Alessandro Putzu

Liberal transfusion strategy improves survival in perioperative but not in critically ill patients. A meta-analysis of randomised trials

BACKGROUND Guidelines support the use of a restrictive strategy in blood transfusion management in a variety of clinical settings. However, recent randomized controlled trials (RCTs) performed in the perioperative setting suggest a beneficial effect on survival of a liberal strategy. We aimed to assess the effect of liberal and restrictive blood transfusion strategies on mortality in perioperative and critically ill adult patients through a meta-analysis of RCTs. METHODS We searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Transfusion Evidence Library, and Google Scholar up to 27 March 2015, for RCTs performed in perioperative or critically ill adult patients, receiving a restrictive or liberal transfusion strategy, and reporting all-cause mortality. We used a fixed or random-effects model to calculate the odds ratio (OR) and 95% confidence interval (CI) for pooled data. We assessed heterogeneity using Cochranes Q and I(2) tests. The primary outcome was all-cause mortality within 90-day follow-up. RESULTS Patients in the perioperative period receiving a liberal transfusion strategy had lower all-cause mortality when compared with patients allocated to receive a restrictive transfusion strategy (OR 0.81; 95% CI 0.66‒1.00; P=0.05; I(2)=25%; Number needed to treat=97) with 7552 patients randomized in 17 trials. There was no difference in mortality among critically ill patients receiving a liberal transfusion strategy when compared with the restrictive transfusion strategy (OR 1.10; 95% CI 0.99‒1.23; P=0.07; I(2)=34%) with 3469 patients randomized in 10 trials. CONCLUSION According to randomized published evidence, perioperative adult patients have an improved survival when receiving a liberal blood transfusion strategy.

Levosimendan reduces mortality in patients with severe sepsis and septic shock: A meta-analysis of randomized trials.

PURPOSE There is controversy about the use of inotropes in the treatment of severe sepsis and septic shock. The objective of this study was to evaluate if levosimendan, as compared with standard inotropic therapy (eg, dobutamine), reduces mortality in septic patients. MATERIALS AND METHODS BioMedCentral, PubMed, EMBASE, and the Cochrane Central Register were searched for pertinent studies, up to 1st May 2015. Randomized trials on the use of levosimendan in patients with severe sepsis and septic shock were included if reporting mortality data. The primary outcome was mortality, whereas secondary outcomes were blood lactate, cardiac index, total fluid infused, norepinephrine dosage, and mean arterial pressure. RESULTS Seven studies for a total of 246 patients were included in the analysis. Levosimendan was associated with significantly reduced mortality compared with standard inotropic therapy (59/125 [47%] in the levosimendan group and 74/121 [61%] in the control group; risk difference = -0.14, risk ratio = 0.79 [0.63-0.98], P for effect = .03, I(2) = 0%, numbers needed to treat = 7). Blood lactate was significantly reduced in the levosimendan group, whereas cardiac index and total fluid infused were significantly higher in the levosimendan group. No difference in mean arterial pressure and norepinephrine usage was noted. CONCLUSIONS In patients with severe sepsis and septic shock, levosimendan is associated with a significant reduction in mortality compared with standard inotropic therapy. A large ongoing multicenter randomized trial will have to confirm these findings.

Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials

Purpose: Low vitamin D blood levels are associated with high mortality in critically ill patients. There is controversy about vitamin D supplementation in this population. The objective of this meta‐analysis was to evaluate if vitamin D administration reduces mortality in critically ill patients. Materials and methods: Online databases were searched up to September 1st, 2016 for randomized placebo‐controlled trials on the use of vitamin D in adult patients with critical illness. The primary end point was mortality among trials with low risk of bias. The secondary end points were length of hospital stay, length of intensive care unit stay, length of mechanical ventilation, and adverse events. Results: Seven studies published between 2011 and 2016, for a total of 716 patients, were included in the analysis. Vitamin D administration was associated with significantly lower mortality compared with placebo (101/320 [32%] in the vitamin D group vs 123/307 [40%] in the placebo group; odds ratio, 0.70 [95% confidence interval, 0.50 to 0.98]; P = .04; I2 = 0%). No differences in adverse events and other secondary end points were found. Conclusions: In critically ill patients, vitamin D administration might be associated with a reduction in mortality without significant adverse events. A large multicenter randomized trial should conclusively confirm these findings.

