Nicola Brienza

Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock: The EUPHAS Randomized Controlled Trial

CONTEXT Polymyxin B fiber column is a medical device designed to reduce blood endotoxin levels in sepsis. Gram-negative-induced abdominal sepsis is likely associated with high circulating endotoxin. Reducing circulating endotoxin levels with polymyxin B hemoperfusion could potentially improve patient clinical outcomes. OBJECTIVE To determine whether polymyxin B hemoperfusion added to conventional medical therapy improves clinical outcomes (mean arterial pressure [MAP], vasopressor requirement, oxygenation, organ dysfunction) and mortality compared with conventional therapy alone. DESIGN, SETTING, AND PATIENTS A prospective, multicenter, randomized controlled trial (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis [EUPHAS]) conducted at 10 Italian tertiary care intensive care units between December 2004 and December 2007. Sixty-four patients were enrolled with severe sepsis or septic shock who underwent emergency surgery for intra-abdominal infection. INTERVENTION Patients were randomized to either conventional therapy (n=30) or conventional therapy plus 2 sessions of polymyxin B hemoperfusion (n=34). MAIN OUTCOME MEASURES Primary outcome was change in MAP and vasopressor requirement, and secondary outcomes were PaO(2)/FIO(2) (fraction of inspired oxygen) ratio, change in organ dysfunction measured using Sequential Organ Failure Assessment (SOFA) scores, and 28-day mortality. RESULTS MAP increased (76 to 84 mm Hg; P = .001) and vasopressor requirement decreased (inotropic score, 29.9 to 6.8; P < .001) at 72 hours in the polymyxin B group but not in the conventional therapy group (MAP, 74 to 77 mm Hg; P = .37; inotropic score, 28.6 to 22.4; P = .14). The PaO(2)/FIO(2) ratio increased slightly (235 to 264; P = .049) in the polymyxin B group but not in the conventional therapy group (217 to 228; P = .79). SOFA scores improved in the polymyxin B group but not in the conventional therapy group (change in SOFA, -3.4 vs -0.1; P < .001), and 28-day mortality was 32% (11/34 patients) in the polymyxin B group and 53% (16/30 patients) in the conventional therapy group (unadjusted hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20-0.94; adjusted HR, 0.36; 95% CI, 0.16-0.80). CONCLUSION In this preliminary study, polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality in a targeted population with severe sepsis and/or septic shock from intra-abdominal gram-negative infections. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00629382.

Goal-directed haemodynamic therapy and gastrointestinal complications in major surgery: a meta-analysis of randomized controlled trials

Postoperative gastrointestinal (GI) dysfunction is one of the most frequent complications in surgical patients. Most cases are associated with episodes of splanchnic hypoperfusion due to hypovolaemia or cardiac dysfunction. It has been suggested that perioperative haemodynamic goal-directed therapy (GDT) may reduce the incidence of these complications in cardiac surgery, and other surgery, but clear evidence is lacking. We have undertaken a meta-analysis of the effects of GDT on postoperative GI and liver complications. A systematic search, using MEDLINE, EMBASE, and The Cochrane Library databases, was performed. Sixteen randomized controlled trials (3410 participants) met the inclusion criteria. Data synthesis was obtained using odds ratio (OR) with 95% confidence interval (CI) by random-effects model. Statistical heterogeneity was assessed by Q and I2 statistics. GI complications were ranked as major (required radiological or surgical intervention or life-threatening condition) or minor (no or only pharmacological treatment required). Major GI complications were significantly reduced by GDT when compared with a control group (OR, 0.42; 95% CI, 0.27-0.65). Minor GI complications were also significantly decreased in the GDT group (OR, 0.29; 95% CI, 0.17-0.50). Treatment did not reduce hepatic injury rate (OR, 0.54; 95% CI, 0.19-1.55). Quality sensitive analyses confirmed the main overall results. In patients undergoing major surgery, GDT, by maintaining an adequate systemic oxygenation, can protect organs particularly at risk of perioperative hypoperfusion and is effective in reducing GI complications.

Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study

Objective:Postoperative acute deterioration in renal function, producing oliguria and/or increase in serum creatinine, is one of the most serious complication in surgical patients. Most cases are due to renal hypoperfusion as a consequence of systemic hypotension, hypovolemia, and cardiac dysfunction. Although some evidence suggests that perioperative monitoring and manipulation of oxygen delivery by volume expansion and inotropic drugs may decrease mortality in surgical patients, no study analyzed this approach on postoperative renal dysfunction. The objective of this investigation is to perform a meta-analysis on the effects of perioperative hemodynamic optimization on postoperative renal dysfunction. Data Sources, Study Selection, Data Extraction:A systematic literature review, using MEDLINE, EMBASE, and The Cochrane Library databases through January 2008 was conducted and 20 studies met the inclusion criteria (4220 participants). Data synthesis was obtained by using odds ratio (OR) with 95% confidence interval (CI) by random-effects model. Data Synthesis:Postoperative acute renal injury was significantly reduced by perioperative hemodynamic optimization when compared with control group (OR 0.64; CI 0.50-0.83; p = 0.0007). Perioperative optimization was effective in reducing renal injury defined consistently with risk, injury, failure, and loss and end-stage kidney disease and Acute Kidney Injury Network classifications, and in studies defining renal dysfunction by serum creatinine and/or need of renal replacement therapy only (OR 0.66; CI 0.50-0.88; p = 0.004). The occurrence of renal dysfunction was reduced when treatment started both preoperatively and intraoperatively or postoperatively, was performed in high-risk patients, and was obtained by fluids and inotropes. Mortality was significantly reduced in treatment group (OR 0.50; CI 0.31-0.80; p = 0.004), but statistical heterogeneity was observed. Conclusions:Surgical patients receiving perioperative hemodynamic optimization are at decreased risk of renal impairment. Because of the impact of postoperative renal complications on adverse outcome, efforts should be aimed to identify patients and surgery that would most benefit from perioperative optimization.

