Helene A. Haeberle

Effect of Remote Ischemic Preconditioning on Kidney Injury Among High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial

IMPORTANCEnNo interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery.nnnOBJECTIVEnTo determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery.nnnDESIGN, SETTING, AND PARTICIPANTSnIn this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle.nnnINTERVENTIONSnPatients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation.nnnMAIN OUTCOMES AND MEASURESnThe primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers.nnnRESULTSnAcute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; Pu2009=u2009.02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; Pu2009=u2009.01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (Pu2009=u2009.04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL2/1000; difference, 0.61; 95% CI, 0.27-0.86; Pu2009<u2009.001). No adverse events were reported with remote ischemic preconditioning.nnnCONCLUSIONS AND RELEVANCEnAmong high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation.nnnTRIAL REGISTRATIONnGerman Clinical Trials Register Identifier: DRKS00005333.

Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis.

IntroductionSepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis.MethodsIn a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis.ResultsSix out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects.ConclusionsThese data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.

Oxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection

Background Hypoxia-inducible factor 1 (HIF)-1α is a transcription factor that functions as master regulator of mammalian oxygen homeostasis. In addition, recent studies identified a role for HIF-1α as transcriptional regulator during inflammation or infection. Based on studies showing that respiratory syncytial virus (RSV) is among the most potent biological stimuli to induce an inflammatory milieu, we hypothesized a role of HIF-1α as transcriptional regulator during infections with RSV. Methodology, Principal Findings We gained first insight from immunohistocemical studies of RSV-infected human pulmonary epithelia that were stained for HIF-1α. These studies revealed that RSV-positive cells also stained for HIF-1α, suggesting concomitant HIF-activation during RSV infection. Similarly, Western blot analysis confirmed an approximately 8-fold increase in HIF-1α protein 24 h after RSV infection. In contrast, HIF-1α activation was abolished utilizing UV-treated RSV. Moreover, HIF-α-regulated genes (VEGF, CD73, FN-1, COX-2) were induced with RSV infection of wild-type cells. In contrast, HIF-1α dependent gene induction was abolished in pulmonary epithelia following siRNA mediated repression of HIF-1α. Measurements of the partial pressure of oxygen in the supernatants of RSV infected epithelia or controls revealed no differences in oxygen content, suggesting that HIF-1α activation is not caused by RSV associated hypoxia. Finally, studies of RSV pneumonitis in mice confirmed HIF-α-activation in a murine in vivo model. Conclusions/Significance Taking together, these studies suggest hypoxia-independent activation of HIF-1α during infection with RSV in vitro and in vivo.

Local anesthetics impair human granulocyte phagocytosis activity, oxidative burst, and CD11b expression in response to Staphylococcus aureus.

Background With invasion of bacteria, the host defense system is activated by a complex cascade of various mechanisms. Local anesthetics previously were shown to interact with diverse components of the immune response, such as leukocyte adherence on endothelial monolayers, oxidative burst, or crosstalk within lymphocyte subset populations. However, effects of newer local anesthetics like bupivacaine and ropivacaine on antibacterial host defense—primarily phagocytosis activity, oxidative burst, or CD11b expression—still remain unclear. Methods Whole blood samples were preincubated with local anesthetics (lidocaine, 9.2, 92.2, and 1,846 &mgr;m; bupivacaine, 6.1, 61, and 770 &mgr;m; ropivacaine, 6.4, 64, and 801 &mgr;m). For the oxidative burst and CD11b assay, dihydroethidium was added to the probes. After viable Staphylococcus aureus was added in a 5 to 1 ratio following leukocyte count, phagocytosis was stopped at different times, and staining with monoclonal antibodies was performed for subsequent flow cytometric analysis of phagocytosis activity, oxidative burst, and CD11b expression. Results Granulocyte phagocytosis activity, CD11b expression, and generation of reactive oxygen species were significantly reduced by lidocaine (P < 0.0002) and bupivacaine (P < 0.005) in the highest concentration (1,846 &mgr;m and 770 &mgr;m, respectively). The capability of granulocytes to ingest bacteria was significantly depressed only by lidocaine (P < 0.003). Ropivacaine had no significant effect on any parameter investigated. Conclusions Local anesthetic dose and structure dependently inhibit inflammatory and immunologic parameters of granulocyte functions. Ropivacaine shows low interference with granulocyte immunologic and inflammatory functions.

