Panton-Valentine Leukocidin-Secreting Staphylococcus aureus Pneumonia Complicating COVID-19.

Necrotizing pneumonia induced by Panton-Valentine leukocidin-secreting Staphylococcus aureus is a rare but life-threatening infection that has been described in patients after they had influenza. We report a fatal case of this superinfection in a young adult who had coronavirus disease.

A composite score combining procalcitonin, C-reactive protein and temperature has a high positive predictive value for the diagnosis of intensive care-acquired infections.

BACKGROUND: Nosocomial infection diagnosis in the intensive care unit (ICU) remains a challenge. We compared routine measurements of procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and temperature in the detection of ICU-acquired infections. METHOD: Prospective observational cohort study in a University hospital Medicosurgical ICU. All patients admitted to the ICU ≥ 5 days (n = 141) were included into two groups, either infected (documented infection, n = 25) or non-infected (discharged from the ICU without diagnosis of infection, n = 88). RESULTS: PCT, CRP, WBC and temperature progression from day -4 (D-4) to day 0 (D0) (day of infection diagnosis or ICU discharge) was analysed. Differences (Δ) were calculated as D0 levels minus the lowest preceding value. D0 PCT and CRP were significantly increased in infected compared to non-infected patients (median, 1st and 3rd quartiles): 3.6 ng/mL (0.92-25) for PCT, 173 mg/L (126-188) for CRP versus 0.02 ng/mL (0.1-0.9) and 57 mg/mL (31-105) respectively (p < 0.0001). In multivariate analysis, D0 temperature > 38.6°C, PCT > 1.86 ng/mL, and CRP > 88 mg/L, performed well (AUCs of 0.88, 0.84, and 0.88 respectively). The sensitivity/specificity profiles of each marker (76%/94% for temperature, 68%/91% for PCT, and 92%/70% for CRP) led to a composite score (0.068 × D0 PCT + 0.005 × D0 CRP + 0.7 × temperature) more highly specific than each component (AUC of 0.90 and sensitivity/specificity of 80%/97%). CONCLUSION: Combining CRP, PCT and temperature is an approach which may increase of nosocomial infection detection in the ICU.

Beta-adrenergic modulation of lung fluid balance in acute P aeruginosa pneumonia in rats.

OBJECTIVE: we investigated the effects of terbutaline, a ß(2)-adrenergic agonist, on lung permeability and alveolar fluid clearance (AFC) in acute lung injury (ALI). METHODS: the study was conducted in vivo on a rat model of P aeruginosa (Pa)-induced ALI. Rats were randomly divided into five groups: the control group (saline group), Pa and saline group, Pa and terbutaline treated group receiving intratracheal instillation of terbutaline at 10(-4) M, Pa and terbutaline plus propranolol treated group (terbutaline+propranolol group) and Pa and propranolol treated group (propranolol group). Hemodynamics, airway pressures, arterial blood gases, extravascular lung water, lung permeability to protein evaluated by the extravascular accumulation of (125)I-albumin (EPE), bacterial counts, and alveolar fluid clearance (AFC) were measured. RESULTS: 4.5 hours after bacterial instillation, the lung wet-to-dry ratio and the EPE were significantly decreased in the terbutaline group compared to saline control group (respectively 4.31 ± 0.51 g/g versus 5.99 ± 0.5 g/g 4.18 ± 0.25 g/g and 148 ± 68 µL versus 349 ± 97 µL respectively p < 0.01). Treatment with terbutaline in the Pa-instilled group significantly increased basal AFC compared with the saline and Pa group, (respectively 22.3 ± 1.3% versus 12.5 ± 4.7%, p < 0.001). Intratracheal instillation of propranolol (10(-4) M) inhibited the effects of terbutaline on lung fluid balance. CONCLUSION: Exogenous instillation of beta2-adrenergic have a beneficial effect on lung fluid balance following Pa pneumonia in rats, by reducing pulmonary endothelial permeability and increasing alveolar fluid clearance. These data suggest that exogenous beta-adrenergic therapy can protect against alveolar edema formation in acute P aeruginosa pneumonia.

