Guido Bertolini

Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial.

ObjectiveTo compare the mortality of critically ill patients given either enteral feeding with an immune-enhancing formula or parenteral nutrition (PN). We report the results of a planned interim analysis on patients with severe sepsis which was undertaken earlier than planned once a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition.DesignRandomised multicentre unblinded controlled clinical trial.SettingThirty-three General Intensive Care Units in Italy.Patients and participantsAmong the 237 recruited patients, 39 had severe sepsis or septic shock; 21 of them received PN.InterventionsEligible patients received either total PN or enteral nutrition, the latter containing extra L-arginine, omega-3 fatty acids, vitamin E, beta carotene, zinc, and selenium.Measurements and resultsThe primary endpoint for the subgroup analysis on patients with severe sepsis was mortality on Intensive Care Unit (ICU). The ICU mortality of patients with severe sepsis given enteral nutrition (EN) was higher than for those given PN (44.4% vs 14.3%; p=0.039). More patients given EN than patients given PN still had severe sepsis when they died (38.9% vs 9.5%, p=0.055). Recruitment of patients with severe sepsis was subsequently stopped.ConclusionsOur results show that enteral immunonutrition, compared to PN, may be associated with excess mortality in patients with severe sepsis.

Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study

Background: Critical illness myopathy (CIM) and polyneuropathy (CIP), alone or in combination (CIP/CIM), are frequent complications in patients in the intensive care unit (ICU). There is no evidence that differentiating between CIP and CIM has any impact on patient prognosis. Methods: 1-year prospective cohort study of patients developing CIP, CIM or combined CIP and CIM during ICU stay. Results: 28 out of 92 (30.4%) patients developed electrophysiological signs of CIP and/or CIM during their ICU stay, which persisted in 18 patients at ICU discharge. At hospital discharge, diagnoses in the 15 survivors were CIM in six cases, CIP in four, combined CIP and CIM in three and undetermined in two uncooperative patients. During the 1-year follow-up of six patients with CIM, one patient died and five recovered completely within 3 (three patients) to 6 (two patients) months. Of three patients with CIP/CIM, one died, one recovered and one with residual CIP remained tetraplegic. Of four patients with CIP, one recovered, two had persisting muscle weakness and one remained tetraparetic. Conclusion: CIM has a better prognosis than CIP. Differential diagnosis is important to predict long-term outcome in ICU patients.

Noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: A 5-year multicenter observational survey

Background:Mortality is high among patients with hematologic malignancies admitted to intensive care units for acute respiratory failure. Early noninvasive mechanical ventilation seems to improve outcomes. Objective:To characterize noninvasive mechanical ventilation use in Italian intensive care units for acute respiratory failure patients with hematologic malignancies and its impact on outcomes vs. invasive mechanical ventilation. Design, Setting, Participants:Retrospective analysis of observational data prospectively collected in 2002–2006 on 1,302 patients with hematologic malignancies admitted with acute respiratory failure to 158 Italian intensive care units. Measurements:Mortality (intensive care unit and hospital) was assessed in patients treated initially with noninvasive mechanical ventilation vs. invasive mechanical ventilation and in those treated with invasive mechanical ventilation ab initio vs. after noninvasive mechanical ventilation failure. Findings were adjusted for propensity scores reflecting the probability of initial treatment with noninvasive mechanical ventilation. Results:Few patients (21%) initially received noninvasive mechanical ventilation; 46% of these later required invasive mechanical ventilation. Better outcomes were associated with successful noninvasive mechanical ventilation (vs. invasive mechanical ventilation ab initio and vs. invasive mechanical ventilation after noninvasive mechanical ventilation failure), particularly in patients with acute lung injury/adult respiratory distress syndrome (mortality: 42% vs. 69% and 77%, respectively). Delayed vs. immediate invasive mechanical ventilation was associated with slightly but not significantly higher hospital mortality (65% vs. 58%, p = .12). After propensity-score adjustment, noninvasive mechanical ventilation was associated with significantly lower mortality than invasive mechanical ventilation. Limitations:The population could not be stratified according to specific hematologic diagnoses. Furthermore, the study was observational, and treatment groups may have included unaccounted for differences in covariates although the risk of this bias was minimized with propensity score regression adjustment. Conclusions:In patients with hematologic malignancies, acute respiratory failure should probably be managed initially with noninvasive mechanical ventilation. Further study is needed to determine whether immediate invasive mechanical ventilation might offer some benefits for those with acute lung injury/adult respiratory distress syndrome.

The relationship between labour cost per patient and the size of intensive care units: a multicentre prospective study

ObjectiveWe examined the relationship between major ICU characteristics and labour cost per patient.DesignFour-week prospective data collection, in which the hours spent by each physician and nurse on both in-ICU and extra-ICU activities were collected.SettingEighty Italian adult ICUs.Measurements and resultsThe cost of the time actually spent by ICU staff on ICU patients (labour cost) was computed for each participating unit, by applying to the average annual salaries the proportions of in-ICU activity working time for physicians and nurses. Multiple regression analysis was used to identify ICU characteristics that predict labour costs per patient. Labour cost per patient was positively correlated with ICU mortality and patients average length of stay (slopes =0.67, p =0.048 and 0.09, p <0.0001, respectively). Labour cost per patient decreases almost linearly as the number of beds increases up to about eight, and it remains nearly constant above about twelve beds. The number of patients admitted per physician (not per nurse) increases with the number of beds (Spearman correlation coefficient =0.567, p <0.0001).ConclusionsOur findings suggest that ICUs with less than about 12 beds are not cost-effective.

Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multi-centre CRIMYNE study

IntroductionCritical illness myopathy and/or neuropathy (CRIMYNE) is frequent in intensive care unit (ICU) patients. Although complete electrophysiological tests of peripheral nerves and muscles are essential to diagnose it, they are time-consuming, precluding extensive use in daily ICU practice. We evaluated whether a simplified electrophysiological investigation of only two nerves could be used as an alternative to complete electrophysiological tests.MethodsIn this prospective, multi-centre study, 92 ICU patients were subjected to unilateral daily measurements of the action potential amplitude of the sural and peroneal nerves (compound muscle action potential [CMAP]). After the first ten days, complete electrophysiological investigations were carried out weekly until ICU discharge or death. At hospital discharge, complete neurological and electrophysiological investigations were performed.ResultsElectrophysiological signs of CRIMYNE occurred in 28 patients (30.4%, 95% confidence interval [CI] 21.9% to 40.4%). A unilateral peroneal CMAP reduction of more than two standard deviations of normal value showed the best combination of sensitivity (100%) and specificity (67%) in diagnosing CRIMYNE. All patients developed the electrophysiological signs of CRIMYNE within 13 days of ICU admission. Median time from ICU admission to CRIMYNE was six days (95% CI five to nine days). In 10 patients, the amplitude of the nerve action potential dropped progressively over a median of 3.0 days, and in 18 patients it dropped abruptly within 24 hours. Multi-organ failure occurred in 21 patients (22.8%, 95% CI 15.4% to 32.4%) and was strongly associated with CRIMYNE (odds ratio 4.58, 95% CI 1.64 to 12.81). Six patients with CRIMYNE died: three in the ICU and three after ICU discharge. Hospital mortality was similar in patients with and without CRIMYNE (21.4% and 17.2%; p = 0.771). At ICU discharge, electrophysiological signs of CRIMYNE persisted in 18 (64.3%) of 28 patients. At hospital discharge, diagnoses in the 15 survivors were critical illness myopathy (CIM) in six cases, critical illness polyneuropathy (CIP) in four, combined CIP and CIM in three, and undetermined in two.ConclusionA peroneal CMAP reduction below two standard deviations of normal value accurately identifies patients with CRIMYNE. These should have full neurological and neurophysiological evaluations before discharge from the acute hospital.

Volume of activity and occupancy rate in intensive care units. Association with mortality

ObjectiveMortality after many procedures is lower in centers where more procedures are done. It is controversial whether this is true for intensive care units, too. We examined the relationship between the volume of activity of intensive care units (ICUs) and mortality by a measure of risk-adjusted volume of activity specific for ICUs.DesignProspective, multicenter, observational study.SettingEighty-nine ICUs in 12 European countries.PatientsDuring a 4-month study period, 12,615 patients were enrolled.InterventionsDemographic and clinical statistics, severity at admission and a score of nursing complexity and workload were collected.ResultsTotal volume of activity was defined as the number of patients admitted per bed per year, high-risk volume as the number of high-risk patients admitted per bed per year (selected combining of length of stay and severity of illness). A multi-step risk-adjustment process was planned. ICU volume corresponding both to overall [odds ratio (OR) 0.966] and 3,838 high-risk (OR 0.830) patients was negatively correlated with mortality. Relative mortality decreased by 3.4 and 17.0% for every five extra patients treated per bed per year in overall volume and high-risk volume, respectively. A direct relationship was found between mortality and the ICU occupancy rate (OR 1.324 and 1.351, respectively).ConclusionsIntensive care patients, whatever their level of risk, are best treated where more high-risk patients are treated. Moreover, the higher the ICU occupancy rate, the higher is the mortality.

Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial

ObjectivesWe compared early parenteral nutrition (PN) and early enteral immunonutrition (iEN) in critically ill patients, distinguishing those with and without severe sepsis or septic shock (SS) on admission to intensive care units (ICUs).Design and settingMulticenter, randomized, unblinded clinical trial in 33 Italian general ICUs.Patients and participantsThe study included 326 patients, 287 of whom did not have SS on ICU admission. Eligibility criteria excluded the two tails in the spectrum of critical conditions, i.e., patients either too well or too ill. Of the patients recruited 160 were randomized to iEN (142 without SS) and 166 to PN (145 without SS).InterventionsPatients were randomized to two arms: early iEN or early PN.Measurements and resultsPrimary endpoint was 28-day mortality for all patients and the occurrence of SS during ICU stay for patients admitted without such condition. While 28-day mortality did not differ between iEN and PN (15.6% vs. 15.1%), patients without SS who received iEN had fewer episodes of severe sepsis or septic shock (4.9% vs. 13.1%). ICU length of stay was 4 days shorter in patients given iEN.ConclusionsCompared to parenteral nutrition iEN appears to be beneficial in critical patients without severe sepsis or septic shock. Parenteral nutrition in these patients should be abandoned, at least when enteral nutrition can be administered, even at an initial low caloric content.