Perioperative levosimendan in cardiac surgery: A systematic review with meta-analysis and trial sequential analysis

BACKGROUND Several studies suggested beneficial effects of perioperative levosimendan on postoperative outcome after cardiac surgery. However, three large randomized controlled trials (RCTs) have been recently published and presented neutral results. We performed a systematic review with meta-analysis and trial sequential analysis (TSA) to assess benefits and harms of perioperative levosimendan therapy in cardiac surgery. METHODS Electronic databases were searched up to September 2017 for RCTs on preoperative levosimendan versus any type of control. The Cochrane methodology was employed. We calculated odds ratio (OR) or Risk Ratio (OR) and 95% confidence interval (CI) using fixed-effects meta-analyses and we further performed TSA. RESULTS We included data from 40 RCTs and 4246 patients. Pooled analysis of 5 low risk of bias trials (1910 patients) showed no association between levosimendan and mortality (OR 0.86 [95% CI, 0.62, 1.18], p=0.34, TSA inconclusive), acute kidney injury, need of renal replacement therapy, myocardial infarction, ventricular arrhythmias, and serious adverse events, but an association with higher incidence of supraventricular arrhythmias (RR 1.11 [95% CI, 1.00, 1.24], p=0.05, TSA inconclusive) and hypotension (RR 1.15 [95% CI, 1.01, 1.30], p=0.04, TSA inconclusive). Analysis including all 40 trials found that levosimendan was associated with lower postoperative mortality (OR 0.56 [95% CI, 0.44, 0.71], p<0.00001, TSA conclusive), acute kidney injury, and renal replacement therapy, and higher incidence of hypotension. CONCLUSIONS There is not enough high-quality evidence to neither support nor discourage the systematic use of levosimendan in cardiac surgery.

Coronary artery bypass graft surgery versus percutaneous coronary intervention with drug-eluting stents for left main coronary artery disease: A meta-analysis of randomized trials

BACKGROUND Despite several clinical studies, efficacy of coronary artery bypass grafting (CABG) surgery versus percutaneous coronary intervention (PCI) in patients with left main (LM) disease remains controversial. The objective of this meta-analysis of randomized trials was to evaluate the clinical outcome of CABG versus PCI with drug-eluting stents in LM coronary disease. METHODS We systematically searched online databases up to March 2017 for randomized trials comparing CABG to PCI with drug-eluting stents. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS We included data from 5 randomized trials and 4595 patients. At 30days, CABG was associated with higher stroke (OR 2.54 [95% CI, 1.02-6.31]) and periprocedural myocardial infarction (OR 1.45 [95% CI, 1.00-2.10]), with no other significant differences compared to PCI. At 1year, CABG reduced repeat revascularization (OR 0.56 [95% CI, 0.40-0.77]), but increased stroke (OR 5.11 [95% CI, 1.62-16.12]). At 3-5years, CABG reduced repeat revascularization (OR 0.55 [95% CI, 0.45-0.67]) and non-periprocedural myocardial infarction (OR 0.45 [95% CI, 0.29-0.70]), without significant differences on other outcomes. CONCLUSIONS From the present updated meta-analysis of available studies on LM coronary disease treatment, there were no differences in mortality, myocardial infarction, and stroke rate at 3-5years follow-up after CABG or PCI, but CABG decreased the rate of repeat revascularization and non-periprocedural infarction. However, at short-term follow-up, CABG showed higher rate of stroke and periprocedural myocardial infarction, but these effects attenuated over time. These findings merit further investigation at longer follow-up.

Embolic protection devices for transcatheter aortic valve replacement

Transcatheter aortic valve replacement (TAVR) is a major advancement in the treatment of severe aortic valve stenosis in elderly high-risk patients. Implementing TAVR also in younger intermediate- or low-risk patients increases interest in the possibility of further lowering the risk of perioperative cerebrovascular events. To this aim, some embolic protection devices (EPDs) have been developed, some of which have already been approved for clinical use. Nevertheless, the cause of cerebrovascular events after TAVR is multifactorial, and selection of patients who would benefit from EPD is crucial to further improve outcomes, survival rate and quality of life. We reviewed the available literature in order to assess the incidence of and the mechanisms responsible for neurological events that can occur during TAVR, and we analysed clinical results and imaging findings following EPD use. Clinical trials for Embrella, TriGuard, Sentinel and Embol-X devices were designed to test their safety and their ability to prevent neurological complications in patients having TAVR. So far, published results showed that EPD may help in reducing the volume and size of periprocedural silent ischaemic brain lesions identified on magnetic resonance images but not in reducing the incidence of new lesions and new neurological events. The clinical impact of EPD in lowering the number of transient ischaemic attacks/strokes during TAVR needs to be further investigated in randomized trials.

Intermittent furosemide administration in patients with or at risk for acute kidney injury: Meta-analysis of randomized trials

Background Furosemide is the most common loop diuretic used worldwide. The off-label administration of furosemide bolus(es) for the prevention or to reverse acute kidney injury (AKI) is widespread but not supported by available evidence. We conducted a meta-analysis of randomized trials (RCTs) to investigate whether bolus furosemide to prevent or treat AKI is detrimental on patients’ survival. Methods Electronic databases were searched through October 2017 for RCTs comparing bolus furosemide administration versus any comparator in patients with or at risk for AKI. The primary endpoint was all-cause longest follow-up mortality. Secondary endpoints included new or worsening AKI, receipt of renal replacement therapy, length of hospital stay, and peak serum creatinine after randomization. Results A total of 28 studies randomizing 3,228 patients were included in the analysis. We found no difference in mortality between the two groups (143/892 [16%] in the furosemide group versus 141/881 [16%] in the control group; odds ratio [OR], 0.84; 95% confidence interval [CI], 0.63 to 1.13; p = 0.25). No significant differences in secondary outcomes were found. A significant improvement in survival was found in the subgroup of patients receiving furosemide bolus(es) as a preventive measure (43/613 [7.0%] versus 67/619 [10.8%], OR 0.62; 95% CI, 0.41 to 0.94; p = 0.03) Conclusions Intermittent furosemide administration is not associated with an increased mortality in patients with or at risk for AKI, although it may reduce mortality when used as a preventive measure. Future high-quality RCTs are needed to define the role of loop diuretics in AKI prevention and management. Trial registration The study protocol was registered on PROSPERO database for systematic reviews (Registration no. CRD42017078607 – http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017078607).

