Mathieu Desmard

A carbon monoxide-releasing molecule (CORM-3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia

The search for new molecules to fight Pseudomonas aeruginosa is of paramount importance. Carbon monoxide (CO) is known to act as an effective inhibitor of the respiratory chain in P. aeruginosa, but the practical use of this gas as an antibacterial molecule is hampered by its toxicity and difficulty to manipulate. Here, we show that a water‐soluble CO releaser (CORM‐3) possesses bactericidal properties against laboratory and antibiotic‐resistant P. aeruginosa. CORM‐3 reduced the bacterial count by 4 logs 180 min after in vitro treatment. CORM‐3‐treated bacteria had a lower O2 consumption than vehicle‐treated bacteria, and the decrease in O2 consumption temporally preceded the bactericidal action of CORM‐3. These results support the hypothesis that the antimicrobial effect of CORM‐3 is mediated by an interaction of CO liberated by the carrier with the bacterial respiratory chain. The antibacterial effect occurred at concentrations of CORM‐3 that are 50fold lower than toxic concentrations for eukaryotic cells. CORM‐3 treatment compared to vehicle treatment decreased bacterial counts in the spleen and increased survival in immunocompetent and immunosuppressed mice following P. aeruginosa bacteremia. Our results suggest that CORMs could form the basis for developing a new therapeutic strategy against P. aeruginosa‐induced infection.—Desmard, M., Davidge, K. S., Bouvet, O., Morin, D., Roux, D., Foresti, R., Ricard, J. D., Denamur, E., Poole, R. K., Montravers, P., Motterlini, R., Boczkowski, J. A carbon monoxide‐releasing molecule (CORM‐3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia. FASEB J. 23, 1023–1031 (2009)

Differential Antibacterial Activity Against Pseudomonas aeruginosa by Carbon Monoxide-Releasing Molecules

AIMS Carbon monoxide (CO) delivered in a controlled manner to cells and organisms mediates a variety of pharmacological effects to the extent that CO-releasing molecules (CO-RMs) are being developed for therapeutic purposes. Recently, ruthenium-based CO-RMs have been shown to posses important bactericidal activity. Here we assessed the effect of fast CO releasers containing ruthenium (Ru(CO)(3)Cl(glycinate) [CORM-3] and tricarbonyldichlororuthenium(II) dimer [CORM-2]) and a novel slow manganese-based CO releaser ([Me(4)N][Mn(CO)(4)(thioacetate)(2)] [CORM-371]) on O(2) consumption and growth of Pseudomonas aeruginosa (PAO1). We then compared these effects with the action elicited by sodium boranocarbonate (CORM-A1), which lacks a transition metal but liberates CO with a rate similar to CORM-371. RESULTS CORM-2, CORM-3, and, to a lesser extent, CORM-371 exerted a significant bactericidal effect and decreased O(2) consumption in PAO1 in vitro. The effect appeared to be independent of reactive oxygen species production, but in the case of metal-containing compounds it was prevented by the thiol donor N-acetylcysteine. In contrast, CORM-A1 was bacteriostatic rather than bactericidal in vitro eliciting only a moderate and transient decrease in O(2) consumption. INNOVATION None of the tested CO-RMs was toxic to murine macrophages or human fibroblasts at the concentration impairing PA01 growth but only ruthenium-containing CO-RMs showed potential therapeutic properties by increasing the survival of mice infected with PA01. CONCLUSION CO carriers inhibit bacterial growth and O(2) consumption in vitro, but transition metal carbonyls appear more powerful than compounds spontaneously liberating CO. The nature of the metal in CO-RMs also modulates the anti-bacterial effect, with ruthenium-based CO-RMs being efficacious both in vitro and in vivo.