A simple functional marker to predict the need for prolonged mechanical ventilation in patients with Guillain-Barré syndrome.

INTRODUCTION: Patients suffering from Guillain-Barré syndrome (GBS) may frequently develop an acute respiratory failure and need ventilatory support. Immune therapy using plasma exchange or immunoglobulins has modified the natural course of the disease and by decreasing the length of the plateau phase, may induce a rapid improvement in ventilatory function. However a substantial proportion of patients still require prolonged mechanical ventilation (MV) and tracheotomy. The present study was designed to search for simple functional markers that could predict the need for prolonged MV just after completion of immune therapy. METHODS: We analyzed the data collected in a cohort of patients with GBS admitted to the intensive care unit (ICU) of our university hospital between 1996 and 2009. Demographic, clinical, biological and electrophysiologic data, results of sequential spirometry, and times of endotracheal intubation, tracheotomy, and MV weaning were prospectively collected for all patients. Sequential daily neurological testing used standardized data collection by the same investigators all along the study period. Results were compared by single and multiple regression analysis at admission to ICU and at the end of immune therapy, according to the need and duration of MV (≤ or > 15 days). RESULTS: Sixty-one patients with severe GBS were studied. Sixty-six percent required MV (median length: 24 days). The lack of foot flexion ability at ICU admission and at the end of immunotherapy was significantly associated with MV length > 15 days (positive predictive value: 82%; odds ratio: 5.4 [1.2 - 23.8] and 82%; 6.4 [1.4 - 28.8], respectively). The association of a sciatic nerve motor conduction block with the lack of foot flexion at the end of immunotherapy was associated with prolonged MV with a 100% positive predictive value. CONCLUSIONS: In patients admitted to ICU with Guillain-Barré syndrome and acute respiratory failure, the lack of foot flexion ability at the end of immune therapy predicts a prolonged duration of MV. Combined with a sciatic motor conduction block, it may be a strong argument to perform an early tracheotomy.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer.

BACKGROUND: Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. CASE REPORT: A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. DISCUSSION: We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.

Impact of tapered-cuff tracheal tube on microaspiration of gastric contents in intubated critically ill patients: a multicenter cluster-randomized cross-over controlled trial.

PURPOSE: Studies on the impact of tapered-cuff tracheal tubes on rates of microaspiration and ventilator-associated pneumonia (VAP) in intubated patients have reported conflicting results. The aim of this study was to determine the influence of this shape of tracheal cuff on abundant microaspiration of gastric contents in critically ill patients. METHODS: All patients intubated in the intensive care unit (ICU) and requiring mechanical ventilation for at least 48 h were eligible for this multicenter cluster-randomized controlled cross-over open-label study. The primary outcome was abundant microaspiration of gastric contents, defined by the presence of pepsin at significant level in >30% of tracheal aspirates. Quantitative measurement of pepsin and salivary amylase was performed in all tracheal aspirates during the 48 h following enrollment. RESULTS: A total of 326 patients were enrolled in the ten participating ICUs (162 in the PVC tapered-cuff group and 164 in the standard-cuff group). Patient characteristics were similar in the two study groups. The proportion of patients with abundant microaspiration of gastric contents was 53.5% in the tapered-cuff and 51.0% in the standard-cuff group (odds ratio 1.14, 95% CI 0.72-1.82). While abundant microaspiration of oropharyngeal secretions was not significantly different (77.4 vs 68.6%, p = 0.095), the proportion of patients with tracheobronchial colonization was significantly lower (29.6 vs 43.3%, p = 0.01) in the tapered-cuff than in the standard-cuff group. No significant difference between the two groups was found for other secondary outcomes, including ventilator-associated events and VAP. CONCLUSIONS: This trial showed no significant impact of tapered-cuff tracheal tubes on abundant microaspiration of gastric contents. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01948635.

Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response.