Vasopressors During Cardiopulmonary Resuscitation. A Network Meta-analysis of Randomized Trials

Objectives: Several randomized controlled trials have compared adrenaline (epinephrine) with alternative therapies in patients with cardiac arrest with conflicting results. Recent observational studies suggest that adrenaline might increase return of spontaneous circulation but worsen neurologic outcome. We systematically compared all the vasopressors tested in randomized controlled trials in adult cardiac arrest patients in order to identify the treatment associated with the highest rate of return of spontaneous circulation, survival, and good neurologic outcome. Design: Network meta-analysis. Patients: Adult patients undergoing cardiopulmonary resuscitation. Interventions: PubMed, Embase, BioMed Central, and the Cochrane Central register were searched (up to April 1, 2017). We included all the randomized controlled trials comparing a vasopressor with any other therapy. A network meta-analysis with a frequentist approach was performed to identify the treatment associated with the highest likelihood of survival. Measurements and Main Results: Twenty-eight studies randomizing 14,848 patients in 12 treatment groups were included. Only a combined treatment with adrenaline, vasopressin, and methylprednisolone was associated with increased likelihood of return of spontaneous circulation and survival with a good neurologic outcome compared with several other comparators, including adrenaline. Adrenaline alone was not associated with any significant difference in mortality and good neurologic outcome compared with any other comparator. Conclusions: In randomized controlled trials assessing vasopressors in adults with cardiac arrest, only a combination of adrenaline, vasopressin, and methylprednisolone was associated with improved survival with a good neurologic outcome compared with any other drug or placebo, particularly in in-hospital cardiac arrest. There was no significant randomized evidence to support neither discourage the use of adrenaline during cardiac arrest.

Prevention of organ dysfunction in septic shock: still looking for an effective treatment

Severe sepsis and septic shock are currently a major medical issue all over the world. Sepsis has a worldwide estimated incidence of up to 19 million per year (1) and accounts for more than one third of intensive care unit (ICU) admissions (2). Furthermore, reported incidence of sepsis has continuously risen in recent years (3). Despite improvement in patients’ care, mortality remains high (2-4), accounting for 5.3 million of deaths every year (5), even if a decrease in mortality rates is evident throughout the last years (3). As a consequence, identifying treatment strategies aimed at improving survival of septic patients is a primary goal of research in the field critical care medicine.

Hemodynamic challenge to early mobilization after cardiac surgery: A pilot study

Background: Active mobilization is a key component in fast-track surgical strategies. Following major surgery, clinicians are often reluctant to mobilize patients arguing that circulatory homeostasis would be impaired as a result of myocardial stunning, fluid shift, and autonomic dysfunction. Aims: We examined the feasibility and safety of a mobilization protocol 12-24 h after elective cardiac surgery. Setting and Design: This observational study was performed in a tertiary nonacademic cardiovascular Intensive Care Unit. Materials and Methods: Over a 6-month period, we prospectively evaluated the hemodynamic response to a two-staged mobilization procedure in 53 consecutive patients. Before, during, and after the mobilization, hemodynamics parameters were recorded, including the central venous oxygen saturation (ScvO 2 ), lactate concentrations, mean arterial pressure (MAP), heart rate (HR), right atrial pressure (RAP), and arterial oxygen saturation (SpO 2 ). Any adverse events were documented. Results: All patients successfully completed the mobilization procedure. Compared with the supine position, mobilization induced significant increases in arterial lactate (34.6% [31.6%, 47.6%], P = 0.0022) along with reduction in RAP (−33% [−21%, −45%], P < 0.0001) and ScvO 2 (−7.4% [−5.9%, −9.9%], P = 0.0002), whereas HR and SpO 2 were unchanged. Eighteen patients (34%) presented a decrease in MAP > 10% and nine of them (17%) required treatment. Hypotensive patients experienced a greater decrease in ScvO 2 (−18 ± 5% vs. −9 ± 4%, P = 0.004) with similar changes in RAP and HR. All hemodynamic parameters, but arterial lactate, recovered baseline values after resuming the horizontal position. Conclusions: Early mobilization after cardiac surgery appears to be a safe procedure as far as it is performed under close hemodynamic and clinical monitoring in an intensive care setting.