Azithromycin regulates bacterial virulence and immune response in a murine model of ceftazidime-treated Pseudomonas aeruginosa acute pneumonia.

Pseudomonas aeruginosa (PA) remains one of the leading causes of nosocomial acute pneumonia. The array of virulence factors expressed by PA and the intense immune response associated with PA pneumonia play a major role in the severity of these infections. New therapeutic approaches are needed to overcome the high resistance of PA to antibiotics and to reduce the direct damage to host tissues. Through its immunomodulatory and anti-virulence effects, azithromycin (AZM) has demonstrated clinical benefits in patients with chronic PA respiratory infections. However, there is relatively little evidence in PA acute pneumonia. We investigated the effects of AZM, as an adjunctive therapy combined with ceftazidime (CAZ), in a murine model of PA acute pneumonia. We observed that the combined therapy (i) reduces the weight loss of mice 24 h post-infection (hpi), (ii) decreases neutrophil influx into the lungs at 6 and 24 hpi, while this effect is absent in a LPS-induced pneumonia or when PA is pretreated with antibiotics and mice do not receive any antibiotics, and that (iii) AZM, alone or with CAZ, modulates the expression of PA quorum sensing regulators and virulence factors (LasI, LasA, PqsE, PhzM, ExoS). Our findings support beneficial effects of AZM with CAZ on PA acute pneumonia by both bacterial virulence and immune response modulations. Further investigations are needed to clarify the exact underlying mechanisms responsible for the reduction of the neutrophils influx and to better discriminate between direct immunomodulatory properties of AZM, and indirect effects on neutrophilia resulting from bacterial virulence modulation.

Pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia.

Hospital-acquired pneumonia is a major cause of morbidity and mortality. The incidence of hospital-acquired pneumonia remains high globally and treatment can often be ineffective. Here, we review the available data and unanswered questions surrounding hospital-acquired pneumonia, discuss alterations of the respiratory microbiome and of the mucosal immunity in patients admitted to hospital, and explore potential approaches to stratify patients for tailored treatments. The lungs have been considered a sterile organ for decades because microbiological culture techniques had shown negative results. Culture-independent techniques have shown that healthy lungs harbour a diverse and dynamic ecosystem of bacteria, changing our comprehension of respiratory physiopathology. Understanding dysbiosis of the respiratory microbiome and altered mucosal immunity in patients with critical illness holds great promise to develop targeted host-directed immunotherapy to reduce ineffective treatment, to improve patient outcomes, and to tackle the global threat of resistant bacteria that cause these infections.

Cefazolin tissue concentrations with a prophylactic dose administered before sleeve gastrectomy in obese patients: a single centre study in 116 patients.

BACKGROUND: In obese patients undergoing sleeve gastrectomy, the blood and fatty-tissue concentrations of cefazolin required for adequate antibiotic prophylaxis are uncertain. METHODS: This was a single centre prospective study in obese (Group A: 40≤ BMI ≤50 kg m-2) and severely obese (Group B: 50< BMI ≤65 kg m-2) patients undergoing bariatric surgery. Blood and fatty-tissue samples were collected after a cefazolin 4 g i.v. injection. The primary aim was to compare cefazolin concentrations in subcutaneous fatty tissue with a targeted tissue concentration of 4 µg g-1 according to Staphylococcus aureus resistance breakpoint. RESULTS: One hundred and sixteen patients were included: 79 in Group A and 37 in Group B. At the beginning of the surgery, cefazolin concentration in subcutaneous fatty tissue was 12.2 (5.4) µg g-1 in Group A and 12 (6.1) µg g-1 in Group B (P=0.7). At the end, cefazolin concentrations in subcutaneous fatty tissue were 9.0 (4.9) and 7.8 (4.2) µg g-1 in Groups A and B, respectively (P=0.2). The plasma concentration of free cefazolin during surgery was higher in Group A than in Group B (P<0.0001). Fatty-tissue concentrations of 95% and 83% patients in Groups A and B, respectively, were above S. aureus resistance breakpoint. CONCLUSIONS: After a 4 g dose, the concentrations of cefazolin in fatty tissue were above the 4 µg g-1 tissue concentration target, providing adequate antibiotic tissue concentrations during bariatric surgery. As cefazolin concentration in fatty tissue is a surrogate endpoint, the results should be considered in conjunction with the results on free cefazolin concentrations in subcutaneous tissue. CLINICAL TRIAL REGISTRATION: NCT01537380.