Clinical review: Intrapericardial fibrinolysis in management of purulent pericarditis

Purulent pericarditis (PP) is a potentially life-threatening disease. Reported mortality rates are between 20 and 30%. Constrictive pericarditis occurs over the course of PP in at least 3.5% of cases. The frequency of persistent PP (chronic or recurrent purulent pericardial effusion occurring despite drainage and adequate antibiotherapy) is unknown because this entity was not previously classified as a complication of PP. No consensus exists on the optimal management of PP. Nevertheless, the cornerstone of PP management is complete eradication of the focus of infection. In retrospective studies, compared to simple drainage, systematic pericardiectomy provided a prevention of constrictive pericarditis with better clinical outcome. Because of potential morbidity associated with pericardiectomy, intrapericardial fibrinolysis has been proposed as a less invasive method for prevention of persistent PP and constrictive pericarditis. Experimental data demonstrate that fibrin formation, which occurs during the first week of the disease, is an essential step in the evolution to constrictive pericarditis and persistent PP. We reviewed the literature using the MEDLINE database. We evaluated the clinical efficacy, outcome, and complications of pericardial fibrinolysis. Seventy-four cases of fibrinolysis in PP were analysed. Pericarditis of tuberculous origin were excluded. Among the 40 included cases, only two treated by late fibrinolysis encountered failure requiring pericardiectomy. No patient encountered clinical or echocardiographic features of constriction during follow-up. Only one serious complication was described. Despite the lack of definitive evidence, potential benefits of fibrinolysis as a less invasive alternative to surgery in the management of PP seem promising. Early consideration should be given to fibrinolysis in order to prevent both constrictive and persistent PP. Nevertheless, in case of failure of fibrinolysis, pericardiectomy remains the primary option for complete eradication of infection.

Pseudomonas aeruginosa Post-Operative Peritonitis: Clinical Features, Risk Factors, and Prognosis

BACKGROUND Postoperative peritonitis (PP) is associated with a high rate of multi-drug-resistant micro-organisms. The role of Pseudomonas aeruginosa in this condition has never been assessed. We evaluated the risk factors and prognosis for PP caused by P. aeruginosa. METHODS Patients hospitalized in the intensive care unit (ICU) after re-operation for PP were identified prospectively. Analyses were performed retrospectively. Specific risk factors were investigated by comparing P. aeruginosa PP with PP having other causes. The main outcome endpoint was death in the hospital. RESULTS We found 55 P. aeruginosa PP among the 349 cases of PP (16%) in the ICU over 14 years. Factors associated with the presence of P. aeruginosa in peritoneal fluid culture were Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.02-1.09; p=0.004) and respiratory failure (OR 2.3; 95% CI 1.26-4.16; p=0.006). These criteria performed poorly in predicting P. aeruginosa PP. Such infections were associated with a higher hospital mortality rate, but not after adjustment for the severity score. Adequate antibiotic therapy comprising two antibiotics effective against P. aeruginosa was associated with a lower mortality rate for P. aeruginosa PP in the ICU. CONCLUSION The prevalence of P. aeruginosa PP is not high. Risk factors do not allow accurate prediction of the infection. Our data suggest two drugs effective against P. aeruginosa should be considered for treating these infections.

Post-operative kinetics of procalcitonin after lung transplantation

BACKGROUND Post-operative infections are a major complication after lung transplantation (LT). Early bacterial pneumonia worsens the prognosis of LT. Procalcitonin (PCT) has been proposed as an early and rapid laboratory marker of infection and sepsis. PCT could be a useful biomarker of pulmonary infection after LT, but the early kinetics of PCT in this setting are unknown. We evaluated the kinetics of PCT and the impact of respiratory tract infection on PCT concentrations. METHODS Over a 12-month period, PCT concentrations were determined daily in each patient admitted to our ICU for LT. Epidemiologic, clinical, laboratory and outcome data were obtained. A diagnosis of respiratory tract infection was suspected on clinical examination and confirmed by microbiologic culture. RESULTS Twenty-six consecutive patients were included and 397 blood samples were obtained (13 [range 4 to 66] samples per patient). Plasma PCT reached a peak in the first 24 hours post-transplantation (5.72 [0.11 to 93.8] ng/ml), with a progressive decline over the first 7 post-operative days. Doubling of plasma PCT levels after an initial decrease was significantly associated with respiratory tract infection in transplanted patients (RR = 4.2 95% CI [1.95 to 9.03]). CONCLUSIONS A non-specific increase in PCT values was observed during the first week post-LT. In combination with microbiologic cultures, PCT assays may be useful after the first post-operative week as an aid in the diagnosis of bacterial pulmonary infection.

