Gyorgy Frendl

Liver in sepsis and systemic inflammatory response syndrome

In patients with sepsis and SIRS, the liver has two opposing roles: a source of inflammatory mediators and a target organ for the effects of the inflammatory mediators. The liver is pivotal in modulating the systemic response to severe infection, because it contains the largest mass of macrophages (Kupffer cells) in the body; these macrophages can clear the endotoxin and bacteria that initiate the systemic inflammatory response. This article summarizes the functional changes that take place in the liver during sepsis and systemic inflammatory response syndrome and discusses the cellular and molecular mechanisms that underlie clinical outcomes.

2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures

PREAMBLE Our mission was to develop evidence-based guidelines for the prevention and treatment of perioperative/postoperative atrial fibrillation and flutter (POAF) for thoracic surgical procedures. Sixteen experts were invited by the American Association for Thoracic Surgery (AATS) leadership: 7 cardiologists and electrophysiology specialists, 3 intensivists/ anesthesiologists, 1 clinical pharmacist, joined by 5 thoracic and cardiac surgeons who represented AATS (see Online Data Supplement 1 for the list of members and Online Data Supplement 2 for the conflict of interest declaration online).

Complement-Mediated Loss of Endothelium-Dependent Relaxation of Porcine Coronary Arteries: Role of the Terminal Membrane Attack Complex

Reperfusion of the ischemic myocardium results in the loss of endothelium-dependent relaxation. We have shown recently that the alternate complement pathway is activated immediately on reperfusion of the ischemic porcine myocardium. We hypothesized that complement activation directly attenuates endothelium-dependent relaxation of porcine coronary arteries. Bradykinin (BK) or substance P concentration-dependently relaxed precontracted (U46619, 50 nmol/L) left anterior descending coronary artery (LAD) rings in vitro. Addition of zymosan to human (10%) or porcine (10%) serum for 30 minutes significantly (P < 0.05) increased the EC50 of BK-induced LAD relaxation from 4 +/- 1 to 418 +/- 159 nmol/L (n = 8) and from 9 +/- 3 to 281 +/- 132 nmol/L (n = 7), respectively. Similarly, addition of zymosan to 10% human serum (HS) for 30 minutes increased the EC50 of substance P-induced LAD relaxation from 0.4 +/- 0.1 to 30 +/- 14 nmol/L (n = 9, P < .05). Basal release of nitric oxide was reduced significantly in LAD rings exposed to zymosan-activated HS compared with HS alone. Addition of soluble CR1 (sCR1, 10 nmol/L) to zymosan-activated HS preserved BK-induced relaxation (EC50) of the LAD rings (control, 4 +/- 1 nmol/L; sCR1 + zymosan+serum, 2 +/- 1 nmol/L; n = 6). Zymosan-activated C8-depleted HS (10%) did not attenuate the EC50 of BK-induced coronary artery relaxation (3 +/- 1 to 3 +/- 1 nmol/L, n = 7, P = NS). Zymosan-activated C8-depleted HS plus C8 (6 micrograms/mL) increased the EC50 of BK-induced coronary artery relaxation from 4 +/- 1 to 423 +/- 141 nmol/L (n = 12, P < .05). We have further demonstrated that C5b-9 complexes can be found on the luminal surface of LAD endothelial cells after 5 minutes of exposure to zymosan-activated HS by using C5b-9 reactive monoclonal antibody fluorescent immunohistochemistry and confocal microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Candidaemia associated with decreased in vitro fluconazole susceptibility: is Candida speciation predictive of the susceptibility pattern?

BACKGROUND Candidaemia is often treated with fluconazole in the absence of susceptibility testing. We examined factors associated with candidaemia caused by Candida isolates with reduced susceptibility to fluconazole. METHODS We identified consecutive episodes of candidaemia at two hospitals from 2001 to 2007. Species identification followed CLSI methodology and fluconazole susceptibility was determined by Etest or broth microdilution. Susceptibility to fluconazole was defined as: full susceptibility (MIC < or = 8 mg/L); and reduced susceptibility (MIC > or = 32 mg/L). Complete resistance was defined as an MIC > 32 mg/L. RESULTS Of 243 episodes of candidaemia, 190 (78%) were fully susceptible to fluconazole and 45 (19%) had reduced susceptibility (of which 27 were fully resistant). Of Candida krusei and Candida glabrata isolates, 100% and 51%, respectively, had reduced susceptibility. Despite the small proportion of Candida albicans (8%), Candida tropicalis (4%) and Candida parapsilosis (4%) with reduced fluconazole susceptibility, these species composed 36% of the reduced-susceptibility group and 48% of the fully resistant group. In multivariate analysis, independent factors associated with reduced fluconazole susceptibility included male sex [odds ratio (OR) 3.2, P < 0.01], chronic lung disease (OR 2.7, P = 0.01), the presence of a central vascular catheter (OR 4.0, P < 0.01) and prior exposure to antifungal agents (OR 2.2, P = 0.04). CONCLUSIONS A significant proportion of candidaemia with reduced fluconazole susceptibility may be caused by C. albicans, C. tropicalis and C. parapsilosis, species usually considered fully susceptible to fluconazole. Thus, identification of these species may not be predictive of fluconazole susceptibility. Other factors that are associated with reduced fluconazole susceptibility may help clinicians choose adequate empirical anti-Candida therapy.

