Prevention of ventilator-associated pneumonia and ventilator-associated conditions: a randomized controlled trial with subglottic secretion suctioning.

OBJECTIVES: Ventilator-associated pneumonia diagnosis remains a debatable topic. New definitions of ventilator-associated conditions involving worsening oxygenation have been recently proposed to make surveillance of events possibly linked to ventilator-associated pneumonia as objective as possible. The objective of the study was to confirm the effect of subglottic secretion suctioning on ventilator-associated pneumonia prevalence and to assess its concomitant impact on ventilator-associated conditions and antibiotic use. DESIGN: Randomized controlled clinical trial conducted in five ICUs of the same hospital. PATIENTS: Three hundred fifty-two adult patients intubated with a tracheal tube allowing subglottic secretion suctioning were randomly assigned to undergo suctioning (n = 170, group 1) or not (n = 182, group 2). MAIN RESULTS: During ventilation, microbiologically confirmed ventilator-associated pneumonia occurred in 15 patients (8.8%) of group 1 and 32 patients (17.6%) of group 2 (p = 0.018). In terms of ventilatory days, ventilator-associated pneumonia rates were 9.6 of 1,000 ventilatory days and 19.8 of 1,000 ventilatory days, respectively (p = 0.0076). Ventilator-associated condition prevalence was 21.8% in group 1 and 22.5% in group 2 (p = 0.84). Among the 47 patients with ventilator-associated pneumonia, 25 (58.2%) experienced a ventilator-associated condition. Neither length of ICU stay nor mortality differed between groups; only ventilator-associated condition was associated with increased mortality. The total number of antibiotic days was 1,696 in group 1, representing 61.6% of the 2,754 ICU days, and 1,965 in group 2, representing 68.5% of the 2,868 ICU days (p < 0.0001). CONCLUSIONS: Subglottic secretion suctioning resulted in a significant reduction of ventilator-associated pneumonia prevalence associated with a significant decrease in antibiotic use. By contrast, ventilator-associated condition occurrence did not differ between groups and appeared more related to other medical features than ventilator-associated pneumonia.

Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients.

OBJECTIVES: To test the usefulness of procalcitonin serum level for the reduction of antibiotic consumption in intensive care unit patients. DESIGN: Single-center, prospective, randomized controlled study. SETTING: Five intensive care units from a tertiary teaching hospital. PATIENTS: All consecutive adult patients hospitalized for >48 hrs in the intensive care unit during a 9-month period. INTERVENTIONS: Procalcitonin serum level was obtained for all consecutive patients suspected of developing infection either on admission or during intensive care unit stay. The use of antibiotics was more or less strongly discouraged or recommended according to the Muller classification. Patients were randomized into two groups: one using the procalcitonin results (procalcitonin group) and one being blinded to the procalcitonin results (control group). The primary end point was the reduction of antibiotic use expressed as a proportion of treatment days and of daily defined dose per 100 intensive care unit days using a procalcitonin-guided approach. Secondary end points included: a posteriori assessment of the accuracy of the infectious diagnosis when using procalcitonin in the intensive care unit and of the diagnostic concordance between the intensive care unit physician and the infectious-disease specialist. MEASUREMENTS AND MAIN RESULTS: There were 258 patients in the procalcitonin group and 251 patients in the control group. A significantly higher amount of withheld treatment was observed in the procalcitonin group of patients classified by the intensive care unit clinicians as having possible infection. This, however, did not result in a reduction of antibiotic consumption. The treatment days represented 62.6±34.4% and 57.7±34.4% of the intensive care unit stays in the procalcitonin and control groups, respectively (p=.11). According to the infectious-disease specialist, 33.8% of the cases in which no infection was confirmed, had a procalcitonin value>1µg/L and 14.9% of the cases with confirmed infection had procalcitonin levels<0.25 µg/L. The ability of procalcitonin to differentiate between certain or probable infection and possible or no infection, upon initiation of antibiotic treatment was low, as confirmed by the receiving operating curve analysis (area under the curve=0.69). Finally, procalcitonin did not help improve concordance between the diagnostic confidence of the infectious-disease specialist and the ICU physician. CONCLUSIONS: Procalcitonin measuring for the initiation of antimicrobials did not appear to be helpful in a strategy aiming at decreasing the antibiotic consumption in intensive care unit patients.