Diagnosis and management of the postoperative surgical and medical complications of bariatric surgery

Perioperative complications following bariatric surgery (BS) have been poorly analysed and their management is not clearly assessed. The associated frequency of ICU admission is difficult to estimate. Among surgical complications, digestive perforations are the most frequent. The most common postoperative complications of sleeve gastrectomy are fistulas, but bleeding on the stapling line is also commonly reported. Complication rates are higher after Roux-en-Y gastric bypass, mainly due to anastomotic leaks. Medical complications are mainly thromboembolic or respiratory complications. All these surgical and medical complications are not easily detected; clinical signs can be atypical or insidious, often resulting in delayed management. Respiratory signs can be predominant and lead erroneously to pulmonary or thromboembolic diseases. Diagnostic criteria are based on minor clinical signs, tachycardia being probably the most frequent one. Lately, complications are revealed by haemodynamic instability, respiratory failure or renal dysfunction and radiographic findings. Management decision according to these abnormal signs is based on a combined multidisciplanary approach including surgical and/or endoscopic procedures and medical care, depending on the nature and severity of the surgical complication. Medical management is based on supportive ICU care of organ dysfunctions, curative anticoagulation if required, nutritional support, and appropriate anti-infective therapy. Pharmacological data are limited in morbidly obese patients and the appropriate doses are debated, especially for anti-infective agents. Complicated BS cases have a poor outcome, probably largely related to delayed diagnosis and reoperation.

Echocardiography to predict tolerance to negative fluid balance in acute respiratory distress syndrome/acute lung injury

PURPOSE In acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), a conservative fluid management strategy improves lung function but could jeopardize extrapulmonary organ perfusion. The objective was to evaluate the diagnostic accuracy of echocardiography to predict tolerance of negative fluid balance (NFB) in patients with ARDS/ALI. MATERIALS AND METHODS A prospective and observational study in an adult intensive care unit of a university hospital was conducted. All hemodynamically stable patients with ARDS/ALI were included. Echocardiography was performed before NFB and again after 24 hours. Tolerance of NFB was evaluated by the presence of hypotension, acute kidney injury, or need for fluid expansion. The 2 patient groups (tolerating and not tolerating NFB) were compared. RESULTS Forty-five patients were included. Median age (Q1-Q3) was 58 (52-66) years, and the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen was 205 (163-258) mm Hg. Negative fluid balance was 1950 (1200-2200) mL within 24 hours in the tolerant group. Complications of NFB were observed in 35% cases. After univariate and multivariate logistic regression analyzes, 2 criteria was independently associates with poor tolerance: mitral inflow E wave to early diastolic mitral annulus velocities ratio (E/Ea ratio; odds ratio, 2.02 [1.02-4.02]; P = .04) and weight gain (odds ratio, 1.2 [1.03-1.4]; P = .02). The area under receiver operating characteristic curves was 0.74 for E/Ea and 0.77 for weight gain. CONCLUSIONS The ratio of E/Ea accurately predicted tolerance of NFB in patients with ARDS/ALI.

