Marina Pieri

Mortality in multicenter critical care trials: An analysis of interventions with a significant effect

Objectives:We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians’ opinion and usual practice for the selected interventions. Data Sources:MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. Study Selection:We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. Data Extraction:For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. Data Synthesis:We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. Conclusions:We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

Concomitant implantation of Impella® on top of veno‐arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock

Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) support stabilizes patients with cardiogenic shock. Despite improved oxygenation and peripheral circulation, LV unloading may be impeded due to the increased afterload, resulting in a failing static left ventricle and in high mortality.

Bivalirudin Versus Heparin as an Anticoagulant During Extracorporeal Membrane Oxygenation: A Case-Control Study

OBJECTIVE Heparin-based anticoagulation for patients undergoing extracorporeal membrane oxygenation has many limitations, including a high risk of heparin-induced thrombocytopenia. However, little experience with other anticoagulants in these patients has been described. The aim of this study was to compare bivalirudin-based anticoagulation with heparin-based protocols in a population of patients treated with venovenous or venoarterial extracorporeal membrane oxygenation. DESIGN In this case-control study, 10 patients received bivalirudin (cases) and 10 heparin (controls). The target activated partial thromboplastin time (aPTT) was 45 to 60 seconds. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS aPTT variations >20% of the previous value were much more frequent in patients treated with heparin than in patients receiving bivalirudin (52 v 24, p < 0.001). The number of corrections of the anticoagulant dose was higher in the heparin group compared with the bivalirudin group (58 v 51), although it did not reach statistical significance. Bleeding, thromboembolic complications, extracorporeal membrane oxygenation (ECMO) support duration, mortality, and the number of episodes of aPTT >80 seconds were not different between the 2 groups. A further analysis was performed in the bivalirudin group according to the presence of acute renal failure requiring continuous venovenous hemofiltration. The median bivalirudin dose in patients with or without hemofiltration was 0.041 (0.028-0.05) mg/kg/h and 0.028 (0-0.041) mg/kg/h, respectively (p = 0.2). CONCLUSIONS Bivalirudin-based anticoagulation may represent a new method of anticoagulation for reducing thromboembolic and bleeding complications, which still jeopardize the application of extracorporeal membrane oxygenation. Moreover, bivalirudin is free from the risk of heparin-induced thrombocytopenia. Higher doses of bivalirudin may be needed in patients undergoing hemofiltration.

Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: A case-control study

OBJECTIVE Diagnosis of infection in patients receiving extracorporeal membrane oxygenation is challenging in clinical practice but represents a crucial aspect of the upgrading of therapeutic options. The aim of this study was to analyze the role of C-reactive protein and procalcitonin in the diagnosis of infection in patients requiring extracorporeal membrane oxygenation and to assess the difference between venovenous and venoarterial extracorporeal membrane oxygenation settings. METHODS A case-control study was performed on 27 patients. Serum values of procalcitonin and C-reactive protein were analyzed according to the presence of infection. RESULTS Forty-eight percent of patients had infection. Gram-negative bacteria were the predominant pathogens, and Candida albicans was the most frequent isolated microorganism. Procalcitonin had an area under the curve of 0.681 (P = .0062) for the diagnosis of infection in the venoarterial extracorporeal membrane oxygenation group but failed to discriminate infection in the venovenous extracorporeal membrane oxygenation group (P = .14). The area under the curve of C-reactive protein was 0.707 (P < .001) in all patients receiving extracorporeal membrane oxygenation. In patients receiving venoarterial extracorporeal membrane oxygenation, procalcitonin had good accuracy with 1.89 ng/mL as the cutoff (sensitivity = 87.8%, specificity = 50%) and C-reactive protein with 97.70 mg/L as the cutoff (sensitivity = 85.3%, specificity = 41.6%). The procalcitonin and C-reactive protein combined assay had a sensitivity of 87.2% and specificity of 25.9%. Four variables were identified as statistically significant predictors of infection: procalcitonin and C-reactive protein combined assay (odds ratio, 1.184; P < .001), age (odds ratio, 0.980; P < .001), presence of infection before extracorporeal membrane oxygenation implantation (odds ratio, 1.782; P < .001), and duration of extracorporeal membrane oxygenation support (odds ratio, 1.056; P < .001). CONCLUSIONS Traditional and emerging inflammatory biomarkers, especially if compounded in the procalcitonin and C-reactive protein combined assay, can aid in the diagnosis of infection in patients undergoing venoarterial extracorporeal membrane oxygenation.