Severity of ICU-acquired pneumonia according to infectious microorganisms.

PURPOSE: To assess the severity of intensive care unit (ICU)-acquired pneumonia (ICUAP) according to the bacteria involved, classified into seven groups: third-generation cephalosporin-resistant non-fermenting Gram-negative bacilli (resistant C3NF); sensitive C3NF; methicillin-resistant Staphylococcus aureus; methicillin-sensitive Staphylococcus aureus; extended-spectrum beta-lactamase-producing Enterobacteriaceae; Enterobacteriaceae not producing extended-spectrum beta-lactamase; Haemophilus influenzae and Streptococcus pneumoniae. METHODS: Over a 4-year period, sequential organ failure assessment (SOFA) score was prospectively measured daily in 453 adult patients with ICUAP. ICUAP severity was evaluated by the severity of sepsis and by the occurrence of new organ dysfunctions or failures (OD/F) during ICUAP. RESULTS: Septic shock occurred in 21% of all cases of ICUAP. The occurrence of new OD/F during ICUAP was similar regardless of the identified microorganism. These new OD/F represented less than 11% of SOFAmax, defined as the sum of all OD/F occurring at any time during the ICU stay. There was a significant association between SOFApreICUAP, defined as the sum of all the OD/F occurring before ICUAP, and ICUAP severity. In the multivariate analysis, the type of bacteria was not a risk factor (RF) for occurrence of septic shock and mortality. Age and SOFApreICUAP were RF for the sepsis severity. The ICUAP severity was an RF for ICU mortality. CONCLUSIONS: ICUAP was responsible for a minor proportion of OD/F occurring during the ICU stay. Severity of ICUAP was related to clinical status prior to ICUAP, but not to the type of bacteria. ICU mortality depended on the severity of ICUAP.

Association between inflammatory mediators and response to inhaled nitric oxide in a model of endotoxin-induced lung injury.

INTRODUCTION: Inhaled nitric oxide (INO) allows selective pulmonary vasodilation in acute respiratory distress syndrome and improves PaO2 by redistribution of pulmonary blood flow towards better ventilated parenchyma. One-third of patients are nonresponders to INO, however, and it is difficult to predict who will respond. The aim of the present study was to identify, within a panel of inflammatory mediators released during endotoxin-induced lung injury, specific mediators that are associated with a PaO2 response to INO. METHODS: After animal ethics committee approval, pigs were anesthetized and exposed to 2 hours of endotoxin infusion. Levels of cytokines, prostanoid, leucotriene and endothelin-1 (ET-1) were sampled prior to endotoxin exposure and hourly thereafter. All animals were exposed to 40 ppm INO: 28 animals were exposed at either 4 hours or 6 hours and a subgroup of nine animals was exposed both at 4 hours and 6 hours after onset of endotoxin infusion. RESULTS: Based on the response to INO, the animals were retrospectively placed into a responder group (increase in PaO2 > or = 20%) or a nonresponder group. All mediators increased with endotoxin infusion although no significant differences were seen between responders and nonresponders. There was a mean difference in ET-1, however, with lower levels in the nonresponder group than in the responder group, 0.1 pg/ml versus 3.0 pg/ml. Moreover, five animals in the group exposed twice to INO switched from responder to nonresponder and had decreased ET-1 levels (3.0 (2.5 to 7.5) pg/ml versus 0.1 (0.1 to 2.1) pg/ml, P < 0.05). The pulmonary artery pressure and ET-1 level were higher in future responders to INO. CONCLUSIONS: ET-1 may therefore be involved in mediating the response to INO.

Intensive care unit acquired infection and organ failure.