High Dose, Extended-Interval Colistin Administration in Critically Ill Patients: Is this the Right Dosing Strategy? A Preliminary Study

In critically ill patients with otherwise untreatable nosocomial infection due to gram-negative bacteria susceptible only to colistin, a high-dose, extended-interval colistin dosing regimen is, according to the pharmacokinetic/pharmacodynamic behavior of the drug, associated with low renal toxicity and high efficacy.

Fluid balance and urine volume are independent predictors of mortality in acute kidney injury

IntroductionIn ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI.MethodsWe performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression.ResultsOf the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 ± 1.24 versus 0.17 ± 0.72 L/day; P <0.001) and lower MUV (1.28 ± 0.90 versus 2.35 ± 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001).ConclusionsIn this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28-day mortality of AKI patients.

Haemodynamic goal-directed therapy and postoperative infections: earlier is better. a systematic review and meta-analysis

IntroductionInfectious complications are the main causes of postoperative morbidity. The early timing of their promoting factors is the rationale for perioperative strategies attempting to reduce them. Our aim was to determine the effects of perioperative haemodynamic goal-directed therapy on postoperative infection rates.MethodsWe performed a systematic review and meta-analysis. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched up to March 2011. Randomised, controlled trials of major surgery in adult patients managed with perioperative goal-directed therapy or according to routine haemodynamic practice were included. Primary outcome measure was specific type of infection.ResultsTwenty-six randomised, controlled trials with a combined total of 4,188 participants met our inclusion criteria. Perioperative goal-directed therapy significantly reduced surgical site infections (pooled OR 0.58, 95% CI 0.46 to 0.74; P < 0.0001), pneumonia (pooled OR 0.71, 95% CI 0.55 to 0.92; P = 0.009), and urinary tract infections (pooled OR 0.44, 95% CI 0.22 to 0.84; P = 0.02). A significant benefit was found regarding total infectious episodes (OR 0.40, 95% CI 0.28 to 0.58; P < 0.00001).ConclusionsFlow-directed haemodynamic therapy designed to optimise oxygen delivery protects surgical patients against postoperative hospital-acquired infections and must be strongly encouraged, particularly in the high-risk surgical population.

A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients*

Objective:Fenoldopam mesylate is a selective dopamine-1 agonist, with no effect on dopamine-2 and &agr;1 receptors, producing a selective renal vasodilation. This may favor the kidney oxygen supply/demand ratio and prevent acute renal failure. The aim of the study was to investigate if fenoldopam can provide greater benefit than low-dose dopamine in early renal dysfunction of critically ill patients. Design:Prospective, multiple-center, randomized, controlled trial. Setting:University and city hospital intensive care units. Patients:One hundred adult critically ill patients with early renal dysfunction (intensive care unit stay <1 wk, hemodynamic stability, and urine output ≤0.5 mL/kg over a 6-hr period and/or serum creatinine concentration ≥1.5 mg/dL and ≤ 3.5 mg/dL). Interventions:Patients were randomized to receive 2 &mgr;g/kg/min dopamine (group D) or 0.1 &mgr;g/kg/min fenoldopam mesylate (group F). Drugs were administered as continuous infusion over a 4-day period. Measurements and Main Results:Systemic hemodynamic and renal function variables were recorded daily. The two groups were well matched at enrollment for illness severity and hemodynamic and renal dysfunction. No differences in heart rate or systolic, diastolic, or mean arterial pressure were observed between groups. Fenoldopam produced a more significant reduction in creatinine values compared with dopamine after 2, 3, and 4 days of infusion (change from baseline at time 2, −0.32 vs. −0.03 mg/dL, p = .047; at time 3, −0.45 vs. −0.09 mg/dL, p = .047; and at time 4, −.041 vs. −0.09 mg/dL, p = .02, in groups F and D, respectively). The maximum decrease in creatinine compared with baseline was significantly greater in group F than group D (−0.53 ± 0.47 vs. −0.34 ± 0.38 mg/dL, p = .027). Moreover, 66% of patients in group F had a creatinine decrease >10% of the baseline value at the end of infusion, compared with only 46% in dopamine group (chi-square = 4.06, p = .04). Total urinary output during drug infusion was not significantly different between groups. After 1 day, urinary output was lower in group F compared with group D (p < .05). Conclusions:In critically ill patients, a continuous infusion of fenoldopam at 0.1 &mgr;g/kg/min does not cause any clinically significant hemodynamic impairment and improves renal function compared with renal dose dopamine. In the setting of acute early renal dysfunction, before severe renal failure has occurred, the attempt to reverse renal hypoperfusion with fenoldopam is more effective than with low-dose dopamine.

