Monique Nys

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.

Endotoxaemia, production of tumour necrosis factor α and polymorphonuclear neutrophil activation following strenuous exercise in humans

Abstract To examine whether endotoxaemia accompanying long-term, strenuous physical exercise is involved in exercise-induced increase in plasma tumour necrosis factor alpha (TNF-α) concentration and polymorphonuclear neutrophil (PMN) activation, 14 male recreational athletes [mean age 28 (SEM 1) years] were studied. Exercise consisted of a 1.5-km river swim, a 40-km bicycle race, and a 10-km road race. Mean time to complete the race was 149.8 (SEM 4.8) min. The plasma concentrations of granulocyte myeloperoxidase (MPO) and TNF-α were significantly higher than baseline values immediately and 1 h after exercise (P < 0.001). Both variables returned to pre-race levels the day after exercise. Marked, transient decreases in plasma concentrations of anti-lipopolysaccharide (LPS) immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies directed against a panel of selected smooth gram-negative LPS were observed after the race, reaching in most cases minimal values in the blood sample drawn immediately following the completion of the triathlon. There was no significant correlation between the magnitude of PMN activation, as assessed by the increase in plasma concentrations of MPO, and the humoral markers of endotoxaemia and TNF-α. An inverse, highly significant relationship between the increase in plasma TNF-α concentrations and the changes in circulating anti-LPS IgM antibodies concentrations was observed (r = −0.7; P < 0.01). These findings suggest that exercise-induced endotoxaemia was involved in the release of TNF-α, that the magnitude of the TNF-α response to exercise was down-regulated by anti-LPS antibodies of the IgM class, and that the production of TNF-α and endotoxaemia did not seem to play a role in the activation of circulating PMN in the exercising subjects.

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.

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.

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

IntroductionCombination 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.MethodsPatients 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.ResultsSeventy-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.ConclusionAntibiotic 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.

Sequential anti-core glycolipid immunoglobulin antibody activities in patients with and without septic shock and their relation to outcome

OBJECTIVE This study follows the sequential changes in anti-lipopolysaccharide antibodies in infected patients with and without septic shock. SUMMARY BACKGROUND DATA A relation between high endogenous levels of anti-LPS antibodies and protection against bacteremia and septic shock in at-risk patient groups has been observed. However, information on the daily follow-up and kinetics of apparition or disappearance of anti-LPS antibody activities and their relations with the protective properties of the different immunoglobulin classes has not been clearly investigated. METHODS Two hundred and five septic surgical patients were studied during their stay in the intensive care unit during a period of 3 years. Among these patients, septic shock developed in 54 and 47 died. A sensitive ELISA was used to study circulating IgM and IgG antibodies to the core glycolipid (CGL) region of Salmonella minnesota R595. The activities were measured each day when sepsis occurred and every hour during septic shock. RESULTS Anti-CGL IgM activity was found in 32% of the septic patients. This response, however, most often appeared to be transient. A strong correlation was observed between the occurrence of septic shock and the absence of anti-CGL IgM activity on admission to the ICU (p < 0.02). Anti-CGL IgG activity was detected in 82% of the patients and better correlated with outcome for patients with high or rising activities during their hospitalization (p < 0.0005). In patients with septic shock or irreversible organ failure, a fall in the anti-CGL IgG activity was observed before death, suggesting that the IgG antibodies were consumed during this acute event. Therefore, the anti-CGL IgG activity measured by ELISA could be used as a marker of the evolution of the illness. CONCLUSIONS Our observations demonstrate the interest to follow-up the evolution of the anti-CGL antibodies during sepsis. The fall of these antibodies during septic shock and in patients who died was an additional argument to perform, as an additive form, passive antibody therapy to decrease lethality in this group of patients.

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

ObjectiveTo assess polymorphonuclear neutrophils activation after stenting in acute coronary syndromes studied by myeloperoxydase, lactoferrin and elastase release in this clinical setting. MethodsMyeloperoxydase, 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). ResultsMyeloperoxydase, 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 &agr;, 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). ConclusionsIn 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.

Correlation between endotoxin level and bacterial count in bronchoalveolar lavage fluid of ventilated patients

ObjectiveTo assess the predictive value of the endotoxin level in the bronchoalveolar lavage (BAL) and to propose to the clinician a guide in the diagnosis of Gram-negative bacterial (GNB) pneumonia. DesignRetrospective and prospective studies to investigate the relation between endotoxin level and quantitative bacterial culture of BAL and to test the predictive value of a defined threshold. SettingUniversity hospital general intensive care unit. PatientsIn the first part of the study, 77 consecutive ventilated patients with clinical suspicion of nosocomial pneumonia between January 1995 and January 1996. In the second part of the study, 93 consecutive ventilated patients studied prospectively between February 1996 and April 1997. Measurements and Main ResultsQuantitative cultures for aerobic bacteria were performed directly from the fluid. Bacterial species were determined with standard techniques. The detection of endotoxin in BAL was made using a quantitative chromogenic Limulus assay.In the retrospective analysis, a significant correlation between quantitative GNB cultures and BAL endotoxin levels was observed (r2 = 0.60, p < .0001). An endotoxin level ≥ 4 endotoxin units/mL (EU/mL) distinguishes patients with a significant GNB count from colonized patients with a sensitivity of 92.6%, a specificity of 81.4% and a correct classification rate of 84.9%.In the prospective analysis, the 4 EU/mL threshold permits identification of infected patients with a sensitivity of 82.2%, a specificity of 95.6%, and a correct classification rate of 90.3%. The receiver operating characteristic curve analysis showed that the Limulus assay still had a good discrimination power in the prediction of significant bacterial count in BAL fluid. ConclusionsEndotoxin detection immediately after bronchoscopy is a distinct advantage to the clinician because antimicrobial Gram-negative therapy may be immediately justified according to the results.

Severity of ICU-acquired pneumonia according to infectious microorganisms

PurposeTo 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.MethodsOver 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.ResultsSeptic 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.ConclusionsICUAP 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.

Possible in vivo tolerance of human polymorphonuclear neutrophil to low-grade exercise-induced endotoxaemia

To address the question of whether translocation of bacterial lipopolysaccharide (LPS) into the blood could be involved in the process of exercise-induced polymorphonuclear neutrophil (PMN) activation, 12 healthy male subjects who took part in a sprint triathlon (1.5 km river swim, 40 km bicycle race, 10 km road race) were studied. While there was no detectable amount of endotoxin in the blood samples drawn at rest, exercise was followed by the appearance of circulating endotoxin molecules at the end of competition in four subjects, and after one and 24 h recovery in three and seven athletes, respectively. The concentrations of plasma granulocyte myeloperoxidase ([MPO]), were significantly higher immediately after exercise and one hour later-than baseline values (P<0.001). This variable returned to pre-race levels the day after exercise, despite the presence of detectable amounts of LPS, at that time, in seven athletes. The absence of significant correlation (r=0.26; P=0.383) and temporal association between [MPO] and plasma endotoxin levels led us to conclude that endotoxaemia was not involved in the process of exercise-induced PMN degranulation observed in our subjects.