OBJECTIVE: To assess the temporal relationship between ICU-acquired infection (IAI) and the prevalence and severity of organ dysfunction or failure (OD/F). DESIGN AND SETTING: Observational, single center study in a mixed intensive care unit of a university hospital. PATIENTS: We analyzed 1,191 patients hospitalized for more than 2 days during a 2-year observation period: 845 did not acquire IAI, 306 of whom had infection on admission (IOA); 346 did acquire IAI, 125 of whom had IOA. MEASUREMENTS AND RESULTS: The SOFA score was calculated daily, both SOFAmax, the sum of the worst OD/F during the ICU stay, and SOFApreinf, the sum of the worst OD/F existing before the occurrence of the first IAI. The SAPS II and SOFA score of the first 24 h were significantly higher in patients with than in those without IAI. SOFApreinf of IAI patients was also higher than the SOFAmax of patients without IAI both in patients with (12.1+/-4.6 vs. 8.9+/-4.7) and those without IOA (9.2+/-4.0 vs. 6.7+/-3.5). SOFApreinf represented 85.7% of the value of SOFAmax in patients with IAI. SOFApreinf increased significantly with the occurrence of sepsis, severe sepsis, or septic shock during ICU stay. Severe sepsis and septic shock during ICU stay as well as SOFApreinf were part of the factors associated with hospital mortality. CONCLUSIONS: IAI is significantly associated with hospital mortality; however, its contribution to OD/F is minor. Moreover, severity of IAI seems to be related to previous health status.

Pancreatic cellular injury after cardiac surgery with cardiopulmonary bypass: frequency, time course and risk factors.

Although often clinically silent, pancreatic cellular injury (PCI) is relatively frequent after cardiac surgery with cardiopulmonary bypass; and its etiology and time course are largely unknown. We defined PCI as the simultaneous presence of abnormal values of pancreatic isoamylase and immunoreactive trypsin (IRT). The frequency and time evolution of PCI were assessed in this condition using assays for specific exocrine pancreatic enzymes. Correlations with inflammatory markers were searched for preoperative risk factors. One hundred ninety-three patients submitted to cardiac surgery were enrolled prospectively. Blood IRT, amylase, pancreatic isoamylase, lipase, and markers of inflammation (alpha1-protease inhibitor, alpha2-macroglobulin, myeloperoxidase) were measured preoperatively and postoperatively until day 8. The postoperative increase in plasma levels of pancreatic enzymes and urinary IRT was biphasic in all patients: early after surgery and later (from day 4 to 8 after surgery). One hundred thirty-three patients (69%) experienced PCI, with mean IRT, isoamylase, and alpha1-protease inhibitor values higher for each sample than that in patients without PCI. By multiple regression analysis, we found preoperative values of plasma IRT >or=40 ng/mL, amylase >or=42 IU/mL, and pancreatic isoamylase >or=20 IU/L associated with a higher incidence of postsurgery PCI (P < 0.005). In the PCI patients, a significant correlation was found between the 4 pancreatic enzymes and urinary IRT, total calcium, myeloperoxidase, alpha1-protease inhibitor, and alpha2-macroglobulin. These data support a high prevalence of postoperative PCI after cardiac surgery with cardiopulmonary bypass, typically biphasic and clinically silent, especially when pancreatic enzymes were elevated preoperatively.

Combination therapy versus monotherapy: a randomised pilot study on the evolution of inflammatory parameters after ventilator associated pneumonia [ISRCTN31976779].

INTRODUCTION: Combination antibiotic therapy for ventilator associated pneumonia (VAP) is often used to broaden the spectrum of activity of empirical treatment. The relevance of such synergy is commonly supposed but poorly supported. The aim of the present study was to compare the clinical outcome and the course of biological variables in patients treated for a VAP, using a monotherapy with a beta-lactam versus a combination therapy. METHODS: Patients with VAP were prospectively randomised to receive either cefepime alone or cefepime in association with amikacin or levofloxacin. Clinical and inflammatory parameters were measured on the day of inclusion and thereafter. RESULTS: Seventy-four mechanically ventilated patients meeting clinical criteria for VAP were enrolled in the study. VAP was microbiologically confirmed in 59 patients (84%). Patients were randomised to receive cefepime (C group, 20 patients), cefepime with amikacin (C-A group, 19 patients) or cefepime with levofloxacin (C-L group, 20 patients). No significant difference was observed regarding the time course of temperature, leukocytosis or C-reactive protein level. There were no differences between length of stay in the intensive care unit after infection, nor in ventilator free days within 28 days after infection. No difference in mortality was observed. CONCLUSION: Antibiotic combination using a fourth generation cephalosporin with either an aminoside or a fluoroquinolone is not associated with a clinical or biological benefit when compared to cephalosporin monotherapy against common susceptible pathogens causing VAP.