Innate immune evasion of Escherichia coli clinical strains from orthopedic implant infections.

Escherichia coli is one of the first causes of Gram-negative orthopedic implant infections (OII). Those infections, usually hematogenous, mostly originate from the urinary tract. We investigated the strategies developed by E. coli in this context to evade host innate immune responses, i.e. complement and polymorphonuclear neutrophils (PMN). Twenty strains from OII were compared with 20 strains from bacteremia in patients with non-infected orthopedic implant. In both groups, 6/20 (30 %) strains lysed PMNs, due to the production of the pore-forming toxin α-hemolysin (HlyA). For the others, resistance to phagocytic killing by PMN was not significantly different between both groups. In contrast, resistance to complement-mediated serum killing was significantly higher in OII strains than in the others (65 % vs 10 %; P <0.001). In E. coli, different mechanisms have been involved in complement resistance. Here, serum resistance was not linked to a group 2 capsule, or a loss of outer membrane permeability, or the recruitment of the complement inhibitor C4bp, but was significantly associated with the synthesis of long-chain LPS, regardless of the O-antigen. Thus, serum resistance could promote seeding of peri-implant tissues by helping E. coli to either persist in blood and reach the site of infection or overcome localized complement activation.

Blood pressure monitoring during arrhythmia: agreement between automated brachial cuff and intra-arterial measurements.

BACKGROUND: Since arrhythmia induces irregular pulse waves, it is widely considered to cause flawed oscillometric brachial cuff measurements of blood pressure (BP). However, strong data are lacking. We assessed whether the agreement of oscillometric measurements with intra-arterial measurements is worse during arrhythmia than during regular rhythm. METHODS: Among patients of three intensive care units (ICUs), a prospective comparison of three pairs of intra-arterial and oscillometric BP readings was performed among patients with arrhythmia and an arterial line already present. After each inclusion in the arrhythmia group, one patient with regular rhythm was included as a control. International Organization for Standardization (ISO) standard validation required a mean bias <5 (sd 8) mm Hg. RESULTS: In 135 patients with arrhythmia, the agreement between oscillometric and intra-arterial measurements of systolic, diastolic and mean BP was similar to that observed in 136 patients with regular rhythm: for mean BP, similar mean bias [-0.1 (sd 5.2) and 1.9 (sd 5.9) mm Hg]. In both groups, the ISO standard was satisfied for mean and diastolic BP, but not for systolic BP (sd >10 mm Hg) in our ICU population. The ability of oscillometry to detect hypotension (systolic BP <90 mm Hg or mean BP <65 mm Hg), response to therapy (>10% increase in mean BP after cardiovascular intervention) and hypertension (systolic BP >140 mm Hg) was good and similar during arrhythmia and regular rhythm (respective areas under the receiver operating characteristic curves ranging from 0.89 to 0.96, arrhythmia vs regular rhythm between-group comparisons all associated with P>0.3). CONCLUSIONS: Contrary to widespread belief, arrhythmia did not cause flawed automated brachial cuff measurements.

[Epidemiology of cerebral perioperative vascular accidents]. / Épidémiologie des accidents vasculaires cérébraux périopératoires.

