Salvatore Lucio Cutuli

The Role of Mannose-Binding Lectin in Severe Sepsis and Septic Shock

Severe sepsis and septic shock are a primary cause of death in patients in intensive care unit (ICU). Investigations upon genetic susceptibility profile to systemic complications during severe infections are a field of increasing scientific interest. Particularly when adaptive immune system is compromised or immature, innate immunity plays a key role in the immediate defense against invasive pathogens. Mannose-binding lectin (MBL) is a serum protein that recognizes a wide range of pathogenic microorganisms and activates complement cascade via the antibody-independent pathway. More than 30% of humans harbor mutations in MBL gene (MBL2) resulting in reduced plasmatic levels and activity. Increased risk of infection acquisition has been largely documented in MBL-deficient patients, but the real impact of this form of innate immunosuppression upon clinical outcome is not clear. In critically ill patients higher incidence and worse prognosis of severe sepsis/septic shock appear to be associated with low-producers haplotypes. However an excess of MBL activation might be also harmful due to the possibility of an unbalanced proinflammatory response and an additional host injury. Strategies of replacement therapies in critically ill patients with severe infections are under investigation but still far to be applied in clinical practice.

Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case–control study

BackgroundRecent reports have suggested the efficacy of a double carbapenem (DC) combination, including ertapenem, for the treatment of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) infections. We aimed to evaluate the clinical impact of such a regimen in critically ill patients.MethodsThis case–control (1:2), observational, two-center study involved critically ill adults with a microbiologically documented CR-Kp invasive infection treated with the DC regimen matched with those receiving a standard treatment (ST) (i.e., colistin, tigecycline, or gentamicin).ResultsThe primary end point was 28-day mortality. Secondary outcomes were clinical cure, microbiological eradication, duration of mechanical ventilation and of vasopressors, and 90-day mortality. Forty-eight patients treated with DC were matched with 96 controls. Occurrence of septic shock at infection and high procalcitonin levels were significantly more frequent in patients receiving DC treatment (p < 0.01). The 28-day mortality was significantly higher in patients receiving ST compared with the DC group (47.9% vs 29.2%, p = 0.04). Similarly, clinical cure and microbiological eradication were significantly higher when DC was used in patients infected with CR-Kp strains resistant to colistin (13/20 (65%) vs 10/32 (31.3%), p = 0.03 and 11/19 (57.9%) vs 7/27 (25.9%), p = 0.04, respectively). In the logistic regression and multivariate Cox-regression models, the DC regimen was associated with a reduction in 28-day mortality (OR 0.33, 95% CI 0.13–0.87 and OR 0.43, 95% CI 0.23–0.79, respectively).ConclusionsImproved 28-day mortality was associated with the DC regimen compared with ST for severe CR-Kp infections. A randomized trial is needed to confirm these observational results.Trial registrationClinicalTrials.gov NCT03094494. Registered 28 March 2017.

Polymyxin B hemoperfusion in septic shock: just look at the evidence!

