diagnostics Department, Careggi University Hospital, Florence Italy

The New MIRUS System for Short-Term Sedation in Postsurgical ICU Patients*

Objectives: To evaluate the feasibility and safety of the MIRUS system (Pall International, Sarl, Fribourg, Switzerland) for sedation with sevoflurane for postsurgical ICU patients and to evaluate atmospheric pollution during sedation. Design: Prospective interventional study. Setting: Surgical ICU. February 2016 to December 2016. Patients: Postsurgical patients requiring ICU admission, mechanical ventilation, and sedation. Interventions: Sevoflurane was administered with the MIRUS system targeted to a Richmond Agitation Sedation Scale from –3 to –5 by adaptation of minimum alveolar concentration. Measurements and Main Results: Data collected included Richmond Agitation Sedation Scale, minimum alveolar concentration, inspired and expired sevoflurane fraction, wake-up times, duration of sedation, sevoflurane consumption, respiratory and hemodynamic data, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment, and laboratory data and biomarkers of organ injury. Atmospheric pollution was monitored at different sites: before sevoflurane delivery (baseline) and during sedation with the probe 15 cm up to the MIRUS system (S1) and 15 cm from the filter-Reflector group (S2). Sixty-two patients were enrolled in the study. No technical failure occurred. Median Richmond Agitation Sedation Scale was –4.5 (interquartile range, –5 to –3.6) with sevoflurane delivered at a median minimum alveolar concentration of 0.45% (interquartile range, 0.4–0.53) yielding a mean inspiratory and expiratory concentrations of 0.79% (SD, 0.24) and 0.76% (SD, 0.18), respectively. Median awakening time was 4 minutes (2.2–5 min). Median duration of sevoflurane administration was 3.33 hours (2.33–5.75 hr), range 1–19 hours with a mean consumption of 7.89 mL/hr (SD, 2.99). Hemodynamics remained stable over the study period, and no laboratory data indicated liver or kidney injury or dysfunction. Median sevoflurane room air concentration was 0.10 parts per million (interquartile range, 0.07–0.15), 0.17 parts per million (interquartile range, 0.14–0.27), and 0.15 parts per million (interquartile range, 0.07–0.19) at baseline, S1, and S2, respectively. Conclusions: The MIRUS system is a promising and safe alternative for short-term sedation with sevoflurane of ICU patients. Atmospheric pollution is largely below the recommended thresholds (< 5 parts per million). Studies extended to more heterogeneous population of patients undergoing longer duration of sedation are needed to confirm these observations.

Endovascular electrocardiography to guide placement of totally implantable central venous catheters in oncologic patients

Purpose Appropriate tip position of totally implantable central venous catheters is essential in order to prevent catheter-related complications, in particular thrombosis. Endovascular electrocardiography is an economic and safe method to guide placement of catheters into the central veins. Although widely utilized, there is still lack of conclusive evidence about its efficacy. The aim of the study was to assess the efficacy and safety of endovascular electrocardiographic guided placement compared to the anthropometric method. Methods Endovascular ECG was employed to guide electrocardiographic placement of a central venous catheter in a cohort of oncologic patients. The rate of correct placement and the incidence of catheter-related thrombosis were considered. Patients in which central venous catheters were inserted with the anthropometric technique were considered as control group. Results The rate of correct placement was 91% and 50% for ECG-guided and anthropometric catheters (p<0.0001) respectively. None of the patients suffered from early insertion-related complications. The rate of catheter-related vascular thrombosis was lower for ECG-guided catheters (3.6% vs. 9.6%, n.s.), in particular for left-inserted catheters (0% vs. 33.3%, p=0.02). Conclusion Endovascular electrocardiography was more effective than the anthropometric technique in placement of implantable central venous catheters and was associated with a lower incidence of catheter-related thrombosis, in particular for those inserted from the left-side.