Measuring Communication in the Surgical ICU: Better Communication Equals Better Care

BACKGROUND The Joint Commission on the Accreditation of Healthcare Organizations reports that communication breakdowns are responsible for 85% of sentinel events in hospitals. Patients in surgical ICUs are the most vulnerable to communication errors. Fellows and residents are an integral part of the surgical ICU team, but little is known about resident-fellow communication and its impact on surgical ICU patient outcomes. The objective of this study is to describe resident-fellow patient care communication patterns in the surgical ICU and correlate established communication patterns with short-term outcomes. STUDY DESIGN A prospective observational trial was conducted for 136 consecutive surgical ICU days. We evaluated resident-fellow communication of four cardiorespiratory events: hypotension, new arrhythmias, tachypnea, and desaturation. We prospectively defined three short-term outcomes: improved, not improved, and worse. An intervention was attempted to improve communication. RESULTS Three hundred twelve events were collected (166 observational and 146 interventional). PGY3 residents covered approximately 60% of days in both phases. PGY3 residents were responsible for 73% of communication errors in the observational phase and 59% of communication errors in the interventional phase. Communication errors were more likely in the late shift (p < 0.0001). The late shift was responsible for 77% of all communication errors. Communication errors resulted in worse short-term outcomes for cardiorespiratory events (p < 0.0002). Effective communication was a significant predictor of improved short-term outcomes (p < 0.0003). The intervention decreased communication errors in the late shift by 10% (p < 0.052). CONCLUSIONS Communication errors occurred more frequently during the late shift. These communication errors were associated with worsened short-term outcomes. Improved communication in the surgical ICU is a fruitful target to improve clinical outcomes.

Interleukin 3: From colony-stimulating factor to pluripotent immunoregulatory cytokine

IL-3 is best known as a multicolony-stimulating factor, produced by T-cells, mast cells and eosinophils. Based on its broad spectrum of hemopoietic growth factor activity, the role of IL-3 in the homeostasis of leukocytes is apparent, although the precise mechanisms of this process are yet to be determined. The fact that activated T-helper cells are one of the most potent sources of IL-3 suggests an additional role for IL-3 in the regulation of the immune response. Although the presence of IL-3 receptors on monocytes has been demonstrated, the role of IL-3 in regulating macrophage functions was not clear until recently. We have demonstrated a unique spectrum of macrophage activating properties of IL-3, distinct from that of IFN gamma, IL-4 and other CSFs. These novel macrophage activating properties of IL-3 include its capacity to directly induce the expression of Ia antigens and members of the beta 2 integrin family (e.g. CD11a/CD18[LFA-1]), as well as to contribute to the regulation of cytokine production (IL-1, IL-6 and TNF alpha). Moreover, we observed a significant synergy between IL-3 and IFN gamma in the induction of Ia and LFA-1, as well as between IL-3 and LPS in the induction of Ia and macrophage cytokines. Our data suggest that IL-3 may help control the antigen presentation (AP) capacity of macrophage via the regulation of Ia, beta 2 integrins and macrophage cytokines. It is also possible that the differential state of activation of macrophages that we demonstrated following their induction with IL-3, IFN gamma or IL-3+IFN gamma results in the development of functionally distinct AP cells. Further immunoregulatory properties of IL-3 were observed in vivo by Kimoto and colleagues when IL-3 administration led to profound enhancement of the T-cell-dependent immune response, with no changes in the antibody response to T-cell-independent antigens. Thus, in vitro and in vivo data both confer an immunoregulatory role for IL-3 in the development of the immune response, most likely via its effects on the antigen presenting cells (macrophages). This review will summarize evidence documenting a range of immunoregulatory properties of IL-3 and discuss the mechanisms of action of IL-3.

