Sergio Livigni

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.

The influence of gender on the epidemiology of and outcome from severe sepsis

IntroductionThe impact of gender on outcome in critically ill patients is unclear. Weinvestigated the influence of gender on the epidemiology of severe sepsis andassociated morbidity and mortality in a large cohort of ICU patients in the regionof Piedmont in Italy.MethodsThis was a post-hoc analysis of data from a prospective, multicenter,observational study in which all patients admitted to one of 24 participatingmedical and/or surgical ICUs between 3 April 2006 and 29 September 2006 wereincluded.ResultsOf the 3,902 patients included in the study, 63.5% were male. Female patients weresignificantly older than male patients (66 ± 16 years vs. 63 ± 16 years,P < 0.001). Female patients were less likely to have severe sepsisand septic shock on admission to the ICU and to develop these syndromes during theICU stay. ICU mortality was similar in men and women in the whole cohort (20.1%vs. 19.8%, P = 0.834), but in patients with severe sepsis wassignificantly greater in women than in men (63.5% vs. 46.4%, P = 0.007).In multivariate logistic regression analysis with ICU outcome as the dependentvariable, female gender was independently associated with a higher risk of ICUdeath in patients with severe sepsis (odds ratio = 2.33, 95% confidence interval =1.23 to 4.39, P = 0.009) but not in the whole cohort (odds ratio = 1.07,95% confidence interval = 0.87 to 1.34).ConclusionIn this large regional Italian cohort of ICU patients, there were more male thanfemale admissions. The prevalence of severe sepsis was lower in women than in men,but female gender was independently associated with a higher risk of death in theICU for patients with severe sepsis.

Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial

Objectives Coupled plasma filtration adsorption (CPFA, Bellco, Italy), to remove inflammatory mediators from blood, has been proposed as a novel treatment for septic shock. This multicenter, randomised, non-blinded trial compared CPFA with standard care in the treatment of critically ill patients with septic shock. Design Prospective, multicenter, randomised, open-label, two parallel group and superiority clinical trial. Setting 18 Italian adult, general, intensive care units (ICUs). Participants Of the planned 330 adult patients with septic shock, 192 were randomised to either have CPFA added to the standard care, or not. The external monitoring committee excluded eight ineligible patients who were erroneously included. Interventions CPFA was to be performed daily for 5 days, lasting at least 10 h/day. Primary and secondary outcome measures The primary endpoint was mortality at discharge from the hospital at which the patient last stayed. Secondary endpoints were: 90-day mortality, new organ failures and ICU-free days within 30 days. Results There was no statistical difference in hospital mortality (47.3% controls, 45.1% CPFA; p=0.76), nor in secondary endpoints, namely the occurrence of new organ failures (55.9% vs 56.0%; p=0.99) or free-ICU days during the first 30 days (6.8 vs 7.5; p=0.35). The study was terminated on the grounds of futility. Several patients randomised to CPFA were subsequently found to be undertreated. An a priori planned subgroup analysis showed those receiving a CPFA dose >0.18 L/kg/day had a lower mortality compared with controls (OR 0.36, 95% CI 0.13 to 0.99). Conclusions CPFA did not reduce mortality in patients with septic shock, nor did it positively affect other important clinical outcomes. A subgroup analysis suggested that CPFA could reduce mortality, when a high volume of plasma is treated. Owing to the inherent potential biases of such a subgroup analysis, this result can only be viewed as a hypothesis generator and should be confirmed in future studies. ClinicalTrials.gov NCT00332371; ISRCTN24534559.