OBJECTIVES: Stroke is a well-described postoperative complication, after carotid and cardiac surgery. On the contrary, few studies are available concerning postoperative stroke in general non-cardiac non-carotid surgery. The high morbid-mortality of stroke justifies an extended analysis of recent literature. ARTICLE TYPE: Systematic review. DATA SOURCES: Firstly, Medline and Ovid databases using combination of stroke, cardiac surgery, carotid surgery, general non-cardiac non-carotid surgery as keywords; secondly, national and European epidemiologic databases; thirdly, expert and French health agency recommendations; lastly, reference book chapters. RESULTS: In cardiac surgery, with an incidence varying from 1.2 to 10% according to procedure complexity, stroke occurs peroperatively in 50% of cases and during the first 48 postoperative hours for the others. The incidence of stroke after carotid surgery is 1 to 20% according to the technique used as well as operator skills. Postoperative stroke is a rare (0.15% as mean, extremes around 0.02 to 1%) complication in general surgery, it occurs generally after the 24-48th postoperative hours, exceptional peroperatively, and 40% of them occurring in the first postoperative week. It concerned mainly aged patient in high-risk surgeries (hip fracture, vascular surgery). Postoperative stroke was associated to an increase in perioperative mortality in comparison to non-postoperative stroke operated patients. CONCLUSION: Postoperative stroke is a quality marker of the surgical teams' skill and has specific onset time and induces an increase of postoperative mortality.

White coats: how long should doctors wear them?

OBJECTIVES: While coat contamination increases progressively with the duration of use, there are no guidelines on how frequently medical white coats should be changed. The purpose of our study was to examine the turnover of individual batch of medical white coats in a university hospital. STUDY DESIGN AND METHODS: A retrospective analysis of the white coat turnover of 826 physicians was performed by using the hospital laundry computerized database and an electronic declarative survey (240 responses) to evaluate the duration of medical white coat use. RESULTS: There was a wide discrepancy between the data extracted from the laundry database and those from the survey. The median factual duration of use (20 days, range: 15-30) corresponding to a turnover of 2 (1-2) coats per month, was widely underestimated by the physicians. Multivariate analysis identified 4 independent factors associated with a declared use of coats longer than 7 days: estimation of insufficient gown turnover (OR 14.8 [4.8-45.8]), daily change considered as not useful (OR 5.1 [2.4-10.8]), non-medical specialty (OR 2.95 [1.5-5.6]) and presence of stains on gowns (2.9 [1.5-5.5]). CONCLUSION: Shortening white coat use should be included in medical education in order to improve the good practice rules of hospital hygiene.

Risk factors and pathogens involved in early ventilator-acquired pneumonia in patients with severe subarachnoid hemorrhage.

Ventilator-acquired pneumonia (VAP) is a common burden in intensive care unit (ICU) patients, but, to date, specific data are not available in patients with severe aneurysmal subarachnoid hemorrhage (SAH). A single neuro-ICU retrospective analysis of 193 patients with SAH requiring mechanical ventilation (MV) ≥48 h admitted from January 2005 to May 2010 was undertaken. The diagnosis of early VAP was prospectively upheld during a multidisciplinary staff meeting, according to the American Thoracic Society (ATS) 2005 guidelines with a threshold of 7 days after the onset of MV. Patients had a median age of 53 (44-62) years and 70 (36 %) were male. The median Glasgow coma scale (GCS) score before MV was 9 (5-14). 142 (74 %) patients had a World Federation of Neurosurgeons (WFNS) score ≥III. Aneurysm was secured with an endovascular coiling procedure in 162 (84 %) patients. 81 (48.7 %) patients declared an early VAP. On multivariate analysis, male sex (odds ratio [OR] 2.26, 95 % confidence interval [CI] [1.14-4.46]), use of mannitol before day 7 (OR 3.03, 95 % CI [1.54-5.95]), and achieving enteral nutrition ≥20 kcal kg(-1) day(-1) after day 7 (OR 2.91, 95 % CI [1.27-6.67]) remained independent risk factors of VAP. The main pathogens involved were methicillin-susceptible Staphylococcus aureus (MSSA) (34.9 %), Haemophilus influenzae (28.1 %), Streptococcus pneumoniae (15.5 %), and Enterobacteriaceae (10.7 %). Early VAP was associated with a longer duration of MV and ICU stay, but not with an excess of mortality. Early VAP bears significant morbidity in patients with severe SAH. Pathogens involved in early VAP are susceptible to antibiotics. Among modifiable risk factors of VAP, early enteral nutrition could be an easy and effective target.

[Organization of mechanical ventilation in French Intensive care units]. / Organisation de la ventilation artificielle dans les unités de réanimation en France.

