Shaul Lev

Effectiveness and safety of colistin: prospective comparative cohort study

BACKGROUND Colistin has re-entered clinical use by necessity. We aimed to assess its effectiveness and safety compared with newer antibiotics. METHODS This was a single-centre, prospective cohort study. Inclusion criteria were microbiologically documented pneumonia, urinary tract infection, surgical site infection, meningitis or bacteraemia treated appropriately with colistin versus imipenem, meropenem or ampicillin/sulbactam (comparators). All consecutive patients were included, only once, between May 2006 and July 2009. The primary outcome was 30 day mortality. Multivariable and Cox regression survival analyses were used to adjust comparisons between groups. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals are reported. RESULTS Two hundred patients treated with colistin and 295 patients treated with comparators were included. Treatment with colistin was associated with older age, admission from healthcare facilities, mechanical ventilation and lower rate of early appropriate antibiotic treatment. The 30 day mortality was 39% (78/200) for colistin versus 28.8% (85/295) for comparators; unadjusted OR 1.58 (1.08-2.31). In the adjusted analysis the OR was 1.44 (0.91-2.26) overall and 1.99 (1.06-3.77) for bacteraemic patients (n = 220). At the end of follow-up, treatment with colistin was significantly associated with cumulative mortality; adjusted HR 1.27 (1.01-1.60) overall and 1.65 (1.18-2.31) among patients with bacteraemia. Nephrotoxicity at the end of treatment was more frequent with colistin; OR adjusted for other risk factors for nephrotoxicity 3.31 (1.54-7.08). Treatment with colistin was followed by increased incidence of Proteus spp. infections during a 3 month follow-up. CONCLUSIONS The need for colistin treatment is associated with poorer survival. Adjusted analyses suggest that colistin is less effective and more toxic than beta-lactam antibiotics.

DJ-1 protects against dopamine toxicity

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons. Dopamine is a highly toxic compound leading to generation of reactive oxygen species (ROS). DJ-1 mutations lead to early-onset inherited PD. Here, we show that DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway. This mechanism elucidates how mutations in DJ-1 prompt PD and imply that modulation of DJ-1 may serve as a novel neuroprotective modality.

Extubation outcome following a spontaneous breathing trial with automatic tube compensation versus continuous positive airway pressure

Objective:We hypothesized that the additional use of automatic tube compensation (ATC) during a spontaneous breathing trial with continuous positive airway pressure (CPAP), by minimizing respiratory work, would result in more patients undergoing successful extubation. Design:Prospective, randomized, controlled study. Setting:A ten-bed, general intensive care department at a tertiary-care hospital. Patients:Adult patients (n = 99) who had undergone mechanical ventilation for >24 hrs and met defined criteria for a weaning trial. Interventions:Patients were randomized to undergo a 1-hr spontaneous breathing trial with either ATC with CPAP (ATC group, n = 51) or CPAP alone (CPAP group, n = 48). ATC was provided by commercially available mechanical ventilators. Patients tolerating the spontaneous breathing trial underwent immediate extubation. The primary outcome measure was successful extubation, defined as the ability to maintain spontaneous breathing for 48 hrs after discontinuation of mechanical ventilation and extubation. Measurements and Main Results:There were no significant differences in demographic, respiratory, or hemodynamic characteristics between the two groups at the start of the spontaneous breathing trial. There was a trend for more patients in the ATC group to tolerate the breathing trial and undergo extubation (96% vs. 85%; p = .08). The rate of reintubation was 14% in the ATC group and 24% in the CPAP group (p = .28). Significantly more patients in the ATC group thus met the criteria for successful extubation (82% vs. 65%; p = 0.04). Conclusion:This is the largest single-center study to date assessing the use of commercially available ATC and suggests that this might be a useful mode for performing a spontaneous breathing trial preceding extubation in a general intensive care population.

Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome

Background: Heart valves lesions and central nervous system involvement are among the most common manifestations of the antiphospholipid syndrome (APS). Objective: To evaluate possible interrelations between these manifestations in a large group of APS patients. Methods: 284 APS patients were evaluated retrospectively, 159 of whom had primary APS. Cardiac–CNS associations were determined for the entire study population, and for subgroups of patients with primary APS or APS associated with systemic lupus erythematosus (SLE). Results: Significant associations where found between cardiac vegetations and epilepsy (p<0.02), and between cardiac valve thickening or dysfunction and migraine (p = 0.002). Borderline association was found between valvar vegetations and migraine (p = 0.09). A significant association was also found between all valvar lesions and stroke or transient ischaemic attacks. Subanalyses showed that patients with primary APS had significant associations between cardiac valve pathology and all CNS manifestations, while patients with APS associated with SLE had no such associations. Conclusions: The study suggests potential differences in biological behaviour between primary APS and APS associated with SLE. The presence of cardiac valve pathology may be a risk factor for several types of CNS involvement in PAPS.