Acute neutrophil activation in direct stenting: comparison of stable and unstable angina patients.

BACKGROUND: Polymorphonuclear neutrophils have been implicated in the pathophysiology of atherosclerosis. A substantial body of evidence has emerged to implicate the role of specific leucocyte derived enzyme myeloperoxidase in atherogenesis, since its initiation through progression until destabilization. The aim of the study was to determine the presence of polymorphonuclear neutrophils activation after coronary stenting, to compare this activation between stable and unstable setting and to evaluate the kinetic relation of this activation with inflammatory response following atherosclerotic plaque rupture. METHODS: Myeloperoxidase, lactoferrin, elastase, C-reactive protein and cytokine plasma levels were assessed in 15 patients undergoing direct coronary stenting for unstable angina (Group A) and compared to 11 patients undergoing this procedure for stable angina (Group B). Serial sampling starting before arteriography and continued for 24 h was carried out in all patients. RESULTS: A significant elevation in myeloperoxidase and lactoferrin levels was observed after stenting in both group A (p<0.0001) and group B (p<0.0001), but was higher in group A. Interleukin-8, interleukin-12 and interleukin-6 levels increased temporarily after stenting in the 2 groups. Baseline values of C-reactive protein were similar in the 2 groups and a progressive increase was observed after the intervention. CONCLUSIONS: Direct coronary artery stenting is associated with an early polymorphonuclear neutrophils activation followed by release of inflammatory cytokines (interleukin-6, interleukin-8, interleukin-12) and C-reactive protein elevation in both stable and unstable patients. We conclude that stenting by itself is associated with myeloperoxidase liberation with a significantly enhanced response in unstable patients.

Selection of resistance during sequential use of preferential antibiotic classes.

OBJECTIVE: To determine the effect of antibiotic class pressure on the susceptibility of bacteria during sequential periods of antibiotic homogeneity. DESIGN AND SETTING: Prospective study in a mixed ICU with three separated subunits of eight, eight, and ten beds. PATIENTS AND PARTICIPANTS: The study examined the 1,721 patients with a length of stay longer than 2 days. INTERVENTIONS: Three different antibiotic regimens were used sequentially over 2 years as first-choice empirical treatment: cephalosporins, fluoroquinolone, or a penicillin-beta-lactamase inhibitor combination. Each regimen was applied for 8 months in each subunits of the ICU, using "latin square" design. RESULTS: We treated 731 infections in 546 patients (32% of patients staying more than 48 h). There were 25.5 ICU-acquired infections per 1,000 patient-days. Infecting pathogens and colonizing bacteria were found in 2,739 samples from 1,666 patients (96.8%). No significant change in global antibiotic susceptibility was observed over time. However, a decrease in the susceptibility of several species was observed for antibiotics used as the first-line therapy in the unit. Selection pressure of antibiotics and occurrence of resistance during treatment was documented within an 8-month rotation period. CONCLUSIONS: Antibiotic use for periods of several months induces bacterial resistance in common pathogens.

Early release of neutrophil markers of activation after direct stenting in patients with unstable angina.