BACKGROUND: Acute lung injury (ALI) induces a coagulation/fibrinolysis imbalance and leads to fibrin deposition. The protein C pathway is an important regulator of the coagulation system and reduces the inflammatory response. The aim of the study was to examine the effects of recombinant human activated protein C (rhAPC) in the early phase of Pseudomonas aeruginosa (Pa)-induced lung injury. METHODS: The study was conducted in vivo on a rat model of Pa-induced ALI. Continuous intravenous (IV) rhAPC was administrated simultaneously with intratracheal (IT) Pa. We instilled into the airspaces a 5% bovine albumin solution with 1 mu(Ci of (125)I-albumin and injected IV 1 mu(Ci of (111)In-albumin to measure lung liquid clearance (LLC) and endothelial injury. Cytokines levels (TNFalpha and IL-6) and thrombin-antithrombin (TAT) complexes were measured in blood and bronchoalveolar lavage fluid (BALF) at 4 hours. Four groups were compared: control (CTR), pneumonia (PNP) receiving IT Pa (0.5 ml/kg of 1 x 10(9) cfu), APC: IV rhAPC (300 microg/kg/h), A-PNP: IT Pa /IV rhAPC. RESULTS: Alveolar-capillary permeability was increased in the PNP versus the CTR group (0.28 +/- 0.08 vs. 0.03 +/- 0.01, p < 0.05). IV rhAPC in Pa-induced ALI led to further injury (0.47 +/- 0.17 vs. 0.28 +/- 0.08, p = 0.2). The LLC was significantly decreased in the A-PNP group compared to PNP group (9.1 +/- (4.3% vs. 33.4 +/- 2.6%, p < 0.05). The lung wet to dry weight ratio was significantly increased in the PNP group (4.62 +/- 0.31) compared to the CTR group (3.87 +/- 0.22, p < 0.05). IV rhAPC administration tends to increase this parameter in Pa-induced ALI (5.80 +/- 0.66, p = 0.07). These findings were associated with a loss of inflammatory response compartmentalization measured by TNFalpha and IL-6 systemic levels. TAT complexes in BALF were increased in the A-PNP group (23.17 +/- 2.89 ng/ml) compared to the CTR group (0.92 +/- 0.17 ng/ml, p < 0.05) and the PNP group (11.06 +/- 2.76 ng/ml, p < 0.05). CONCLUSION: rhAPC reduces LLC following Pa-induced ALI and may influence pulmonary edema formation. The early massive fibrin formation is probably beneficial in ALI limiting both the extent of injury and permeability disorders.

Predictors of extubation failure in patients with chronic obstructive pulmonary disease.

Few studies have focused on extubation outcome in patients with chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation (MV). We conducted a study using prospectively collected data in a cohort of patients with COPD requiring invasive MV to identify variables associated with extubation failure. Use of noninvasive or invasive MV within 48 hours after extubation was defined as extubation failure. A total of 148 patients with COPD were studied. Extubation failure occurred in 35% of studied patients. Using multiple regression analysis, independent predictors of extubation failure were physiologic abnormalities measured by Simplified Acute Physiology Score II above 35 on intensive care unit (ICU) admission (odds ratio [OR], 3.88; 95% confidence interval [CI], 1.65-9.12), home noninvasive MV (OR, 12.99; 95% CI, 2.86-58.89), and sterile endotracheal aspirations on the day of extubation were predictors of success (OR, 0.23; 95% CI, 0.10-0.52). Despite high rate of extubation failure, survival to ICU discharge was 91% of the studied population. Extubation failure in patients with COPD remains high despite a successful spontaneous breathing on T piece. Simplified Acute Physiology Score II at ICU admission, home noninvasive MV, and isolated pathogens on quantitative cultures of tracheobronchial secretions within 72 hours preceding extubation were predictors of extubation failure in the study population.