Efficacy and safety of a low-flow veno-venous carbon dioxide removal device: results of an experimental study in adult sheep

IntroductionExtracorporeal lung assist, an extreme resource in patients with acute respiratory failure (ARF), is expanding its indications since knowledge about ventilator-induced lung injury has increased and protective ventilation has become the standard in ARF.MethodsA prospective study on seven adult sheep was conducted to quantify carbon dioxide (CO2) removal and evaluate the safety of an extracorporeal membrane gas exchanger placed in a veno-venous pump-driven bypass. Animals were anaesthetised, intubated, ventilated in order to reach hypercapnia, and then connected to the CO2 removal device. Five animals were treated for three hours, one for nine hours, and one for 12 hours. At the end of the experiment, general anaesthesia was discontinued and animals were extubated. All of them survived.ResultsNo significant haemodynamic variations occurred during the experiment. Maintaining an extracorporeal blood flow of 300 ml/minute (4.5% to 5.3% of the mean cardiac output), a constant removal of arterial CO2, with an average reduction of 17% to 22%, was observed. Arterial partial pressure of carbon dioxide (PaCO2) returned to baseline after treatment discontinuation. No adverse events were observed.ConclusionWe obtained a significant reduction of PaCO2 using low blood flow rates, if compared with other techniques. Percutaneous venous access, simplicity of circuit, minimal anticoagulation requirements, blood flow rate, and haemodynamic impact of this device are more similar to renal replacement therapy than to common extracorporeal respiratory assistance, making it feasible not only in just a few dedicated centres but in a large number of intensive care units as well.

Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC)

BACKGROUND The lack of prospective, randomized, controlled trial data to guide optimal antibiotic use in bacteraemic critically ill patients has led to a wide variety of strategies and major issues with drug resistance. We therefore prospectively investigated the epidemiology of bacteraemia and fungaemia in intensive care units (ICUs); and the impact of timing, type and appropriateness of antibiotic intervention. METHODS We conducted a multinational, multicentre, prospective observational study in 132 ICUs from 26 countries with no interventions. RESULTS 1702 patients [European (69.6%), Australasian (12.2%), South American (8.3%) and Asian (9.9%)] developed 1942 bacteraemic episodes over the study period. Mortality rates were similar for those receiving empirical (40.5%), semi-targeted (37.6%) or fully targeted (33.3%) antibiotic therapy (P=0.40), and in those initially receiving broad- (39.3%) or restricted-spectrum (39.1%) therapy (P=0.94). First-line therapy was effective in terms of the antibiogram (where available) in 70.4% of cases. This in vitro susceptibility ranged from 76.3% for broad-spectrum antibiotics to 46.3% for restricted-spectrum antibiotics (P<0.0001). However, no antibiotic policy-associated variable, including in vitro susceptibility (odds ratio 0.89, 95% confidence interval 0.61-1.30), was a statistically significant predictor of mortality. CONCLUSIONS We could not show an impact of antibiotics on mortality in critically ill patients, despite in vitro activity and early commencement. Randomized, multicentre trials are urgently needed to establish the appropriate duration, timing and combinations of antibiotics that will both optimally treat infection and minimize development of resistance and other complications.

Building a continuous multicenter infection surveillance system in the intensive care unit: Findings from the initial data set of 9,493 patients from 71 Italian intensive care units

Objective:To describe the epidemiology of infections in intensive care units (ICUs), whether present at admission or acquired during the stay. Methods:Prospective data collection lasting 6 months in 71 Italian adult ICUs. Patients were screened for infections and risk factors at ICU admission and daily during their stay. Main Results:Out of 9,493 consecutive patients admitted to the 71 ICUs, 11.6% had a community-acquired infection, 7.4% a hospital-acquired infection, and 11.4% an ICU-acquired infection. The risk curve of acquiring infection in the ICU was higher in patients who entered without infection than in those already infected (log-rank test, p < .0001; at 15 days, 44.0% vs. 34.6%). Hospital mortality (27.8% overall) was higher in patients admitted with infection than in those who acquired infection in the ICU (45.0% vs. 32.4%, p < .0001). Although the presence of infection per se did not influence mortality, the conditions of severe sepsis and septic shock were strong prognostic factors (odds ratio, 2.3 and 4.8, respectively). Apart from ICU-acquired peritonitis, no other site of infection reached statistical significance as an independent prognostic factor for hospital mortality. Conclusions:Adding specific data on infections and risk factors to a well-established electronic data collection system is a reliable basis for a continuous multicenter infection surveillance program in the ICU. Given the well-established importance of infection prevention programs, our data suggest that the improvement of the treatment of severe sepsis and septic shock is the key to lower infection-related mortality in the ICU. This calls for closer attention to severe infections in surveillance programs.