Postoperative Pulmonary Complications, Early Mortality, and Hospital Stay Following Noncardiothoracic Surgery: A Multicenter Study by the Perioperative Research Network Investigators

Importance Postoperative pulmonary complications (PPCs), a leading cause of poor surgical outcomes, are heterogeneous in their pathophysiology, severity, and reporting accuracy. Objective To prospectively study clinical and radiological PPCs and respiratory insufficiency therapies in a high-risk surgical population. Design, Setting, and Participants We performed a multicenter prospective observational study in 7 US academic institutions. American Society of Anesthesiologists physical status 3 patients who presented for noncardiothoracic surgery requiring 2 hours or more of general anesthesia with mechanical ventilation from May to November 2014 were included in the study. We hypothesized that PPCs, even mild, would be associated with early postoperative mortality and use of hospital resources. We analyzed their association with modifiable perioperative variables. Exposure Noncardiothoracic surgery. Main Outcomes and Measures Predefined PPCs occurring within the first 7 postoperative days were prospectively identified. We used bivariable and logistic regression analyses to study the association of PPCs with ventilatory and other perioperative variables. Results This study included 1202 patients who underwent predominantly abdominal, orthopedic, and neurological procedures. The mean (SD) age of patients was 62.1 (13.8) years, and 636 (52.9%) were men. At least 1 PPC occurred in 401 patients (33.4%), mainly the need for prolonged oxygen therapy by nasal cannula (n = 235; 19.6%) and atelectasis (n = 206; 17.1%). Patients with 1 or more PPCs, even mild, had significantly increased early postoperative mortality, intensive care unit (ICU) admission, and ICU/hospital length of stay. Significant PPC risk factors included nonmodifiable (emergency [yes vs no]: odds ratio [OR], 4.47, 95% CI, 1.59-12.56; surgical site [abdominal/pelvic vs nonabdominal/pelvic]: OR, 2.54, 95% CI, 1.67-3.89; and age [in years]: OR, 1.03, 95% CI, 1.02-1.05) and potentially modifiable (colloid administration [yes vs no]: OR, 1.75, 95% CI, 1.03-2.97; preoperative oxygenation: OR, 0.86, 95% CI, 0.80-0.93; blood loss [in milliliters]: OR, 1.17, 95% CI, 1.05-1.30; anesthesia duration [in minutes]: OR, 1.14, 95% CI, 1.05-1.24; and tidal volume [in milliliters per kilogram of predicted body weight]: OR, 1.12, 95% CI, 1.01-1.24) factors. Conclusions and Relevance Postoperative pulmonary complications are common in patients with American Society of Anesthesiologists physical status 3, despite current protective ventilation practices. Even mild PPCs are associated with increased early postoperative mortality, ICU admission, and length of stay (ICU and hospital). Mild frequent PPCs (eg, atelectasis and prolonged oxygen therapy need) deserve increased attention and intervention for improving perioperative outcomes.

Increased plasma catalytic iron in patients may mediate acute kidney injury and death following cardiac surgery

Catalytic iron, the chemical form of iron capable of participating in redox cycling, is a key mediator of acute kidney injury (AKI) in multiple animal models, but its role in human AKI has not been studied. Here we tested in a prospective cohort of 250 patients undergoing cardiac surgery whether plasma catalytic iron levels are elevated and associated with the composite outcome of AKI requiring renal replacement therapy or in-hospital mortality. Plasma catalytic iron, free hemoglobin, and other iron parameters were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3. Plasma catalytic iron levels, but not other iron parameters, rose significantly at the end of cardiopulmonary bypass and were directly associated with bypass time and number of packed red blood cell transfusions. In multivariate analyses adjusting for age and preoperative eGFR, patients in the highest compared with the lowest quartile of catalytic iron on postoperative day 1 had a 6.71 greater odds of experiencing the primary outcome, and also had greater odds of AKI, hospital mortality, and postoperative myocardial injury. Thus, our data are consistent with and expand on findings from animal models demonstrating a pathologic role of catalytic iron in mediating adverse postoperative outcomes. Interventions aimed at reducing plasma catalytic iron levels as a strategy for preventing AKI in humans are warranted.

Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423

Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423.

Utilization of Arterial Blood Gas Measurements in a Large Tertiary Care Hospital

We describe the patterns of utilization of arterial blood gas (ABG) tests in a large tertiary care hospital. To our knowledge, no hospital-wide analysis of ABG test utilization has been published. We analyzed 491 ABG tests performed during 24 two-hour intervals, representative of different staff shifts throughout the 7-day week. The clinician ordering each ABG test was asked to fill out a utilization survey. The most common reasons for requesting an ABG test were changes in ventilator settings (27.6%), respiratory events (26.4%), and routine (25.7%). Of the results, approximately 79% were expected, and a change in patient management (eg, a change in ventilator settings) occurred in 42% of cases. Many ABG tests were ordered as part of a clinical routine or to monitor parameters that can be assessed clinically or through less invasive testing. Implementation of practice guidelines may prove useful in controlling test utilization and in decreasing costs.