Impact of tracheal cuff shape on microaspiration of gastric contents in intubated critically ill patients: study protocol for a randomized controlled trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common infection in intubated critically ill patients. Microaspiration of the contaminated gastric and oropharyngeal secretions is the main mechanism involved in the pathophysiology of VAP. Tracheal cuff plays an important role in stopping the progression of contaminated secretions into the lower respiratory tract. Previous in vitro studies suggested that conical cuff shape might be helpful in improving tracheal sealing. However, clinical studies found conflicting results. The aim of this study is to determine the impact of conical tracheal cuff shape on the microaspiration of gastric contents in critically ill patients. METHODS/DESIGN: This prospective cluster randomized controlled crossover open-label trial is currently being conducted in ten French intensive care units (ICUs). Patients are allocated to intubation with a polyvinyl chloride (PVC) standard (barrel)-shaped or a PVC conical-shaped tracheal tube. The primary objective is to determine the impact of the conical shaped tracheal cuff on abundant microaspiration of gastric contents. Secondary outcomes include the incidence of microaspiration of oropharyngeal secretions, tracheobronchial colonization, VAP and ventilator-associated events. Abundant microaspiration is defined as the presence of pepsin at significant level (>200 ng/ml) in at least 30 % of the tracheal aspirates. Pepsin and amylase are quantitatively measured in all tracheal aspirates during the 48 h following inclusion. Quantitative tracheal aspirate culture is performed at inclusion and twice weekly. We plan to recruit 312 patients in the participating ICUs. DISCUSSION: BEST Cuff is the first randomized controlled study evaluating the impact of PVC tracheal-cuff shape on gastric microaspirations in patients receiving invasive mechanical ventilation. Enrollment began in June 2014 and is expected to end in October 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01948635 (registered 31 August 2013).

Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.

In acute lung injury (ALI), a coagulation/fibrinolysis imbalance leads to fibrin deposition, persistence of which contributes to fibrotic evolution. Our study evaluated the effects of early inhibition of coagulation in Pseudomonas aeruginosa (Pa)-induced ALI through the use of recombinant human antithrombin (rhAT). The study was conducted in vivo on a murine model of Pa-induced ALI. Intravenous rhAT was administered simultaneously with intratracheal Pa. Four experimental groups were compared: CTR, intratracheal saline (0.5 mL/kg)/intravenous saline (1 mL); PNP, intratracheal Pa (0.5 mL/kg of 2 x 10(9) cfu)/intravenous saline; AT, intratracheal saline/intravenous rhAT (500 IU/kg); ATPNP, intratracheal Pa/intravenous rhAT. Epithelial and endothelial permeabilities were evaluated with radiolabeled albumin flux across the alveolar barrier (125I- and 131I-labeled albumin). Thrombin-antithrombin (TAT) complexes levels were used as markers of coagulation activation in blood samples and in BAL fluid. Epithelial and endothelial protein permeability were increased in Pa-induced ALI versus control. Intravenous rhAT administration led to further permeability disorders. Administration of rhAT in Pa ALI led to a rise in TAT complexes in ATPNP blood serum and BAL fluids compared with the other groups. In Pa-induced ALI the administration intravenous rhAT leads to major histologic damage, alveolar capillary barrier injury, and permeability increase. Such effects of the inhibition of thrombin activation by rhAT lead to the hypothesis of a probable beneficial role of early coagulation activation in ALI as a factor limiting both the extent of injury and permeability disorders. Our study suggests that inhibition of this initial procoagulative imbalance is potentially dangerous.

Ventilation-induced lung injury is associated with an increase in gut permeability.

Mechanical ventilation is associated with several harmful effects mainly related to high tidal volumes (Vt). Ventilator-induced lung injury can be responsible for an increased production of inflammatory mediators. We evaluated remote consequences on the gut of lung triggered inflammatory response, neutralizing anti-tumor necrosis factor (TNF) antibody was administered to assess the role of TNF in lung and gut permeability changes. Rats were anesthetized and ventilated for 2 h. A control group (Con: Vt = 10 mL/kg) was compared with a high Vt group (HV: Vt = 30 ml/kg). One microCi of I125-labeled human serum albumin was injected to measure extravascular albumin space. Gut permeability was evaluated by plasma-to-lumen ratio leakage of I125 human serum albumin. Extravascular albumin space increased in the HV group from 446 +/- 50 microL to 2783 +/- 887 microL. Gut index of permeability increased from 5.1 +/- 1.2 to 14.2 +/- 4.9. Anti-TNF antibody prevented both lung and gut increase in permeability. High tidal volume ventilation resulted in an increase in lung edema and gut permeability, antagonism of TNF with neutralizing antibodies abrogated the increase in gut permeability as well as lung edema.