Study protocol: the DOse REsponse Multicentre International collaborative initiative (DO-RE-MI)

IntroductionCurrent practices for renal replacement therapy in intensive care units (ICUs) remain poorly defined. The DOse REsponse Multicentre International collaborative initiative (DO-RE-MI) will address the issue of how the different modes of renal replacement therapy are currently chosen and performed. Here, we describe the study protocol, which was approved by the Scientific and Steering Committees.MethodsDO-RE-MI is an observational, multicentre study conducted in ICUs. The primary end-point will be the delivered dose of dialysis, which will be compared with ICU mortality, 28-day mortality, hospital mortality, ICU length of stay and number of days of mechanical ventilation. The secondary end-point will be the haemodynamic response to renal replacement therapy, expressed as percentage reduction in noradrenaline (norepinephrine) requirement. Based on the the sample analysis calculation, at least 162 patients must be recruited. Anonymized patient data will be entered online in electronic case report forms and uploaded to an internet website. Each participating centre will have 2 months to become acquainted with the electronic case report forms. After this period official recruitment will begin. Patient data belong to the respective centre, which may use the database for its own needs. However, all centres have agreed to participate in a joint effort to achieve the sample size needed for statistical analysis.ConclusionThe study will hopefully help to collect useful information on the current practice of renal replacement therapy in ICUs. It will also provide a centre-based collection of data that will be useful for monitoring all aspects of extracorporeal support, such as incidence, frequency, and duration.

Making a case for controlled organ donation after cardiac death: the story of Italy's first experience

Donation after circulatory death (DCD) is a valuable option for the procurement of organs for transplantation. In Italy, organ procurement after controlled DCD is legally and ethically conceivable within the current legislative framework. However, although formal impediments do not exist, the health care team is faced with many obstacles that may hinder the implementation of such programs. We report the case of Italys first controlled DCD, specifically discussing the role of the patients family in the shared decision-making process. In our case, the death of the patient subsequent to the withdrawal of life-sustaining therapies was consistent with the patients wishes, showing respect for his dignity and honoring his autonomy, as expressed to his family previously. By making donation possible, the medical team was able to fulfill the familys last request on behalf of the patient. This case should stimulate deliberation regarding the potential to shorten the 20-minute no-touch period currently in place in Italy. Such an action would not have injured this patient and would certainly have increased the quality of the procured organs.

Drotrecogin alfa (activated) in severe sepsis

PROWESS was a multicentre, double-blind, randomised placebocontrolled study that enrolled 1658 patients with severe sepsis and septic shock and showed a 6% absolute reduction in 28 day mortality with drotrecogin alfa (activated) treatment. However, two additional randomised controlled trials, ADDRESS and PROWESSSHOCK, failed to show a benefi t of the drug in all patients and in the subgroup with an APACHE II score of more than 25. A meta-analysis of the three randomised controlled trials shows no overall benefi t (fi gure). In this context, the meta-analysis by Kalil and LaRosa and the accompanying Comment by Vincent are disconcerting. A meta-analysis is considered the highest level of evidence when done to exacting standards. Kalil and LaRosa included retrospective cohort studies and studies with no control groups, and used complicated propensity matching, which added further ambiguity to their analysis. The Metaanalysis of Observational Studies in Epidemiology (MOOSE) group and a review on systematic reviews emphasise that the “meta-analysis of observational data may produce spurious results due to bias and confounding...and that the statistical combination of data should not be a prominent component of systematic reviews of observational data”. PROWESS, ADDRESS, and PROWESS-SHOCK should stand alone, and the uncontrolled and retrospective studies should be excluded from analysis. Limiting the analysis to these three trials does not get rid of statistical heterogeneity (I2 =72%, p=0·03, with PROWESS as a statistical outlier). The removal of PROWESS eliminates this heterogeneity (I2=0) and shifts the treatment eff ect towards harm (odds ratio 1·12, 95% CI 0·96–1·29), which suggests that drotrecogin alfa (activated) does not improve the outcome of patients with sepsis and septic shock. Therefore, I believe that the results of the analysis by Kalil and LaRosa are spurious.

Response to the letter by Williams et al.