The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trials

IntroductionDynamic predictors of fluid responsiveness, namely systolic pressure variation, pulse pressure variation, stroke volume variation and pleth variability index have been shown to be useful to identify in advance patients who will respond to a fluid load by a significant increase in stroke volume and cardiac output. As a result, they are increasingly used to guide fluid therapy. Several randomized controlled trials have tested the ability of goal-directed fluid therapy (GDFT) based on dynamic parameters (GDFTdyn) to improve post-surgical outcome. These studies have yielded conflicting results. Therefore, we performed this meta-analysis to investigate whether the use of GDFTdyn is associated with a decrease in post-surgical morbidity.MethodsA systematic literature review, using MEDLINE, EMBASE, and The Cochrane Library databases through September 2013 was conducted. Data synthesis was obtained by using odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) by random-effects model.ResultsIn total, 14 studies met the inclusion criteria (961 participants). Post-operative morbidity was reduced by GDFTdyn (OR 0.51; CI 0.34 to 0.75; P <0.001). This effect was related to a significant reduction in infectious (OR 0.45; CI 0.27 to 0.74; P = 0.002), cardiovascular (OR 0.55; CI 0.36 to 0.82; P = 0.004) and abdominal (OR 0.56; CI 0.37 to 0.86; P = 0.008) complications. It was associated with a significant decrease in ICU length of stay (WMD -0.75 days; CI -1.37 to -0.12; P = 0.02).ConclusionsIn surgical patients, we found that GDFTdyn decreased post-surgical morbidity and ICU length of stay. Because of the heterogeneity of studies analyzed, large prospective clinical trials would be useful to confirm our findings.

Patient-requested neuraxial analgesia for labor: impact on rates of cesarean and instrumental vaginal delivery.

A systematic review, including a meta-analysis, on the timing effects of neuraxial analgesia (NA) on cesarean and instrumental vaginal deliveries in nulliparous women was conducted. Of 20 articles identified, 9 met the inclusion quality criteria (3,320 participants). Cesarean delivery (odds ratio, 1.00; 95% confidence interval, 0.82–1.23) and instrumental vaginal delivery (odds ratio, 1.00; 95% confidence interval, 0.83–1.21) rates were similar in the early NA and control groups. Neonates of women with early NA had a higher umbilical artery pH and received less naloxone. In the early NA group, fewer women were not compliant with assigned treatment and crossed over to the control group. Women receiving early NA for pain relief are not at increased risk of operative delivery, whereas those receiving early parenteral opioid and late epidural analgesia present a higher risk of instrumental vaginal delivery for nonreassuring fetal status, worse indices of neonatal wellness, and a lower quality of maternal analgesia.

Haemodynamic goal-directed therapy in cardiac and vascular surgery. A systematic review and meta-analysis

In cardiovascular surgery, reduced organ perfusion and oxygen delivery contribute to increased postoperative morbidity and prolonged intensive care unit stay. Goal-directed therapy (GDT), a perioperative haemodynamic strategy aiming to increase cardiac output, is helpful in preventing postoperative complications, but studies in the context of cardiovascular surgery have produced conflicting results. The purpose of the present meta-analysis is to determine the effects of perioperative haemodynamic goal-directed therapy on mortality and morbidity in cardiac and vascular surgery. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched until July 2011. Randomized controlled trials reporting on adult cardiac or vascular surgical patients managed with perioperative GDT or according to routine haemodynamic practice were included. Primary outcome measures were mortality and morbidity. Data synthesis was obtained by using odds ratio (OR) with 95% confidence interval (CI) by a random effects model. An OR <1 favoured GDT. Statistical heterogeneity was assessed by Q and I(2) statistics. Eleven articles (five cardiac surgery and six vascular procedures), enrolling a total sample of 1179 patients, were included in the analysis. As compared with routine haemodynamic practice, perioperative GDT did not reduce mortality in either cardiac or vascular surgery (pooled OR 0.87; 95% CI 0.37-2.02; statistical power 64%). GDT significantly reduced the number of cardiac patients with complications (OR 0.34; 95% CI 0.18-0.63; P = 0.0006), but no effect was observed in vascular patients (OR, 0.84; 95% CI 0.45-1.56; P = 0.58). Perioperative GDT prevents postoperative complications in cardiac surgery patients, while it has no effect in vascular surgery. The different characteristics and comorbidities of the population enrolled could explain these conflicting results. More trials conforming to the characteristics of low-risk-of-bias studies and enrolling a larger and well-defined population of patients are needed to better clarify the effect of GDT in the specific setting of cardiovascular surgery.