Mechanisms of leukocyte distribution during sepsis: an experimental study on the interdependence of cell activation, shear stress and endothelial injury

IntroductionThis study was carried out to determine whether interactions of cell activation, shear stress and platelets at sites of endothelial injury explain the paradoxical maldistribution of activated leukocytes during sepsis away from local sites of infection towards disseminated leukocyte accumulation at remote sites.MethodsHuman umbilical venous endothelial cells (HUVEC) and polymorphonuclear neutrophils (PMN) were activated with lipopolysaccharide at 100 and 10 ng/ml to achieve adhesion molecule patterns as have been reported from the hyper- and hypo-inflammatory stage of sepsis. To examine effects of leukocyte activation on leukocyte-endothelial interactions, activated HUVEC were perfused with activated and non-activated neutrophils in a parallel plate flow chamber. Adhesion molecule expression and function were assessed by flow cytometry and blocking antibodies. In a subset of experiments the sub-endothelial matrix was exposed and covered with platelets to account for the effects of endothelial injury. To investigate interactions of these effects with flow, all experiments were done at various shear stress levels (3 to 0.25 dyne/cm2). Leukocyte-endothelial interactions were analyzed by videomicroscopy and analysis of covariance.ResultsActivation of neutrophils rendered adhesion increasingly dependent on shear stress reduction. At normal shear stress, shedding of L-selectin decreased adhesion by 56%. Increased rolling fractions of activated PMN at low shear stress revealed impaired integrin affinity despite numerical up-regulation of CD11b. On sub-maximally activated, intact HUVEC shear stress became the prevailing determinant of adhesion. Presence of a platelet-covered injury with high surface density of P-selectin was the strongest variable for adhesion. When compared to maximally activated HUVEC, platelets increased neutrophil adhesion by 2.7-fold. At sub-maximal activation a 10-fold increase was observed (P < 0.05 for all).ConclusionsL-selectin shedding and integrin dysfunction render leukocyte adhesion increasingly susceptible to shear stress and alternative adhesion receptors. In combination, these effects inhibit recruitment to normally perfused sites with intact endothelium and favor maldistribution towards sites with compromised perfusion or endothelial injury.

Role of cross-allergies to latex in clinical routine of anesthesia

STUDY OBJECTIVEnTo determine the applicability and reliability of a screening questionnaire to detect patients at high-risk of latex allergy; to assess the importance of other allergies such as profilin allergies (pollinosis) for presence of latex sensitization; and to determine the clinical effectiveness of preemptive avoidance of latex exposure in high-risk patients.nnnDESIGNnProspective, clinical trial.nnnSETTINGnOperative theater of a university hospital.nnnPATIENTSn95 adult patients.nnnINTERVENTIONSnPatients were preoperatively screened and classified for present latex allergy (high-risk and low-risk group) according to a specially designed screening questionnaire. Anesthesia and surgery in the high-risk group were performed strictly avoiding latex-containing materials. The low-risk group (other allergies including pollinosis) received routine treatment, without latex-avoidance. Effects of latex avoidance or exposure were evaluated by measuring specific IgE titers perioperatively.nnnMEASUREMENTS AND MAIN RESULTSnAccording to the questionnaire, 45 patients at high risk were defined. Validity of classification of high-risk patients is supported by significantly higher total IgE and latex and grass profilin specific IgE compared to the low-risk group. There were no significant differences in other profilin-specific IgEs. In one case of severe anaphylactic reaction a drop of latex-specific IgE during surgery could be observed.nnnCONCLUSIONnThe questionnaire allowed the identification of most patients at high risk for latex allergy. In isolated pollinosis no changes in any specific IgE levels were detectable. Strict avoidance of perioperative latex exposure in high-risk patients increases safety during anesthesia and surgery.

Impella 5.0 Support in INTERMACS II Cardiogenic Shock Patients Using Right and Left Axillary Artery Access

The catheter-based Impella 5.0 left ventricular assist device (LVAD) is a powerful and less invasive alternative for patients in cardiogenic shock. The use of this device as a primary mechanical circulatory support strategy in INTERMACS II patients should be evaluated. From April 2014 to August 2014, eight Impella 5.0 devices were implanted in seven patients via the axillary artery access (six right and two left). We analyzed the outcome of the four patients in whom the Impella 5.0 device was implanted for the purpose of primary stabilization of cardiogenic shock (INTERMACS II). The remaining three patients had a contraindication for a permanent LVAD and received the device for prolonged weaning from extracorporeal life support (ECLS) system. The implantation of the Impella 5.0 was technically successful in all patients and resulted in the stabilization of the clinical situation. All four patients could be bridged to a long-term device (nu2009=u20093) or to cardiac recovery (nu2009=u20091). In one patient, 2 days of ECLS support was necessary because of pump thrombosis after 31 days of Impella 5.0 support. One patient with bronchopneumonia had the Impella 5.0 exchanged from the right to the left axillary artery after 22 days of support because of the progressive loss of purge flow and the need for longer bridging to a permanent LVAD. The last patient was supported for giant-cell myocarditis for 22 days and bridged to cardiac recovery. All patients were transferred to the intensive care unit with the Impella device in place. In INTERMACS II situations, the implantation of the Impella 5.0 via the right or left axillary access allowed additional time for decision making. Early patient mobilization, including walking with the Impella device in place, optimized the conditions for either weaning or the implantation of a permanent LVAD. This novel technique of left axillary approach leads to more flexibility in the case of anatomical- or device-related contraindications to right-side access, or when the device needs to be exchanged while continuous support is necessary.