OBJECTIVES: To clarify the procedures related to mechanical ventilation in the intensive care unit setting: allocation of ventilators, team education, maintenance and reference documents. STUDY DESIGN: Declarative survey. METHODS: Between September and December 2010, we assessed the assignment and types of ventilators (ICU ventilators, temporary repair ventilators, non-invasive ventilators [NIV], and transportation ventilators), medical and nurse education, maintenance of the ventilators, presence of reference documents. Results are expressed in median/range and proportions. RESULTS: Among the 62 participating ICUs, a median of 15 ventilators/ICU (range 1-50) was reported with more than one trademark in 47 (76%) units. Specific ventilators were used for NIV in 22 (35%) units, temporary repair in 49 (79%) and transportation in all the units. Nurse education courses were given by ICU physicians in 54 (87%) units or by a company in 29 (47%) units. Medical education courses were made by ICU senior physicians in 55 (89%) units or by a company in 21 (34%) units. These courses were organized occasionally in 24 (39%) ICU and bi-annually in 16 (26%) units. Maintenance procedures were made by the ICU staff in 39 (63%) units, dedicated staff (17 [27%]) or bioengineering technicians (14 [23%] ICU). Reference documents were written for maintenance procedures in 48 (77%) units, ventilator setup in 22 (35%) units and ventilator dysfunction in 20 (32%) ICU. CONCLUSIONS: This first survey shows disparate distribution of ventilators and practices among French ICU. Education and understanding of the proper use of ventilators are key issues for security improvement.

Study of agreement of aortic, radial and femoral blood pressures during aortic endografting.

PURPOSE: To estimate the agreement between radial or femoral, and ascending aortic invasive blood pressure values. PATIENTS AND METHODS: Prospective study on 32 patients who underwent an aortic endografting under general anesthesia. After deploying the prosthesis under controlled hypotension, a catheter was introduced in the aorta to measure the staged systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures, in particular at the level of ascending aorta and femoral artery. RESULTS: No differences were observed between SAP, DAP or MAP measured in the aorta versus femoral or radial arteries. A better agreement was observed between the aortic and femoral MAP (bias of 1mmHg, limits of agreement between: -8.8mmHg and +10.8mmHg) than between the aortic and the radial MAP (bias of 1.7mmHg, limits of agreement between: -14.1mmHg and +17.5mmHg). The comparison between radial and femoral MAP was not satisfying (bias of -4.7mmHg and limits of agreement between -19.1mmHg and +9.7mmHg). CONCLUSION: The femoral MAP is more accurate to predict value of the aortic MAP than the radial MAP in a hypotensive setting. The clinician should be aware of these discrepancies in conditions of hemodynamic impairment to optimize the treatment.

Operative care and surveillance in severe trauma patients. Interference between resuscitation treatments and anaesthesiology, and consequence on immunity.

Major trauma remains a worldwide cause of morbi-mortality. Early mortality is the consequence of hemorrhagic shock and traumatic brain injury. During early resuscitation, anaesthesia is often mandatory to perform surgery. It is mandatory to master the hemodynamic effects of hypnotic drugs in order to anticipate their potential deleterious effects in the setting of hemorrhagic shock. After early resuscitation, trauma patients present a high prevalence of nosocomial pneumonia, which sustains major morbidity. Nosocomial pneumonia are the consequence of an overwhelming systemic inflammatory response syndrome (SIRS) as well as a trauma-related immunosuppression. The administration of hemisuccinate of hydrocortisone modulates the SIRS and reduces the risk of nosocomial pneumonia as well as the length of mechanical ventilation. Finally in the operating theatre, fighting against hypothermia and un-anatomical positions, which can aggravate rhabdomyolysis, are both mandatory.

Ammonia plasma concentration and prolonged infusion of remifentanil in patients with acute kidney injury.