Timing and Strategy for Weaning From Venoarterial ECMO are Complex Issues

OBJECTIVE Weaning from venoarterial extracorporeal membrane oxygenation (VA ECMO) usually is performed without clear guidelines; yet, patients still die after removal of extracorporeal circulation because of inadequate heart or end-organ recovery. The aim of the study was to address the weaning procedure, analyzing the hemodynamic and echocardiographic picture of patients weaned and to identify predictors of poor outcome among this population. DESIGN Observational study. SETTING University hospital. PARTICIPANTS One hundred twenty-nine VA ECMO cases. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Forty-nine patients (38%) were weaned, 7 (5.4%) were bridged to a ventricular assist device, and 6 (5.2%) were listed for heart transplantation. Weaned patients showed a significant increase of pulse pressure (35 [0-50] mmHg before ECMO, 59 [53-67] mmHg at weaning, 61 [51-76] mmHg after ECMO (p<0.001]) and reduction of dose of inotropes (inotropic score [as defined in the text] 20 [14-40] before ECMO, 10 [3-15] at weaning, and 10 [5-15] after ECMO, p<0.001). Left ventricular ejection fraction (LVEF) increased from 19 (0-22.5)% before ECMO to 35 (22-55)% after ECMO (p<0.001). A significant improvement of right ventricular (RV) function was observed in weaned patients (RV dysfunction from 52% to 21%, p<0.001). Among weaned patients, 15 (31%) died. Patients who died after weaning had longer ECMO duration compared to discharged patients (8 [5-11] v 4 [2-6] days, p = 0.01) and more transfusions (22 [10-37] v 7 [0.5-15] units, p = 0.02); survival was lower in patients with central ECMO (postcardiotomy) compared to peripheral ECMO (p = 0.045). Mortality was higher in those with persistence of RV failure, continuous venovenous hemofiltration, higher inotropic score, lower systolic pressure, or higher leucocyte count at weaning. CONCLUSIONS Successful weaning from ECMO is a multifaceted process, which encompasses consistent recovery of myocardial and end-organ function; LVEF, though improved, is still low at weaning. Hospital survival is correlated significantly to the duration of ECMO support and to bleeding complications.

Cardiac index assessment by the pressure recording analytic method in unstable patients with atrial fibrillation.

OBJECTIVE Most-Care (powered by the pressure-recording analytic method [PRAM]; Vytech HealthTM, Padova, Italy) is a minimally invasive cardiac output monitoring. This system already has been studied and validated in cardiac surgery and in children. It already showed a correlation with thermodilution methods in hemodynamically unstable patients. The purpose of this study was to confirm the reliability of cardiac index determinations by Most-Care in unstable patients with atrial fibrillation. DESIGN A prospective study. SETTING A teaching hospital. PARTICIPANTS Forty-nine patients. INTERVENTIONS Simultaneous cardiac index measurements by bolus thermodilution and by PRAM from a standard arterial access (radial and femoral) were obtained. The thermodilution cardiac index was calculated as the mean of 3 separate measurements. Because PRAM is a beat-to-beat monitoring system, the mean cardiac index of 12 consecutive beats was considered for the analysis. Correlations were calculated and differences compared by Bland-Altman analysis. MEASUREMENTS Eight patients were excluded because the signal was altered by the arterial catheter resonance so that the study described the remaining 41 patients. The overall estimates of cardiac index measured by PRAM did not show agreement with the reference cardiac index by thermodilution (mean difference = 0.136 L/min/m(2) [0,43 L/min/m(2)-0.15 L/min/m(2)], with an upper limit of agreement of 1.94 L/min/m(2) and a lower limit of agreement of -1.665 L/min/m(2), respectively). The median (interquartile) value of cardiac index assessed by thermodilution was 2.42 L/min/m(2) (2.21-2.98 L/min/m(2)), and by PRAM it was 2.48 L/min/m(2) (1.80-3.00 L/min/m(2), p = 0.6). CONCLUSIONS The authors concluded that PRAM did not compare well with thermodilution in unstable patients with atrial fibrillation.