Dear Editor, We read with interest the paper on the ABDO-MIX trial by Payen et al. [1] that showed the inefficacy of the early use of Polymyxin B hemoperfusion (PMX-HP) in peritonitis-induced septic shock after surgery. The authors should be commended for their interesting study and efforts, but we would like to make some additional comments. Payen et al. observed an unexpectedly lower 28-day mortality (PMX-HP group 27.7 % vs control group 19.5 %, p = 0.14) than that ranging between 32.7 % and 53 % reported in larger studies [2–4] about similar cohorts. ABDO-MIX enrolled patients affected by peritonitis due to gut or biliary tract perforation, excluding other life-threatening abdominal diseases included in EUPHAS2 such as ischemia, obstruction, inflammatory colitis, and trauma. A total of 232 out of the estimated 240 patients were enrolled in ABDO-MIX, but only 81 of the 119 treated had completed two sessions of PMX-HP. In EUPHAS, whose results were used for the ABDO-MIX sample size calculation, all patients enrolled had completed the two planned sessions of PMX-HP with a definitely higher mortality in the control group. Among the reasons for non-completion of the two planned sessions of PMX-HP, Payen et al. indicated cartridge clotting and severe hemodynamic instability. A suboptimal anticoagulation regime could be responsible for the higher clotting rate observed in ABDO-MIX compared to EUPHAS (11 % receiving heparin 2000–4000 IU vs 6 % receiving heparin 3000 IU bolus plus 20 IU/kg/ h, respectively). There is no plausible reason for hemoperfusion-induced hemodynamic instability, since fluid balance is even due to a zero ultrafiltration setting. Payen et al. advised caution with PMX-HP prescription as a result of higher renal replacement therapy (RRT) and platelet reduction in PMXHP than in the control group. Early, sepsis-related, hematologic SOFA score alteration was recovered in 7 days after PMX-HP. RRT was more frequent in the PMX-HP group than in the control group (53 vs 37 %, p = 0.02), but the number of patients on RRT at the time of randomization and the incidence of RRT after the enrolment were not reported. The distribution of microbiological findings in ABDO-MIX was shown only in surgical samples, without clear information on other sampling sites, incidence of polymicrobial isolates, or sepsis duration before surgery, all factors potentially influencing the final outcome. The isolation of yeasts from the peritoneum was more frequent in the PMX-treated group than in controls, even though without statistical differences, but peritoneal candidiasis is a severe life-threatening condition [2] not susceptible to improve by the endotoxin-adsorption blood purification techniques. IL-6 was tested but this is not a specific marker for the infection, because it increases in cases of simple surgical trauma or chemical inflammation due to biliary peritoneum. Procalcitonin could have served better than IL-6 to monitor the efficacy of PMX-HP and sepsis evolution. We believe that the ABDO-MIX study is not conclusive. We recommend waiting for the results of the EUPHRATES North American double blind randomized control trial and the European EUPHAS2 follow-up study. At present, the conflicting results suggest the need for caution, technical standardization, and careful patient selection for the prescription to avoid confounding factors affecting the signal-to-noise ratio.

Lice, rodents, and many hopes: a rare disease in a young refugee

Migrants from countries with scarce resources represent an increasing worldwide phenomenon providing a daily challenge for governments and humanitarian organizations [1, 2]. A teenage refugee from East Africa was admitted to our intensive care unit (ICU) with acute respiratory distress syndrome (ARDS), hypotension, and jaundice. Nits were present on her scalp and she had no relevant past medical history. She arrived in Italy after travelling for 7 months under poor hygienic conditions. ARDS was managed with protective mechanical ventilation (tidal volume 350 ml, plateau pressure 28 cmH2O), high positive end-expiratory pressure (15 cmH2O), neuromuscular blocking agents, prone positioning, and inhaled nitric oxide. Septic shock and sepsis-induced cardiac dysfunction required administration of high doses of norepinephrire (0.8 μg/kg/min) and dobutamine (8 μg/kg/min). Continuous renal replacement therapy (CRRT) was started for acute kidney injury. Laboratory findings were relevant for anemia, low platelet count, altered blood coagulation, and high procalcitonin. Microbiological tests were performed before the administration of piperacillin-tazobactam and levofloxacin along with the application of pyrethrins foam. In the differential diagnosis we evaluated epatotropic viruses, Legionella species, miliary tuberculois, intestinal parasites, Schistosoma Haematobium, Rickettsia species, Leptospira species, Borrelia species, Leishmania species, and Malaria species related infections. On day 3, the blood and urine samples were positive on real-time polymerase chain reaction (PCR) [3, 4] for Leptospira spp. (Fig. 1a) and Borrelia recurrentis (only in the blood sample; Fig. 1b). Antibiotic therapy with 100 mg doxycycline every 12 h and 2 g ceftriaxone every 12 h was started, leading to a progressive improvement of the patient’s clinical status. On day 21 she was moved to the infectious disease ward, and 10 days later she ran away the hospital and has never come back for clinic follow-up. Borrelia recurrentis infection is a louse-borne disease and Leptospirosis is a rat-borne zoonosis, both endemic in areas characterized by a low hygiene condition. This is the first case of life-threatening Borrelia recurrentis and Leptospira species co-infection [1, 2, 5]. Spirochetosis-related disease is considered a rare pathology in nonendemic areas whereby the infection might be underdiagnosed. Delay in diagnosis and therapy may lead to dangerous outbreaks in refugees camps leading to severe clinical pictures in infected subjects. Our patient ran away from the hospital without completing the path of care, being afraid of being repatriated. Indeed, even though we are able provide such patients with all the latest technologies, we cannot completely care for them without taking into account their social, psychological, and human needs.