Polyphenols in the prevention and treatment of sepsis syndromes: Rationale and pre-clinical evidence

Sepsis is the overwhelming systemic response to infection of a normally sterile body compartment. Despite advances in elucidating its pathophysiology, severe sepsis remains a leading cause of death in the critically ill. Polyphenols are a family of chemicals found in food and beverages derived from plants, such as cocoa, green tea, turmeric, and soya, as well as in medicinal herbs. These phytochemicals exhibit anti-inflammatory and vasculoprotective properties in clinical and preclinical studies. The oral or systemic administration of polyphenols protects rodents from endotoxinemia and microbial sepsis. Under these circumstances, polyphenols reproducibly attenuate microvascular hyperpermeability, tissue infiltration by leukocytes, oxidative and nitrosative stress, tissue injury, organ dysfunction, shock and vasoplegia, lactate production, and mortality. Importantly, efficacy is maintained in some cases even when treatment is initiated hours after the onset of sepsis. The inhibition of nuclear factor-kappaB activation and subsequent expression of inducible nitric oxide synthase, adhesion molecules, and tumor necrosis factor-alpha by polyphenols is operative in ameliorating the sequelae of sepsis. Enhancement of the endogenous antioxidant capacity probably also contributes to the effectiveness of the polyphenols. Because several of the polyphenols reviewed in this article appear to be safe and to exert anti-inflammatory effects in humans, clinical trials assessing their efficacy in the critically ill are indicated. Whether delivered alone or in combination with nutritional formulas, polyphenols may help to prevent and treat sepsis.

Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis

Objective International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock. Methods Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled. Results Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels. Conclusions Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

Organ transplantation from a donor colonized with a multidrug-resistant organism: a case report

The number of intensive care unit patients with infections caused by multidrug‐resistant organisms is increasing in most developed countries. We report the case of a deceased multiorgan donor, who was an asymptomatic carrier of carbapenem‐resistant Klebsiella pneumoniae (CR‐KP) in the respiratory tract, a condition that was not diagnosed before organ harvesting and transplantation. The outcome of the 2 kidney recipients, the liver recipient, and 1 of the lung recipients was uneventful; in particular, no evidence of infection transmission or adverse graft outcomes was noted. The other lung recipient had a complicated postoperative course and, 4 weeks post transplantation, he developed a bacteremic pneumonia with CR‐KP from which he subsequently died. These results suggest that, in well defined conditions, organs from donors who are CR‐KP positive may be considered for transplantation.

Prediction of extubation outcome: a randomised, controlled trial with automatic tube compensation vs. pressure support ventilation

IntroductionTolerance of a spontaneous breathing trial is an evidence-based strategy to predict successful weaning from mechanical ventilation. Some patients may not tolerate the trial because of the respiratory load imposed by the endotracheal tube, so varying levels of respiratory support are widely used during the trial. Automatic tube compensation (ATC), specifically developed to overcome the imposed work of breathing because of artificial airways, appears ideally suited for the weaning process. We further evaluated the use of ATC in this setting.MethodsIn a prospective study, patients who had received mechanical ventilation for more than 24 hours and met defined criteria for a weaning trial, underwent a one-hour spontaneous breathing trial with either ATC (n = 87) or pressure support ventilation (PSV; n = 93). Those tolerating the trial were immediately extubated. The primary outcome measure was the ability to maintain spontaneous, unassisted breathing for more than 48 hours after extubation. In addition, we measured the frequency/tidal volume ratio (f/VT) both with (ATC-assisted) and without ATC (unassisted-f/VT) at the start of the breathing trial as a pretrial predictor of extubation outcome.ResultsThere were no significant differences in any of the baseline characteristics between the two groups apart from a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score in the ATC group (p = 0.009). In the PSV group, 13 of 93 (14%) patients failed the breathing trial compared with only 6 of 87 (6%) in the ATC group; this observed 8% difference, however, did not reach statistical significance (p = 0.12). The rate of reintubation was not different between the groups (total group = 17.3%; ATC = 18.4% vs. PSV = 12.9%, p = 0.43). The percentage of patients who remained extubated for more than 48 hours was similar in both groups (ATC = 74.7% vs. PSV = 73.1%; p = 0.81). This represented a positive predictive value for PSV of 0.85 and ATC of 0.80 (p = 0.87). Finally, the ATC-assisted f/VT was found to have a significant contribution in predicting successful liberation and extubation compared with the non-significant contribution of the unassisted f/VT (unassisted f/VT, p = 0.19; ATC-assisted f/VT, p = 0.005).ConclusionsThis study confirms the usefulness of ATC during the weaning process, being at least as effective as PSV in predicting successful extubation outcome and significantly improving the predictive value of the f/VT.Trial registrationCurrent Controlled Trials ISRCTN16080446

Indirect calorimetry measurements in the ventilated critically ill patient: facts and controversies--the heat is on.

The provision of nutrition to critically ill patients in the ICU often receives lower priority compared with hemodynamic and ventilation control. This frequently results in a significant calorie deficit. Overestimation of daily energy expenditure may also result in adverse outcomes. In many centers, nutritional decision making is based on predictive formulas, which have been shown to underestimate true energy requirements. Such estimations are ideally performed using indirect calorimetry. Nevertheless, the use of indirect calorimetry has been limited owing to costs and technical difficulties. Controversies about its actual clinical benefits are the focus of recent clinical studies and recommendations. The aim of this review was to describe the advantages of measuring indirect calorimetry within the concept of energy-protein goal-oriented therapy.

The utilization of solid organs for transplantation in the setting of infection with multidrug‐resistant organisms: an expert opinion

Organ transplantation remains the optimal treatment for many patients suffering from end‐stage organ disease. Increasing numbers of patients admitted to intensive care units, among them potential heart‐beating, brain‐dead organ donors, are exposed to infections with multidrug‐resistant organisms, in particular carbapenem‐resistant Klebsiella pneumoniae (CR‐KP). An extensive literature search failed to reveal any information regarding the eligibility for transplantation of organs from such donors. For this reason, in 2009, the Israel Transplant Center, together with the Israeli Society for Infectious Diseases, established a working group with the intention of developing a national‐specific approach to the use of these organs. In this viewpoint article, we present an algorithm based on expert opinion and our clinical experience with a donor who was found to be an asymptomatic carrier of CR‐KP.