Protective effect of endogenous beta-adrenergic tone on lung fluid balance in acute bacterial pneumonia in mice.

Some investigators have reported that endogenous beta-adrenoceptor tone can provide protection against acute lung injury. Therefore, we tested the effects of beta-adrenoceptor inhibition in mice with acute Escherichia coli pneumonia. Mice were pretreated with propranolol or saline and then intratracheally instilled with live E. coli (10(7) colony-forming units). Hemodynamics, arterial blood gases, plasma catecholamines, extravascular lung water, lung permeability to protein, bacterial counts, and alveolar fluid clearance were measured. Acute E. coli pneumonia was established after 4 h with histological evidence of acute pulmonary inflammation, arterial hypoxemia, a threefold increase in lung vascular permeability, and a 30% increase in extravascular lung water as an increase in plasma catecholamine levels. beta-Adrenoceptor inhibition resulted in a marked increase in extravascular lung water that was explained by both an increase in lung vascular permeability and a reduction in net alveolar fluid clearance. The increase in extravascular lung water with propranolol pretreatment was not explained by an increase in systemic or vascular pressures. The increase in lung vascular permeability was explained in part by anti-inflammatory effects of beta-adrenoceptor stimulation because plasma macrophage inflammatory protein-2 levels were higher in the propranolol pretreatment group compared with controls. The decrease in alveolar fluid clearance with propranolol was explained by a decrease in catecholamine-stimulated fluid clearance. Together, these results indicate that endogenous beta-adrenoceptor tone has a protective effect in limiting accumulation of extravascular lung water in acute severe E. coli pneumonia in mice by two mechanisms: 1) reducing lung vascular injury and 2) upregulating the resolution of alveolar edema.

Alveolar epithelium: role in lung fluid balance and acute lung injury.

The resolution of alveolar edema is regulated by active sodium and chloride transport across the pulmonary epithelium, including alveolar epithelial type I and II cells as well as distal airway epithelia. Catecholamine-dependent mechanisms can markedly upregulate alveolar fluid clearance even under pathological conditions, an effect that is mediated by both epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR). Under pathological conditions, impaired alveolar fluid clearance is associated with worse survival in patients with acute lung injury. However, there is some experimental and clinical evidence that cAMP stimulation could accelerate the resolution of pulmonary edema in the presence of acute lung injury. Clinical trials are needed to test this potential therapeutic strategy in patients with acute lung injury.

Direct visual instillation as a method for efficient delivery of fluid into the distal airspaces of anesthetized mice.

Although several methods have been used to deliver fluid into the distal airspaces of the lung, the efficiency of these methods has been variable. Therefore, the authors have modified prior techniques to design a better method for direct visual instillation (DVI) of fluid into the trachea and compared its efficiency with two commonly used methods: nasal inhalation and invasive intratracheal instillation (delivery of the instillate by needle puncture of the trachea). The results showed that this method (DVI) can deliver fluid efficiently into either both lungs or into a single lung. Using an 131I-albumin labeling technique, DVI resulted in 92 +/- 1% retention of the labeled albumin in the lungs 1 hour after instillation, significantly greater than nasal inhalation (48 +/- 3%, P < .01) and invasive intratracheal instillation (77 +/- 3%, P < .05). Also, when bacteria (Escherichia coli) were instilled with the DVI method, the severity of gram-negative pneumonia was greater (6.5 +/- 0.5 g water/g dry weight) compared to delivery by nasal inhalation (5.5 +/- 0.4 g water/g dry weight, P < .05) or by invasive intratracheal instillation (5.9 +/- 0.4g water/g dry weight, P < .05). The authors conclude that DVI is more efficient than nasal inhalation and invasive intratracheal instillation for delivering experimental fluids into the distal airspaces of anesthetized mice. This method should be valuable for experimental lung studies in mice.