Improving the care for elective surgical patients: post-operative ICU admission and outcome

Surgery has been defined by the World Health Organization (WHO) as an “essential component of health care worldwide and often the only therapy that can alleviate disabilities and reduce the risk of death from common conditions” (1,2).

Nitric Oxide in Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials

OBJECTIVES To investigate the efficacy and safety of perioperative administration of nitric oxide in cardiac surgery. DESIGN Meta-analysis of randomized controlled trials (RCTs). PARTICIPANTS Cardiac surgery patients. INTERVENTIONS A search of Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE for RCTs that compared nitric oxide with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS The primary outcome was intensive care unit (ICU) stay, and secondary outcomes were mortality, duration of mechanical ventilation, and reduction of mean pulmonary artery pressure. The study included 18 RCTs comprising 958 patients. The authors calculated the pooled odds ratio (OR) and the mean difference (MD) with random-effects model. Quantitative synthesis of data demonstrated a clinically negligible reduction in the length of ICU stay (MD -0.38 days, confidence interval CI [-0.65 to -0.11]; p = 0.005) and mechanical ventilation duration (MD -4.81 hours, CI [-7.79 to -1.83]; p = 0.002) compared with all control interventions with no benefit on mortality. CONCLUSIONS Perioperative delivery of inhaled nitric oxide resulted to be of no or minimal benefit in patients with pulmonary hypertension undergoing cardiac surgery. Large, randomized trials are needed to further assess its effect on major clinical outcomes and its cost-effectiveness.

CO2 driven endotracheal tube cuff control in critically ill patients: A randomized controlled study

Background To determine the safety and clinical efficacy of an innovative integrated airway system (AnapnoGuard™ 100 system) that continuously monitors and controls the cuff pressure (Pcuff), while facilitating the aspiration of subglottic secretions (SS). Methods This was a prospective, single centre, open-label, randomized, controlled feasibility and safety trial. The primary endpoint of the study was the rate of device related adverse events (AE) and serious AE (SAE) as a result of using AnapnoGuard (AG) 100 during mechanical ventilation. Secondary endpoints were: (1) mechanical complications rate (2) ICU staff satisfaction; (3) VAP occurrence; (4) length of mechanical ventilation; (5) length of Intensive Care Unit stay and mortality; (6) volume of evacuated subglottic secretions. Sixty patients were randomized to be intubated with the AG endotracheal-tube (ETT) and connected to the AG 100 system allowing Pcuff adjustment and SS aspiration; or with an ETT combined with SS drainage and Pcuff controlled manually. Results No difference in adverse events rate was identified between the groups. The use of AG system was associated with a significantly higher incidence of Pcuff determinations in the safety range (97.3% vs. 71%; p<0.01) and a trend to a greater volume of aspirated SS secretions: (192.0[64–413] ml vs. 150[50–200], p = 0.19 (total)); (57.8[20–88.7] ml vs. 50[18.7–62] ml, p = 0.11 (daily)). No inter-group difference was detected using AG system vs. controls in terms of post-extubation throat pain level (0 [0–2] vs. 0 [0–3]; p = 0.7), hoarseness (42.9% vs. 75%; p = 0.55) and tracheal mucosa oedema (16.7% vs. 10%; p = 0.65). Patients enrolled in the AG group had a trend to reduced VAP risk of ventilator-associated pneumonia(VAP) (14.8% vs. 40%; p = 0.06), which were more frequently monomicrobial (25% vs. 70%; p = 0.03). No statistically significant difference was observed in duration of mechanical ventilation, ICU stay, and mortality. Conclusions The use AG 100 system and AG tube in critically ill intubated patients is safe and effective in Pcuff control and SS drainage. Its protective role against VAP needs to be confirmed in a larger randomized trial. Trial registration ClinicalTrials.gov NCT01550978. Date of registration: February 21, 2012.

‘σήψις’ yesterday, sepsis nowadays: what’s changing?

Is my patient septic or not?—that is the question. Sepsis (from the ancient Greek, σήψις) is an “antique” medical issue, a multi-faced life threatening disease characterized by organ dysfunction due to a dis-regulated host response to infection (1). Hyper-inflammation and immunoparalysis (2) along with tissue damage caused by pathogens play a key role into the onset and progression of the disease.