Extracorporeal Membrane Oxygenation in 5 Patients With Bronchial Fistula With Severe Acute Lung Injury

PURPOSE The management of bronchial fistula associated with acute lung injury raises two major concerns: (1) high ventilation pressures are necessary for lung recruitment but detrimental for fistula healing, and (2) adequate lung recruitment is prevented by large air leak. Primary surgical closure of bronchial fistula should be attempted but is rarely successful during mechanical ventilation. We sought to evaluate the efficacy of extracorporeal membrane oxygenation associated with lung-protective ventilation in case of failure of conventional management. DESCRIPTION Arteriovenous extracorporeal membrane oxygenation was initiated by femorofemoral cannulation. A stepwise increase of extracorporeal membrane oxygenation output and a decrease of mechanical ventilation settings were simultaneously performed, aiming at lung-protective ventilation. EVALUATION During a 1-year period, this protocol management was used in 5 patients with refractory respiratory failure associated with bronchial fistula after thoracic operations. This strategy allowed fistula healing in 3 patients. CONCLUSIONS If correctly timed, extracorporeal membrane oxygenation can provide a therapeutic bridge to lung-protective ventilation and allow bronchial fistula healing in case of refractory respiratory failure.

A Long-Term Clinical Evaluation of AutoFlow During Assist-Controlled Ventilation: A Randomized Controlled Trial

BACKGROUND:Many new mechanical ventilation modes are proposed without any clinical evaluation. “Dual-controlled” modes, such as AutoFlow™, are supposed to improve patient– ventilator interfacing and could lead to fewer alarms. We performed a long-term clinical evaluation of the efficacy and safety of AutoFlow during assist-controlled ventilation, focusing on ventilator alarms. METHODS:Forty-two adult patients, receiving mechanical ventilation for more than 2 days with a Dräger Evita 4 ventilator were randomized to conventional (n = 21) or AutoFlow (n = 21) assist-controlled ventilation. Sedation was given using a nurse-driven protocol. Ventilator-generated alarms were exhaustively recorded from the ventilator logbook with a computer. Daily blood gases and ventilation outcome were recorded. RESULTS:A total of 403 days of mechanical ventilation were studied and 45,022 alarms were recorded over a period of 8074 hours. The course of respiratory rate, minute ventilation, FIO2, positive end-expiratory pressure, PaO2/FIO2, PaCO2, and pH and doses and duration of sedation did not differ between the 2 groups. Outcome (duration of mechanical ventilation, ventilator-associated pneumonia, course of Sequential Organ Failure Assessment score, or death) was not different between the 2 groups. The number of alarms per hour was lower with AutoFlow assist-controlled ventilation: 3.3 [1.5 to 17] versus 9.1 [5 to 19], P < 0.0001 (median [quartile range]). In multivariate analysis, a low alarm rate was associated with activation of AutoFlow and a higher midazolam dose. CONCLUSIONS:This first long-term clinical evaluation of the AutoFlow mode demonstrated its safety with regard to gas exchange and patient outcome. AutoFlow also allowed a very marked reduction in the number of ventilator alarms.

Morbidity and mortality related to pneumonia and TRACHEOBRONCHITIS in ICU after lung transplantation

BackgroundBacterial respiratory infections (BRI) are major complications contributing to increased morbidity and mortality after lung transplantation (LT). This study analyzed epidemiology and outcome of 175 consecutive patients developing BRI in ICU after LT between 2006 and 2012.MethodsThree situations were described: colonization determined in donors and recipients, pneumonia and tracheobronchitis during the first 28 postoperative days. Severity score, demographic, bacteriologic and outcome data were collected.Results26% of donors and 31% of recipients were colonized. 92% of recipients developed BRI, including at least one episode of pneumonia in 19% of recipients. Only 21% of recipients developed BRI with an organism cultured from the donor’s samples, while 40% of recipients developed BRI with their own bacteria cultured before LT. Purulent sputum appears to be an important factor to discriminate tracheobronchitis from pneumonia. When compared to patients with tracheobronchitis, those with pneumonia had longer durations of mechanical ventilation (13 [3–27] vs 3 [29], p = 0.0005) and ICU stay (24 [16–34] vs 14 [9-22], p = 0.002). Pneumonia was associated with higher 28-day (11 (32%) vs 9 (7%), p = 0.0004) and one-year mortality rates (21 (61%) vs 24 (19%), p ≤ 0.0001).ConclusionsThese data confirm the high frequency of BRI right from the early postoperative period and the poor prognosis of pneumonia after LT.