Roberta Meroni

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.

A new clinical multivariable model that predicts postoperative acute kidney injury: impact of endogenous ouabain

BACKGROUND Acute kidney injury (AKI) is an important complication of cardiac surgery. Recently, elevated levels of endogenous ouabain (EO), an adrenal stress hormone with haemodynamic and renal effects, have been associated with worse renal outcome after cardiac surgery. Our aim was to develop and evaluate a new risk model of AKI using simple preoperative clinical parameters and to investigate the utility of EO. METHODS The primary outcome was AKI according to Acute Kidney Injury Network stage II or III. We selected the Northern New England Cardiovascular Disease Study Group (NNECDSG) as a reference model. We built a new internal predictive risk model considering common clinical variables (CLIN-RISK), compared this model with the NNECDSG model and determined whether the addition of preoperative plasma EO improved prediction of AKI. RESULTS All models were tested on >800 patients admitted for elective cardiac surgery in our hospital. Seventy-nine patients developed AKI (9.9%). Preoperative EO levels were strongly associated with the incidence of AKI and clinical complication (total ICU stay and in-hospital mortality). The NNECDSG model was confirmed as a good predictor of AKI (AUC 0.74, comparable to the NNECDSG reference population). Our CLIN-RISK model had improved predictive power for AKI (AUC 0.79, CI 95% 0.73-0.84). Furthermore, addition of preoperative EO levels to both clinical models improved AUC to 0.79 and to 0.83, respectively (ΔAUC +0.05 and +0.04, respectively, P < 0.01). CONCLUSION In a population where the predictive power of the NNECDSG model was confirmed, CLIN-RISK was more powerful. Both clinical models were further improved by the addition of preoperative plasma EO levels. These new models provide improved predictability of the relative risk for the development of AKI following cardiac surgery and suggest that EO is a marker for renal vascular injury.

A survey on the use of intra-aortic balloon pump in cardiac surgery

Intra-aortic balloon pump (IABP) is an established tool in the management of cardiac dysfunction in cardiac surgery. The best timing for IABP weaning is unknown and varies greatly among cardiac centers. The authors investigated the differences in IABP management among 66 cardiac surgery centers performing 40,675 cardiac surgery procedures in the 12-month study period. The centers were contacted through email, telephone, or in person interview. IABP management was very heterogeneous in this survey: In 43% centers it was routinely removed on the first postoperative day, and in 34% on the second postoperative day. In 50% centers, it was routinely removed after extubation of the patients whereas in 15% centers it was removed while the patients were sedated and mechanically ventilated. In 66% centers, patients were routinely receiving pharmacological inotropic support at the time of removal of IABP. The practice of decreasing IABP support was also heterogeneous: 57% centers weaned by reducing the ratio of beat assistance whereas 34% centers weaned by reducing balloon volume. We conclude that the management of IABP is heterogeneous and there is a need for large prospective studies on the management of IABP in cardiac surgery.

Feasibility of Anesthesia Maintenance With Sevoflurane During Cardiopulmonary Bypass: A Pilot Pharmacokinetics Study

OBJECTIVE Adequate maintenance of hypnosis during anesthesia throughout surgery using sevoflurane alone was investigated. In addition, sevoflurane pharmacokinetics during cardiopulmonary bypass were analyzed. DESIGN This was a pilot pharmacokinetic study. SETTING Tertiary care university hospital. PARTICIPANTS The study comprised 10 patients aged between 18 and 75 years who underwent elective mitral valve surgery. INTERVENTIONS The end-tidal and sevoflurane plasma concentrations were measured throughout cardiac surgery procedures involving cardiopulmonary bypass. The sevoflurane plasma concentration was measured using gas chromatography. In addition, the ratio between sevoflurane alveolar concentration and inspired concentration over time (FA/FI) was analyzed to describe wash-in and wash-out curves. MEASUREMENTS AND MAIN RESULTS Hypnosis was maintained adequately throughout surgery using sevoflurane alone. The bispectral index was maintained between 40 and 60 during cardiopulmonary bypass. The end-tidal sevoflurane was significantly different before and during cardiopulmonary bypass (1.86%±0.54% v 1.30%±0.58%, respectively; p<0.001). However, the sevoflurane plasma concentration was not significantly different before and after cardiopulmonary bypass start-up (40.55 µg/mL [76.62-125.33] before cardiopulmonary bypass and 36.24 µg/mL [56.49-81-42] during cardiopulmonary bypass). This mismatch possibly can be explained by changes that occured after cardiopulmonary bypass start-up, such as reductions of body temperature (36.33°C±0.46°C v 32.98°C±2.38°C, respectively; p<0.001) and hematocrit (35.62%±3.98% v 25.5%±3.08%, respectively; p<0.001). The sevoflurane alveolar concentration varied according to sevoflurane plasma concentration and bispectral index values. No adverse events regarding sevoflurane administration during cardiopulmonary bypass were observed. CONCLUSIONS Sevoflurane end-tidal values were reliable indicators of adequate anesthesia during all cardiac surgery procedures involving cardiopulmonary bypass.

