Vito Fanelli

Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure: a matched cohort study with historical control.

Objectives:To assess efficacy and safety of noninvasive ventilation-plus-extracorporeal Co2 removal in comparison to noninvasive ventilation-only to prevent endotracheal intubation patients with acute hypercapnic respiratory failure at risk of failing noninvasive ventilation. Design:Matched cohort study with historical control. Setting:Two academic Italian ICUs. Patients:Patients treated with noninvasive ventilation for acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease (May 2011 to November 2013). Interventions:Extracorporeal CO2 removal was added to noninvasive ventilation when noninvasive ventilation was at risk of failure (arterial pH ⩽ 7.30 with arterial PCO2 > 20% of baseline, and respiratory rate ≥ 30 breaths/min or use of accessory muscles/paradoxical abdominal movements). The noninvasive ventilation-only group was created applying the genetic matching technique (GenMatch) on a dataset including patients enrolled in two previous studies. Exclusion criteria for both groups were mean arterial pressure less than 60 mm Hg, contraindications to anticoagulation, body weight greater than 120 kg, contraindication to continuation of active treatment, and failure to obtain consent. Measurements and Main Results:Primary endpoint was the cumulative prevalence of endotracheal intubation. Twenty-five patients were included in the noninvasive ventilation-plus-extracorporeal CO2 removal group. The GenMatch identified 21 patients for the noninvasive ventilation-only group. Risk of being intubated was three times higher in patients treated with noninvasive ventilation-only than in patients treated with noninvasive ventilation-plus-extracorporeal CO2 removal (hazard ratio, 0.27; 95% CI, 0.07–0.98; p = 0.047). Intubation rate in noninvasive ventilation-plus-extracorporeal CO2 removal was 12% (95% CI, 2.5–31.2) and in noninvasive ventilation-only was 33% (95% CI, 14.6–57.0), but the difference was not statistically different (p = 0.1495). Thirteen patients (52%) experienced adverse events related to extracorporeal CO2 removal. Bleeding episodes were observed in three patients, and one patient experienced vein perforation. Malfunctioning of the system caused all other adverse events. Conclusions:These data provide the rationale for future randomized clinical trials that are required to validate extracorporeal CO2 removal in patients with hypercapnic respiratory failure and respiratory acidosis nonresponsive to noninvasive ventilation.

Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome

BackgroundMechanical ventilation with a tidal volume (VT) of 6 mL/kg/predicted body weight (PBW), to maintain plateau pressure (Pplat) lower than 30 cmH2O, does not completely avoid the risk of ventilator induced lung injury (VILI). The aim of this study was to evaluate safety and feasibility of a ventilation strategy consisting of very low VT combined with extracorporeal carbon dioxide removal (ECCO2R).MethodsIn fifteen patients with moderate ARDS, VT was reduced from baseline to 4 mL/kg PBW while PEEP was increased to target a plateau pressure – (Pplat) between 23 and 25 cmH2O. Low-flow ECCO2R was initiated when respiratory acidosis developed (pH < 7.25, PaCO2 > 60 mmHg). Ventilation parameters (VT, respiratory rate, PEEP), respiratory compliance (CRS), driving pressure (DeltaP = VT/CRS), arterial blood gases, and ECCO2R system operational characteristics were collected during the period of ultra-protective ventilation. Patients were weaned from ECCO2R when PaO2/FiO2 was higher than 200 and could tolerate conventional ventilation settings. Complications, mortality at day 28, need for prone positioning and extracorporeal membrane oxygenation, and data on weaning from both MV and ECCO2R were also collected.ResultsDuring the 2 h run in phase, VT reduction from baseline (6.2 mL/kg PBW) to approximately 4 mL/kg PBW caused respiratory acidosis (pH < 7.25) in all fifteen patients. At steady state, ECCO2R with an average blood flow of 435 mL/min and sweep gas flow of 10 L/min was effective at correcting pH and PaCO2 to within 10 % of baseline values. PEEP values tended to increase at VT of 4 mL/kg from 12.2 to 14.5 cmH2O, but this change was not statistically significant. Driving pressure was significantly reduced during the first two days compared to baseline (from 13.9 to 11.6 cmH2O; p < 0.05) and there were no significant differences in the values of respiratory system compliance. Rescue therapies for life threatening hypoxemia such as prone position and ECMO were necessary in four and two patients, respectively. Only two study-related adverse events were observed (intravascular hemolysis and femoral catheter kinking).ConclusionsThe low-flow ECCO2R system safely facilitates a low volume, low pressure ultra-protective mechanical ventilation strategy in patients with moderate ARDS.