Primary Anticoagulation With Bivalirudin for Patients With Implantable Ventricular Assist Devices

Bivalirudin is a direct thrombin inhibitor that is increasingly used in patients undergoing mechanical circulatory support as it presents many advantages compared with unfractionated heparin. The aim of this study was to describe our experience with bivalirudin as primary anticoagulant in patients undergoing ventricular assist device (VAD) implantation. An observational study was performed on 12 consecutive patients undergoing VAD implantation at our institution. Patients received a continuous infusion of bivalirudin, with a starting dose of 0.025 mg/kg/h; the target activated partial thromboplastin time (aPTT) was between 45 and 60 s. Patients never received heparin during hospitalization nor had a prior diagnosis of heparin-induced thrombocytopenia (HIT). All patients received a continuous flow pump except one. Preoperative platelets count was 134 000 ± 64 000 platelets/mm(3) . Mean bivalirudin dose was 0.040 ± 0.026 mg/kg/h over the course of therapy (5-12 days). Lowest platelets count during treatment was 73 000 ± 23 000 platelets/mm(3) . No thromboembolic complications occurred. Two episodes of minor bleeding from chest tubes that subsided after reduction or temporary suspension of bivalirudin infusion were observed. Intensive care unit stay was 8 (7-17) days, and hospital stay was 25 (21-33) days. Bivalirudin is a valuable option for anticoagulation in patients with a VAD and can be easily monitored with aPTT. The use of a bivalirudin-based anticoagulation strategy in the early postoperative period may overcome many limitations of heparin and, above all, the risk of HIT, which is higher in patients undergoing VAD implantation. Bivalirudin should no longer be regarded as a second-line therapy for anticoagulation in patients with VAD. [Correction added on 6 December 2013, after first online publication: The dose of bivalirudin in the Abstract to 0.025 mg/kg/h].

A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience

Phosphorylcholine coating has a major role in the improvement of biocompatibility, durability and antihrombogenicity of the circuit for extracorporeal membrane oxygenation (ECMO). Moreover, if heparin-induced thrombocytopenia ensues, removal of all the sources of heparin is challenging if the circuit is coated with heparin. We report our preliminary experience with the new EUROSETS A.L.ONE ECMO oxygenator (Eurosets, Medolla, MO, Italy), which is aimed at providing better biocompatibility thanks to its full coating with phosphorylcholine. We retrospectively collected data on the 16 patients supported with ECMO and with the EUROSETS A.L.ONE ECMO oxygenator at San Raffaele Hospital. Mean ECMO duration was 6 ± 4 days, and 37.5% of the patients died on ECMO. Four episodes of major bleeding and three episodes of minor bleeding were recorded. The oxygenator had an excellent performance in gas exchange and the median pressure drop was 57 (26-85) mmHg at full blood flow (2.5 L/m2/min). The EUROSETS A.L.ONE ECMO oxygenator was an excellent device in our preliminary experience. Further evaluation on a larger sample is encouraged.

Infections occurring in adult patients receiving mechanical circulatory support: The two-year experience of an Italian National Referral Tertiary Care Center

OBJECTIVE Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS None. RESULTS Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role.

The contemporary role of Impella in a comprehensive mechanical circulatory support program: a single institutional experience

BackgroundThe treatment of cardiogenic shock with percutaneous mechanical circulatory support (MCS) is attractive: however, at present it is not clear which is the best strategy, as no survival benefit has been demonstrated for any device as single therapy. Aim of this study is to describe the role of percutaneous Impella in a comprehensive MCS program.MethodsObservational study on 22 patients supported with the Impella device in our hospital from May 2013 to June 2014.ResultsFour patients (18 %) were treated with Impella alone, 8 patients (36 %) were treated with Impella and IABP, 6 patients (27 %) with Impella and VA ECMO, and 4 patients (18 %) with Impella, IABP and VA ECMO.The cause of cardiogenic shock was myocardial infarction (CSMI) in 9 patients (41 %), postcardiotomic cardiogenic shock in 5 (23 %), and a miscellaneous of other causes in the remaining 8 (36 %). Eight Impella devices (36 %) were placed under transesophageal echocardiographic guidance, while 14 (64 %) under fluoroscopy. The device was removed with manual compression at bedside and no vascular complications were observed.Duration of Impella support was 107 (54–141) hours and duration of ventilation was 48 (14–92) hours. Hemolysis occurred in 6 patients (27 %), while major bleeding in 4 patients (18 %). Survival was 73 %: 13 patients (58 %) showed recovery of cardiac function; 1 patient (5 %) was bridged to left ventricular assist device (LVAD) implantation, 1 patient (5 %) to heart transplantation (HTx) and 1 patient (5 %) received a BiVAD and was eventually bridged to HTx.ConclusionsOur data suggest that a multi-device approach, encompassing active LV support with Impella, is safe and can significantly improve survival in patients with cardiogenic shock.