Urinary neutrophil gelatinase-associated lipocalin time course during cardiac surgery.

Background: NGAL is one of the most promising AKI biomarkers in cardiac surgery. However, the best timing to dose it and the reference values are still matter of discussion. Aim of the Study: We performed a uNGAL perioperative time course, to better understand its perioperative kinetics and its role in AKI diagnosis. Setting of the Study: San Raffaele University Hospital, cardiac surgery department. Material and Methods: We enrolled in this prospective observational study 19 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Based on preoperative characteristics, they were divided in low-risk and high-risk patients. uNGAL measurements were collected at pre-defined times before, during, and up to 24 hours after surgery. Statistical Analysis: Data were analysed by use of SAS 1999-2001 program or IBM SPSS Statistics. Results: In low-risk patients, uNGAL had the highest value immediately after general anesthesia induction (basal dosage: uNGAL: 12.20ng×ml-1, IQR 14.00). It later decreased significantly (3.40 ng×ml-1, IQR 4.80; P = 0.006) during CPB, and finally return to its original value 24 hours after surgery. In high-risk patients, uNGAL increased immediately after surgery; it had the highest value on ICU arrival (38,20 ng×ml-1; IQR 133,10) and remained high for several hours. A difference in uNGAL levels between the two groups was already observed at the end of surgery, but it became statistically significant on ICU arrival (P = 0.002). Conclusion: This study helps to better understand the different kinetics of this new biomarker in low-risk and high-risk cardiac patients.

Preoperative Urinary Neutrophil Gelatinase-Associated Lipocalin and Outcome in High-Risk Heart Failure Patients Undergoing Cardiac Surgery

OBJECTIVE To investigate the ability of early urinary neutrophil gelatinase-associated lipocalin to predict postoperative complications in adult patients with ventricular dysfunction undergoing cardiac surgery. DESIGN Prospective observational study. SETTING Single-center study, university hospital. PARTICIPANTS Fifty-six adult high-risk cardiac surgical patients with preoperative cardiac failure. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Demographic and clinical characteristics were obtained, and neutrophil gelatinase-associated lipocalin was measured at baseline and at several time points after surgery. Patient characteristics and neutrophil gelatinase-associated lipocalin levels were related to renal and patient outcome. On multivariate analyses, preoperative urinary neutrophil gelatinase-associated lipocalin was an independent predictor of length of intensive care stay (p = 0.004) and in-hospital stay (p = 0.04), but not of acute kidney injury or renal replacement therapy and was not associated with baseline renal function. CONCLUSIONS In a cohort of high-risk cardiac surgery patients, preoperative urinary neutrophil gelatinase-associated lipocalin value provided prognostic information that was independent of the onset of acute kidney injury or of preoperative renal function.

Biomarkers in acute kidney injury: that’s all the story?

Initial correspondence from Drs. Meroni, Simonini, Casamassima, Bignami We would like to add to the recent editorial by McMahon [1] on biomarkers of acute kidney injury (AKI), with a specific focus on biomarkers in the clinical setting of cardiac surgery-associated AKI (CSA-AKI). We agree with McMahon that biomarkers may aid in the early diagnosis of AKI and that they represent an excellent tool for predicting treatment response. Their role may be pivotal in CSA-AKI, since the pre-operative identification of high-risk patients remains challenging. Most pre-operative AKI prognostication tools include patient-specific risk factors, comorbidities and type of surgery. We propose that incorporating one or more biomarkers into this battery of tools will improve the definition of individual susceptibility to AKI and could support decision-making, pre-operative optimization and outcome improvement [2]. To this end, we studied endogenous ouabain (EO), an adrenal stress hormone, in a large cohort of patients undergoing cardiac surgery. We found that the pre-operative plasmatic EO value was a strong predictor of CSAAKI, likely identifying those patients with pre-existing subclinical kidney injury. Furthermore, higher EO values were associated with increased mortality and length of hospital and ICU stay, further supporting the prognostic power of EO values. We then added EO pre-operative levels to two validated clinical-based AKI prediction tools (the Northern New England Cardiovascular Disease Study Group score and our recently published CLINRISK score), assessed in >800 patients. Captivatingly, the prediction power of both models was significantly improved (area under the curve values of 0.74 and 0.79 increased to 0.79 and 0.83, respectively, P < 0.01) [3]. In conclusion, biomarkers could be powerful predictive and prognostic tools in pre-operative assessment, especially as a part of multifactorial models that comprise also clinical and possibly genetic data, paving the way toward patient-tailored medicine.