Pulmonary atelectasis during low stretch ventilation: "open lung" versus "lung rest" strategy

Objective:Limiting tidal volume (VT) may minimize ventilator-induced lung injury (VILI). However, atelectasis induced by low VT ventilation may cause ultrastructural evidence of cell disruption. Apoptosis seems to be involved as protective mechanisms from VILI through the involvement of mitogen-activated protein kinases (MAPKs). We examined the hypothesis that atelectasis may influence the response to protective ventilation through MAPKs. Design:Prospective randomized study. Setting:University animal laboratory. Subjects:Adult male 129/Sv mice. Interventions:Isolated, nonperfused lungs were randomized to VILI: VT of 20 mL/kg and positive end-expiratory pressure (PEEP) zero; low stretch/lung rest: VT of 6 mL/kg and 8–10 cm H2O of PEEP; low stretch/open lung: VT of 6 mL/kg, two recruitment maneuvers and 14–16 cm H2O of PEEP. Ventilator settings were adjusted using the stress index. Measurement and Main Result:Both low stretch strategies equally blunted the VILI-induced derangement of respiratory mechanics (static volume-pressure curve), lung histology (hematoxylin and eosin), and inflammatory mediators (interleukin-6, macrophage inflammatory protein-2 [enzyme-linked immunosorbent assay], and inhibitor of nuclear factor-kB[Western blot]). VILI caused nuclear swelling and membrane disruption of pulmonary cells (electron microscopy). Few pulmonary cells with chromatin condensation and fragmentation were seen during both low stretch strategies. However, although cell thickness during low stretch/open lung was uniform, low stretch/lung rest demonstrated thickening of epithelial cells and plasma membrane bleb formation. Compared with the low stretch/open lung, low stretch/lung rest caused a significant decrease in apoptotic cells (terminal deoxynucleotidyl transferase mediated deoxyuridine-triphosphatase nick end-labeling) and tissue expression of caspase-3 (Western blot). Both low stretch strategies attenuated the activation of MAPKs. Such reduction was larger during low stretch/open lung than during low stretch/lung rest (p < 0.001). Conclusion:Low stretch strategies provide similar attenuation of VILI. However, low stretch/lung rest strategy is associated to less apoptosis and more ultrastructural evidence of cell damage possibly through MAPKs-mediated pathway.

Acute respiratory distress syndrome: new definition, current and future therapeutic options.

Since acute respiratory distress syndrome (ARDS) was first described in 1967 there has been large number of studies addressing its pathogenesis and therapies. Despite this intense research activity, there are very few effective therapies for ARDS other than the use of lung protection strategies. This lack of therapeutic modalities is not only related to the complex pathogenesis of this syndrome but also the insensitive and nonspecific diagnostic criteria to diagnose ARDS. This review article will summarize the key features of the new definition of ARDS, and provide a brief overview of innovative therapeutic options that are being assessed in the management of ARDS.