Population pharmacokinetics and pharmacodynamic evaluation of intravenous and enteral moxifloxacin in surgical intensive care unit patients

OBJECTIVESnTo describe the plasma concentration-time profile of moxifloxacin after intravenous and enteral administration in intensive care unit (ICU) patients and to provide a pharmacodynamic (PD) evaluation with regard to pneumonia.nnnPATIENTS AND METHODSnTwenty-five adult patients from a cardiothoracic/mixed surgical ICU were enrolled. Moxifloxacin was given as a standard dose (400 mg once daily). Therapy was successfully switched to enteral administration on day 5 in 16 patients. A rich data sampling schedule was performed after intravenous (day 4) and enteral (day 8) administration. Moxifloxacin concentrations were analysed by HPLC. A population pharmacokinetic (PK) model was developed using NONMEM VII. Simulated concentration-time profiles were evaluated for their probability of attaining PK/PD target values relevant for community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP).nnnRESULTSnA linear-elimination two-compartment model described the data adequately. Parameter estimates (coefficient of variation of inter-individual variability) were: absorption rate constant, 1.09/h (135%); enteral bioavailability, 76% (20.0%); central volume of distribution, 55.6 L; peripheral volume of distribution, 59.6 L (15.3%); inter-compartmental clearance, 47.7 L/h; and clearance, 11.3 L/h (23.7%). Both intravenously and enterally administered standard-dose moxifloxacin reliably attained the PK/PD target values for pathogens with MICs ≤ 0.25 mg/L for CAP and ≤ 0.125 mg/L for HAP.nnnCONCLUSIONSnDrug exposure to moxifloxacin in ICU patients was more variable than in healthy volunteers. The standard dosing provides sufficient drug exposure for treatment of CAP but for HAP it does so only when a highly susceptible pathogen is present. Intravenous/enteral sequential therapy may be considered for cautiously selected cases in ICU patients.

Extracorporeal life support prior to left ventricular assist device implantation leads to improvement of the patients INTERMACS levels and outcome

Background The objective of this study was to evaluate the outcome of left ventricular assist device (LVAD) implantation after initial extracorporeal life support (ECLS) in patients with cardiogenic shock and the incidence of post implantation right ventricular failure. Methods & results All patients on ECLS therapy for cardiogenic shock prior to LVAD implantation (n = 15) between October 2011 and January 2014 were analyzed. Baseline patient characteristics, as well as detailed pre-operative treatment and postoperative outcome data were collected retrospectively. At time of admission to our unit all patients were classified INTERMACS II or higher (12 [80%] INTERMACS I). Improvement to INTERMACS III temporary cardiac support (TCS) at time of LVAD implantation was successful in 14 patients (93.3%). End-organ function recovered during ECLS support. No patient needed ongoing ECLS or additional right ventricular support after LVAD implantation. Both in-hospital and 30-day mortality was 6.7% (n = 1). The median duration of LVAD support was 687.9 ± 374.5 days. At the end of the study (follow-up 810.7 +/- 338.9 days), 13 (86.7%) patients were alive. The majority of patients (10 [66.7%]) remained on LVAD support. Transplantation could be performed in 1 (6.7%) patient, 2 (13.3%) patients could be successfully weaned. Conclusion LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to-bridge therapy may help to lower mortality in primarily unstable patients.

Monocyte Phagocytosis of Viable Staphylococcus aureus is Impaired by Barbiturates, but not by Propofol

Background:Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus.Materials and Methods:Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity.Results:Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 ×10-3 M thiopental or 1.1 × 10-3 M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was8.4 × 10-3 M for monocyte recruitment and 8.6 × 10-3 M for phagocytosis activity. The corresponding values for methohexital were 4.1 × 10-3 M and 1.1 × 10-3 M, respectively.Conclusion:The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.