OBJECTIVE: To assess polymorphonuclear neutrophils activation after stenting in acute coronary syndromes studied by myeloperoxydase, lactoferrin and elastase release in this clinical setting. METHODS: Myeloperoxydase, lactoferrin, elastase, C-reactive protein and cytokines serum levels were assessed in 20 patients undergoing catheterization for unstable angina. Serial sampling starting before arteriography and continued up to 24 h was carried out in 15 patients undergoing direct stenting (group A) and in five patients assessed by coronary angiography only (group B). RESULTS: Myeloperoxydase, lactoferrin and elastase levels remained unchanged following catheterization, whereas a significant increase in myeloperoxydase (P = 0.0009) and lactoferrin (P = 0.004) was observed after stenting. No change in levels of tumour necrosis factor alpha, interleukin (IL)-8 and IL-11 was found in group B after catheterization at the different sampling times, although IL-8 and IL-11 levels increased transiently following stenting. IL-6 values increased in both groups. Baseline values of C-reactive protein were similar in each group. A progressive increase in C-reactive protein was noted in both groups and appeared to be larger following stenting (group A: P = 0.0002; group B: P = 0.01). CONCLUSIONS: In patients with unstable angina, stenting is associated by immediate neutrophil activation followed by release of inflammatory cytokines (IL-6, IL-8, IL-11) and C-reactive protein elevation. This study points out a potential role of myeloperoxydase as a trigger for inflammatory reaction in patients with unstable coronary syndromes undergoing percutaneous coronary intervention.

Effects of glucocorticoids on the respiratory burst of Chlamydia-primed THP-1 cells.

We previously observed that the respiratory burst of human monocytes (THP-1 cell line) triggered by phorbol myristate acetate was strongly enhanced by a priming of the cells by Chlamydia pneumoniae [Biochem. Biophys. Res. Commun. 287 (2001) 781]. We describe here the modifications of the responses of Chlamydia-primed THP-1 cells to hydrocortisone (HCT) and methylprednisolone (MPL). HCT and MPL inhibited the production of the cytokines TNFalpha and IL-8. But HCT, which inhibited the respiratory burst in LPS-primed monocytes, paradoxically stimulated the phenomenon in Chlamydia-primed cells; MPL exerted no significant effect. Both glucocorticoids did not significantly modify the triggering effect of Chlamydia on NF-kappaB binding activity. On the expression of p22(phox), a protein subunit of the NADPH oxidase, HCT had an increasing and MPL a decreasing effect. Glucocorticoids thus had unexpected effects on the inflammatory response of Chlamydia-primed monocytes.

Systemic release of endotoxins induced by gentle mastication: association with periodontitis severity.

BACKGROUND: Periodontitis has recently been identified as a potential risk factor for systemic pathologies such as cardiovascular disease, the hypothesis being that periodontal pockets could release pro-inflammatory bacterial components, for instance endotoxins, into the bloodstream. It is known that the oral cavity can be a source of circulating bacteria, but this has never been shown for bacterial endotoxins, and no evidence exists so far that the risk of systemic injury is related to the severity of periodontitis. The aim of the present study was to test the influence of gentle mastication on the occurrence of endotoxemia in patients with or without periodontal disease. METHODS: A total of 67 subjects were periodontally examined and grouped according to their periodontal status. This classification was based on an original index of severity of periodontal disease (periodontal index for risk of infectiousness, PIRI) aimed at reflecting the individual risk of systemic injury from the periodontal niches. Thus, the patients were classified into 3 risk groups: low, PIRI = 0; n = 25; moderate, 1 < or = PIRI < or = 5, n = 27; and high 6 < or = PIRI < or = 10, n = 15. Blood samples were collected before and 5 to 10 minutes after a standardized session of gentle mastication for detection of circulating endotoxins. Blood samples were tested with a chromogenic limulus amoebocyte lysate assay. RESULTS: Overall, blood levels of endotoxin after mastication were found to be significantly higher than before mastication (0.89 +/- 3.3 pg/ml versus 3.0 +/- 5.8 pg/ml; P= 0.0002). Likewise, the incidence of positive endotoxemia rose from 6% before mastication to 24% after mastication (P = 0.001). When accounting for the PIRI index, endotoxin levels and positive endotoxemia proved to be significantly higher in patients with severe periodontal disease than in the subjects with low or moderate periodontitis. CONCLUSIONS: Gentle mastication is able to induce the release of bacterial endotoxins from oral origin into the bloodstream, especially when patients have severe periodontal disease. This finding suggests that a diseased periodontium can be a major and underestimated source of chronic, or even permanent, release of bacterial pro-inflammatory components into the bloodstream.