Phosphoinositide-3 Kinase γ Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

RATIONALE Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase γ (PI3Kγ) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. OBJECTIVES This study aimed to determine the specific role of the kinase activity of PI3Kγ in the pathogenesis of sepsis and multiorgan damage. METHODS PI3Kγ wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation-induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3Kγ inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. MEASUREMENTS AND MAIN RESULTS Both genetic and pharmaceutical PI3Kγ kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3Kγ pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. CONCLUSIONS This study establishes PI3Kγ as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

Lack of phosphoinositide 3-kinase-γ attenuates ventilator-induced lung injury*

Objective:G protein-coupled receptors may up-regulate the inflammatory response elicited by ventilator-induced lung injury but also regulate cell survival via protein kinase B (Akt) and extracellular signal regulated kinases 1/2 (ERK1/2). The G protein-sensitive phosphoinositide-3-kinase &ggr; (PI3K&ggr;) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3K&ggr; on ventilator-induced lung injury. Design:Prospective, randomized, experimental study. Setting:University animal research laboratory. Subjects:Wild-type (PI3K&ggr;+/+), knock-out (PI3K&ggr;−/− ), and kinase-dead (PI3K&ggr;KD/KD) mice. Interventions:Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3K&ggr;+/+, PI3K&ggr;−/−, and PI3K&ggr;KD/KD mice. Measurements and Main Results:Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3K&ggr;+/+ than in PI3K&ggr;−/− and PI3K&ggr;KD/KD (p < .01). Inflammatory cytokines and IkB&agr; phosphorylation with high stretch did not differ among PI3K&ggr;+/+, PI3K&ggr;−/−, and PI3K&ggr;KD/KD. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p < .01) in PI3K&ggr;−/− and PI3K&ggr;KD/KD than in PI3K&ggr;+/+. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3K&ggr;−/− mice whereas PI3K&ggr;+/+ mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3K&ggr;+/+ than in PI3K&ggr;−/− and PI3K&ggr;KD/KD (p < .01). Conclusions:Silencing PI3K&ggr; seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.

Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome.

Background:Guidelines suggest a plateau pressure (PPLAT) of 30 cm H2O or less for patients with acute respiratory distress syndrome, but ventilation may still be injurious despite adhering to this guideline. The shape of the curve plotting airway pressure versus time (STRESS INDEX) may identify injurious ventilation. The authors assessed accuracy of PPLAT and STRESS INDEX to identify morphological indexes of injurious ventilation. Methods:Indexes of lung aeration (computerized tomography) associated with injurious ventilation were used as a “reference standard.” Threshold values of PPLAT and STRESS INDEX were determined assessing the receiver-operating characteristics (“training set,” N = 30). Accuracy of these values was assessed in a second group of patients (“validation set,” N = 20). PPLAT and STRESS INDEX were partitioned between respiratory system (Pplat,Rs and STRESS INDEX,RS) and lung (PPLAT,L and STRESS INDEX,L; esophageal pressure; “physiological set,” N = 50). Results:Sensitivity and specificity of PPLAT of greater than 30 cm H2O were 0.06 (95% CI, 0.002–0.30) and 1.0 (95% CI, 0.87–1.00). PPLAT of greater than 25 cm H2O and a STRESS INDEX of greater than 1.05 best identified morphological markers of injurious ventilation. Sensitivity and specificity of these values were 0.75 (95% CI, 0.35–0.97) and 0.75 (95% CI, 0.43–0.95) for PPLAT greater than 25 cm H2O versus 0.88 (95% CI, 0.47–1.00) and 0.50 (95% CI, 0.21–0.79) for STRESS INDEX greater than 1.05. Pplat,Rs did not correlate with PPLAT,L (R2 = 0.0099); STRESS INDEX,RS and STRESS INDEX,L were correlated (R2 = 0.762). Conclusions:The best threshold values for discriminating morphological indexes associated with injurious ventilation were Pplat,Rs greater than 25 cm H2O and STRESS INDEX,RS greater than 1.05. Although a substantial discrepancy between Pplat,Rs and PPLAT,L occurs, STRESS INDEX,RS reflects STRESS INDEX,L.

Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion

OBJECTIVES Ex vivo lung perfusion (EVLP) is a novel technique used to evaluate and recondition marginal or rejected grafts. Primary graft dysfunction (PGD) is a major early complication after lung transplantation (LTx). The use of marginal or initially rejected grafts may increase its incidence and severity. The aim of this study is to evaluate the incidence of PGD after LTx using rejected grafts reconditioned with EVLP. METHODS PGD has been evaluated immediately after LTx (t0) and after 72 h (t72) in patients receiving standard (Group A) or reconditioned (Group B) grafts. EVLP was performed using a controlled acellular perfusion according to the Toronto technique. RESULTS From July 2011 to February 2013, 36 LTxs have been performed: 28 patients (21 M/7 F, mean age 51.7 ± 14.7 years) in Group A and 8 (6 M/2 F, mean age 46.6 ± 9.8 years) in Group B (successful recondition rate of 73%, 8 of 11 cases). Incidence rate of PGD 3 at t0 and at t72 (Group A versus Group B) was 50 vs 37% (P = NS) and 25 vs 0% (P = NS), respectively. Post-transplant extracorporeal membrane oxygenation was required in 5 and 2 patients in Groups A and B, respectively (P = NS). CONCLUSIONS The use of initially rejected grafts treated with EVLP does not increase the incidence and severity of PGD after LTx. Although comparison of PGD 3 incidence in the two groups did not reach a statistical difference, all EVLP patients suffering from severe PGD early after transplant recovered normal lung function at 72 h, suggesting a protective role of EVLP against PGD occurrence and severity.

Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1.

Background:Neuromuscular blocking agents (NMBAs) bind the nicotinic acetylcholine receptor &agr;1 (nAChR&agr;1) that also contributes to inflammatory signaling. Thus, the author hypothesized that the use of NMBA mitigates lung injury by improving ventilator synchrony and decreasing inflammatory responses. Methods:Lung injury was induced by intratracheal instillation of hydrogen chloride in rats that were randomized to receive no NMBA with evidence of asynchronous ventilation (noNMBA/aSYNC, n = 10); no NMBA with synchronous ventilation (noNMBA/SYNC, n = 10); cisatracurium (CIS, n = 10); or pancuronium (PAN, n = 10). Mechanical ventilation was set at a tidal volume of 6 ml/kg and positive end-expiratory pressure 8 cm H2O for 3 h. Human lung epithelial, endothelial, and CD14+ cells were challenged with mechanical stretch, lipopolysaccharide, lung lavage fluids (bronchoalveolar lavage fluid), or plasma obtained from patients (n = 5) with acute respiratory distress syndrome, in the presence or absence of CIS or small-interfering RNA and small hairpin RNA to attenuate the cell expression of nAChR&agr;1. Results:The use of CIS and PAN improved respiratory compliance (7.2 ± 0.7 in noNMBA/aSYNC, 6.6 ± 0.5 in noNMBA/SYNC, 5.9 ± 0.3 in CIS, and 5.8 ± 0.4 cm H2O/l in PAN; P < 0.05), increased PaO2 (140 ± 54, 209 ± 46, 269 ± 31, and 269 ± 54 mmHg, respectively, P < 0.05), and decreased the plasma levels of tumor necrosis factor-&agr; (509 ± 252 in noNMBA, 200 ± 74 in CIS, and 175 ± 84 pg/ml in PAN; P < 0.05) and interleukin-6 (5789 ± 79, 1608 ± 534, and 2290 ± 315 pg/ml, respectively; P < 0.05). The use of CIS and PAN or silencing the receptor nAChR&agr;1 resulted in decreased cytokine release in the human cells in response to a variety of stimuli mentioned earlier. Conclusions:The use of NMBA is lung protective through its antiinflammatory properties by blocking the nAChR&agr;1.

