Zsolt Molnár

Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 μg or 200 μg IC43 with adjuvant, or 100 μg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 μg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1–10.6%) was observed in the IC43 groups. This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 μg IC43 without adjuvant compared with 200 μg IC43 with adjuvant, the 100 μg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Introduction: Several single-center studies and meta-analyses have shown that perioperative goal-directed therapy may significantly improve outcomes in general surgical patients. We hypothesized that using a treatment algorithm based on pulse pressure variation, cardiac index trending by radial artery pulse contour analysis, and mean arterial pressure in a study group (SG), would result in reduced complications, reduced length of hospital stay and quicker return of bowel movement postoperatively in abdominal surgical patients, when compared to a control group (CG). Methods: 160 patients undergoing elective major abdominal surgery were randomized to the SG (79 patients) or to the CG (81 patients). In the SG hemodynamic therapy was guided by pulse pressure variation, cardiac index trending and mean arterial pressure. In the CG hemodynamic therapy was performed at the discretion of the treating anesthesiologist. Outcome data were recorded up to 28 days postoperatively. Results: The total number of complications was significantly lower in the SG (72 vs. 52 complications, p = 0.038). In particular, infection complications were significantly reduced (SG: 13 vs. CG: 26 complications, p = 0.023). There were no significant differences between the two groups for return of bowel movement (SG: 3 vs. CG: 2 days postoperatively, p = 0.316), duration of post anesthesia care unit stay (SG: 180 vs. CG: 180 minutes, p = 0.516) or length of hospital stay (SG: 11 vs. CG: 10 days, p = 0.929). Conclusions: This multi-center study demonstrates that hemodynamic goal-directed therapy using pulse pressure variation, cardiac index trending and mean arterial pressure as the key parameters leads to a decrease in postoperative complications in patients undergoing major abdominal surgery. Trial registration: ClinicalTrial.gov, NCT01401283.

Introduction: Postoperative care after oesophageal tumour resection holds a high risk of respiratory complications. We therefore aimed to determine the value of systemic inflammatory markers in predicting arterial hypoxaemia as the earliest sign of developing lung injury after oesophageal tumour resection. Methods: In a prospective observational study, 33 consecutive patients were observed for three days (T1–T3) after admission (T0) to an intensive care unit following oesophageal tumour resection. The daily highest values of the heart rate, axillary temperature, leukocyte count and PaCO₂ were recorded. Serum C-reactive protein and procalcitonin concentrations and the leukocyte antisedimentation rate (LAR) were determined at T1 and T2. Respiratory function was monitored 6-hourly measurement of the PaO₂/FIO₂ ratio, and the lowest value was recorded at T3. Patients were categorised as normoxaemic or hypoxaemic using the cutoff value of 300 mmHg for PaO₂/FIO₂. Results: Seventeen out of 33 patients were classified as hypoxaemic and 16 patients as normoxaemic at T3. Increases of temperature at T0 and of the procalcitonin and LAR values at T2 were predictive of hypoxaemia at T3 (P < 0.05, P < 0.01 and P < 0.001, respectively). The area under the receiver-operating characteristic curve was 0.65 for the temperature at T0, which was significantly lower than that for the procalcitonin level at T2 (0.83; 95% confidence interval, 0.69–0.97; P < 0.01) and that for LAR at T2 (0.89; 95% confidence interval, 0.77–1.00; P < 0.001). Conclusion: These results suggest that an elevated LAR (>15%) and an elevated procalcitonin concentration (>2.5 ng/ml) measured on the second postoperative day can predict next-day arterial hypoxaemia (PaO₂/FIO₂ < 300 mmHg) after oesophageal tumour resection.

The aim of this study was to investigate the short-term effect of fluid resuscitation with 4% modified fluid gelatine (GEL) versus 6% hydroxyethyl starch (HES) on haemodynamics and oxygenation in patients with septic shock and acute lung injury (ALI).

Our objective was to investigate whether short-term infusion of the oxygen free radical scavenger N-acetylcysteine (NAC) administered before and during extensive abdominal surgery could ameliorate the progression of early systemic inflammatory response. Prospective, randomised, double-blinded, placebo-controlled clinical trial. Twenty-bed intensive care unit in a university hospital. Following written informed consent, 100 patients were randomised into NAC and placebo groups. Three patients from the NAC group and four from the placebo group withdrew before the final analysis. The treatment group (n=47) received NAC (150 mg/kg^–1 bolus followed by a continuous infusion of 12 mg/kg^–1/h^–1) and the placebo group (n=46) received the same volume of 5% dextrose during surgery. Serum procalcitonin (PCT), C-reactive protein (CRP) and microalbuminuria was monitored preoperatively, on admission to ICU, then daily during the first 3 postoperative days. For statistical analysis Mann Whitney and Chi-squared tests were used. Patients' clinical course was similar in each group as monitored by the Multiple Organ Dysfunction Scores. There was no significant difference between the two groups regarding PCT and microalbuminuria at any assessment point. Significantly lower CRP levels were found in the NAC group on days 1 and 2 (t₂₄: median: 84.5 interquartile range: [62–120] vs. 118 [86–137] mg/l; p=0.020; t₄₈: 136 [103–232] vs. 195 [154–252] mg/l; p=0.013, NAC vs. placebo respectively). In this study, short-term NAC treatment decreased CRP levels, but failed to attenuate any other inflammatory response, as monitored by serum PCT and microalbuminuria. Overall, our results do not support the routine prophylactic use of NAC as a free radical scavenger in abdominal surgery.

Objective To investigate the correlation between microalbuminuria and extravascular lung water in patients in septic shock who require mechanical ventilation for severe respiratory failure. Design and setting Prospective, observational, clinical study in the 20-bed intensive care unit of a university hospital. Patients and participants 25 consecutive patients in septic shock and also in severe respiratory failure requiring mechanical ventilation. Interventions Hemodynamic parameters and extravascular lung water were determined by single arterial thermodilution. Together with each hemodynamic measurement the PaO₂/FIO₂ ratio and urinary microalbumin to creatinine ratio (M:Cr) was measured. Serum C-reactive protein (CRP) and procalcitonin (PCT) levels were also determined daily. Measurements and results The EVLW index was significantly higher than normal throughout the study. Microalbuminuria was in the normal range on entry and remained so for the rest of the study period. Serum PCT and CRP levels were significantly higher than normal at every assessment points. No significant correlation was found between M:Cr and either EVLW or PaO₂/FIO₂ . Conclusions In this study patients in septic shock with significantly elevated EVLW had normal urinary M:Cr, and there was no correlation between M:Cr and EWLV, and PaO₂/FIO₂. Therefore based on the current results routine measurements of microalbuminuria to determine endothelial permeability cannot be recommended in critically ill patients.