Sir: The experts at Eli Lilly and Company appear concerned about whether the covariates considered in our multivariate analysis were predefined or not. We object that since observational studies often carry unforeseeable confounders, it is advisable to explore available data to find the variables needed to adjust the estimates of interest, in an effective multivariate analysis [1]. Therefore, unlike subgroup analysis in randomised controlled trials (RCTs), it is illogical to prospectively define all confounders in observational studies. However, the covariates that turned out to be significant in our study were a logical choice suggested by the literature and were selected before performing the statistical analysis. We are aware that RCTs offer the best evidence for drug efficacy. As asserted in our article [2], the conclusions that the target population for drotrecogin alfa (activated) (DrotAA) is not clearly defined, and that some subsets of patients could suffer harm from treatment, are based not only on the results of our study but also on evidence provided by available RCTs, which we believe are insufficient to demonstrate the efficacy of DrotAA in the subgroups of patients for whom the drug has been labelled. Actually, both the EMEA [3] and the FDA [4] have indicated DrotAA for subgroups of patients that were not included in a predefined confirmatory plan of the PROWESS protocol, as Lilly’s researchers acknowledged [5]. The overall positive result of the trial does not substantially modify the inappropriateness of the post-hoc subgroup analyses performed [6], especially when dealing with a drug approval based on a single pivotal trial. We believe that in the light of the flawed approval of DrotAA, the greatest attention should be paid to results from post-marketing studies, such as the one we carried out in Italy. In this context, where the efficacy of the drug for at least part of the population eligible for treatment is questioned, it is advisable to warn about the risk of life-threatening adverse events, although their occurrence is infrequent. Since Lilly has always rejected any criticism regarding the efficacy of DrotAA, we are quite surprised to observe that its experts acknowledge the need for a confirmatory trial. We interpret this as an agreement on at least one of the conclusions of our article, namely that the septic population target of DrotAA is not clearly defined. We hope that this confirmatory trial will recruit patients who meet the current indications for DrotAA administration, in order to avoid creating more confusion on indications. Finally, why are we convinced that the confirmatory trial should not be carried out by researchers who have any kind of conflict of interest? The debate on the efficacy and safety of DrotAA has been rather intense, with harsh conflicting opinions being expressed. Serious concerns have been raised regarding the conduction and analysis of the PROWESS trial: inadequacy of blinding, “favourable” changes in enrolment sites, differences in “do not resuscitate” orders between treated and placebo groups, and imbalances in important covariates in the subgroups for which the drug is labelled [7–9]. Moreover, it is well known that biases in sponsored trials may exist on multiple levels, and some suggest that the role of industry should be restricted to the funding of trials, while the design, conduct, analysis, and reporting should be left to independent researchers [10, 11]. In the case of DrotAA, this model for independent research represents a logical solution to guarantee transparent results and bring an end to the endless dispute about the safety, efficacy and indications of the drug. We believe that this is in the interest of patients and physicians, and it should also be in the interest of the company.

Reply to the comment on “Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock”

CRRT and further prospectively studied the temperature in the inlet and outlet lines for blood and dialysate of 27 other patients at various flow settings during continuous venovenous hemodialysis (CVVHD). These authors found that hypothermia occurred in 50% of the cases and was rather long lasting (2.6±1.8 days). However, the increase in mean arterial blood pressure was not statistically significant. In a prospective arm using CVVHD the same authors reported that, using room temperature dialysate, CRRT significantly lowered patients’ core temperatures. In our own study [2] we did not investigate changes in core temperatures and cannot rule out their potential clinical relevance. Nevertheless, the saw-tooth pattern of PaO2/FIO2, mean arterial blood pressure, and systemic vascular resistance index would be more indicative for a nonspecific blood purification effect. In a preceding randomized pilot study [3] we observed that these hemodynamic effects observed with CPFA are significantly more marked than with CVVHDF. These data on the whole suggest that the nonspecific removal of bioactive mediators obtained by CPFA augments temperature-dependent hemodynamic effects common to any CRRT mode.