Pharmacokinetics of high dosage of linezolid in two morbidly obese patients

Sir, Obesity represents a major burden on healthcare as an independent risk factor for mortality in infected patients and its association with comorbidities. Adequate antimicrobial exposure is essential for treatment success, but there are few published data on the pharmacokinetics (PK) of antibiotics in obesity. Furthermore, the degree of alteration depends on several factors: degree of obesity, comorbidities and pharmacological characteristics of the drugs. In addition, the volume of distribution (V) may vary according to the amount of adipose tissue and the lipophilic properties of the antibiotic, resulting in lower serum concentrations. Linezolid is active against Gram-positive bacteria used for skin and lung infections and is a highly lipophilic molecule with a high rate of penetration into tissues. Canut et al. proposed as a PK index predictive of efficacy an AUC/MIC .100 (where AUC1⁄4area under the antimicrobial concentration–time curve for 24 h). The achievement of a Cmin ≥2 mg/L and/or AUC24 .160–200 mg.h/L was proposed as a theoretical threshold to ensure efficacy. Data reported so far show significantly lower concentrations with standard doses of linezolid in obese patients. We report here the main PK parameters in two morbidly obese patients, as defined by BMI, receiving a higher dosage of linezolid. Patient 1 was a male ,50 years old with a BMI of 72 kg/m admitted to the ICU for community-acquired pneumonia with severe sepsis. He had hypoxaemic respiratory failure and later developed methicillin-resistant Staphylococcus epidermidis bloodstream infection (BSI) with a linezolid MIC of 2 mg/L. Patient 2 was a male .60 years old with a BMI of 66 kg/m and acute hypercapnic respiratory failure, admitted to the ICU with a diagnosis of healthcare-associated pneumonia and septic shock. Bronchoalveolar lavage identified an MRSA with a linezolid MIC of 1 mg/L. Plasma concentrations of linezolid were studied at steadystate with a dose of 600 mg every 8 h intravenously by 1 h infusion. The AUC of daily (AUC0 – 24) plasma concentrations was calculated with blood samples collected before (time 0) and at 2, 4, 6 and 8 h after intravenous administration. The Cmin was defined as the concentration before the administration and the maximum plasma concentration (Cmax) as the concentration at the end of the infusion. Linezolid was determined in plasma by a UPLC–photodiode array method. PK data were analysed using Kinetica software (Thermo Scientific, Waltham, MA, USA). AUC0–24 was calculated as 3×AUC0–8. Informed consent was waived due to the clinical need for monitoring plasma levels. The main linezolid PK parameters for Patient 1 were as follows: Cmax 4.83 mg/L, Cmin 0.88 mg/L, AUC0 – 24 55.05 mg.h/L, half-life (t1/2) 3.01 h, clearance (CL) 32.70 L/h, V 141.6 L and 0.51 L/kg, AUC/MIC (MIC1⁄41 mg/L) 55.05 and AUC/MIC (MIC1⁄42 mg/L) 27.52. The main linezolid PK parameters for Patient 2 were as follows: Cmax 15.54 mg/L, Cmin 11.89 mg/L, AUC0 – 24 335.69 mg.h/L, t1/2 10.39 h, CL 5.40 L/h, V 80.98 L and 0.45 L/kg, AUC/MIC (MIC1⁄41 mg/L) 335.69 and AUC/MIC (MIC1⁄42 mg/L) 167.50. See Figure 1. There were satisfactory Cmax and Cmin only in Patient 2, whereas in Patient 1 there was an increased CL and reduced AUC. Since the PK/pharmacodynamic parameter of importance for linezolid activity is the AUC/MIC ratio, assessing changes in AUC exposure by body size is of paramount importance. Only Patient 2 had satisfactory values of AUC and AUC/MIC. Furthermore, since linezolid PK is not related to renal function, the creatinine clearance values of .120 and 40 mL/min in Patients 1 and 2, respectively, are not helpful in understanding the alteration of plasma clearance. Moreover, the observation of higher V (141.6 and 80.9 L in Patients 1 and 2, respectively, when compared with healthy volunteers (52 L) confirms the suggestion of a relationship between weight and V in determining a significant decrease of plasma exposure. Taken together, these data suggest that linezolid PK may be strongly influenced by the degree of obesity and standard doses are not sufficient, further noting that linezolid undergoes slow non-enzymatic oxidation mediated by ubiquitous reactive species in vivo.