BACKGROUND: Glycine is an excipient of remifentanil and may induce side effects. To investigate glycine and ammonia concentration with the use of remifentanil in Intensive Care Unit patients with acute kidney injury (AKI) defined by a decrease in creatinine clearance above 50%. METHODS: Prospective open-label cohort study in three surgical Intensive Care Units. Thirty-three patients with AKI and requiring sedation for at least 72 hours. Sedation with remifentanil and midazolam or propofol was adapted every six hours according to ATICE. Glycine and ammonia plasma concentrations were measured at H0 (start of infusion) and every 12 hours during a continuous intravenous 72 hours remifentanil infusion, and 24 hours after the end of the infusion. Clinical and biological glycine or ammonia toxicity were evaluated. RESULTS: Fifteen patients required continuous veno-venous hemodiafiltration (CVVHDF). Glycine and ammonia plasma concentrations exceeded the normal value respectively for 11 (33%) and 15 (45%) patients before remifentanil infusion (H0). Accumulation of glycine or ammonia was observed neither for patients with or without CVVHDF. For patients without CVVHDF, the plasma ammonia concentration at the end of remifentanil infusion was significantly correlated with the creatinine clearance at H72 (P=0.03) and with the mean rate of remifentanil infusion (P=0.002). No side effect was reported. CONCLUSION: Remifentanil was not associated with an accumulation of glycine or ammonia in patients with AKI. Plasma ammonia concentration was correlated with the mean rate of remifentanil and creatinine clearance. A 72-hours remifentanil infusion appeared safe for sedation of patients with AKI.

[Brain injury, immunity and infections]. / Agressions cérébrales, immunité et infections.

Infections are a major cause of death and morbidity after acute injury of the central nervous system (CNS). Acute lesions of the CNS alter immune homeostasis contributing to the development of immunosuppression (IS), and making the bed of the infection. IS results in a decreased phagocytic functions of neutrophils and macrophages as well as monocyte deactivation (decreased capacity of antigen presentation to lymphocytes). The immune abnormalities occur very quickly and may last for weeks. The neurovegetative system is closely connected to the secondary lymphoid organs where cells of innate immunity receive information from injured organs inducing the long lasting adaptive immune response (immune synapse). The sympathetic system is critically involved in the IS through production of anti-inflammatory mediators like interleukin-10. This may prove important as all types of acute injury of the CNS can lead to direct damage to sympathetic centers. Specialized units of care for ischemic stroke, taking into account the risk of infection related to the IS, have improved the prognosis until 18th month after the initial damage of the SNC. It is now well recognized that the improved long-term prognosis is related with the secondary prevention of recurrent ischaemia as well as aggressive management of pulmonary infections. A better understanding of the pathophysiology of IS can be considered in the near future, opening the door to immunomodulatory therapeutic trials.

Risk factors of postoperative vomiting in children receiving continuous intravenous morphine.

BACKGROUND: Risk factors of postoperative vomiting (POV) have been less extensively explored in children compared to adults. We analyzed the risk factors of POV in children receiving continuous intravenous (i.v.) morphine in a standardized manner without POV prophylaxis after major surgery. METHODS: This observational retrospective study included 235 children aged from 2 to 216 months (91 F:144 M, 11.5% <6 months, 31.5% 6-11 months). The primary end point was the occurrence of at least one episode of POV recorded on the nursing chart. The independent predictors of POV were determined by univariate analysis followed by a multivariate analysis by logistic regression. The data are presented as either medians (25th-75th percentile) or as values with a 95% confidence interval. RESULTS: Continuous i.v. morphine was administered over 42 (22-60) h with an initial infusion rate of 20 µg x kg(-1) x h(-1) in 63% of cases, which was increased in 31.5% of cases and was accompanied by an additional bolus in 39.2% of children. At least one episode of POV occurred in 22.6% of children. The following three independent factors were associated with POV: female gender (OR 3.324 [1.695-6.519], P=0.0005), urological surgery (OR 5.605 [1.291-24.340], P=0.0214) and age (OR 1.012 [1.006-1.018], P<0.0001). The discriminating characteristics of the model were good with an ROC curve AUC of 0.778, sensitivity of 71.7% and specificity of 71.4% for a 0.22 cut-off value of POV incidence. The positive predictive value was 42.2%, and the negative predictive value was 89.6%. CONCLUSION: Female gender, which is usually considered a risk factor after puberty, should be taken into account independent of age to guide the POV prophylaxis in children receiving a postoperative continuous i.v. morphine infusion.