Rosanna Vaschetto

Nasal High-Flow versus Venturi Mask Oxygen Therapy after Extubation. Effects on Oxygenation, Comfort, and Clinical Outcome

RATIONALE Oxygen is commonly administered after extubation. Although several devices are available, data about their clinical efficacy are scarce. OBJECTIVES To compare the effects of the Venturi mask and the nasal high-flow (NHF) therapy on PaO2/FiO2SET ratio after extubation. Secondary endpoints were to assess effects on patient discomfort, adverse events, and clinical outcomes. METHODS Randomized, controlled, open-label trial on 105 patients with a PaO2/FiO2 ratio less than or equal to 300 immediately before extubation. The Venturi mask (n = 52) or NHF (n = 53) were applied for 48 hours postextubation. MEASUREMENTS AND MAIN RESULTS PaO2/FiO2SET, patient discomfort caused by the interface and by symptoms of airways dryness (on a 10-point numerical rating scale), interface displacements, oxygen desaturations, need for ventilator support, and reintubation were assessed up to 48 hours after extubation. From the 24th hour, PaO2/FiO2SET was higher with the NHF (287 ± 74 vs. 247 ± 81 at 24 h; P = 0.03). Discomfort related both to the interface and to airways dryness was better with NHF (respectively, 2.6 ± 2.2 vs. 5.1 ± 3.3 at 24 h, P = 0.006; 2.2 ± 1.8 vs. 3.7 ± 2.4 at 24 h, P = 0.002). Fewer patients had interface displacements (32% vs. 56%; P = 0.01), oxygen desaturations (40% vs. 75%; P < 0.001), required reintubation (4% vs. 21%; P = 0.01), or any form of ventilator support (7% vs. 35%; P < 0.001) in the NHF group. CONCLUSIONS Compared with the Venturi mask, NHF results in better oxygenation for the same set FiO2 after extubation. Use of NHF is associated with better comfort, fewer desaturations and interface displacements, and a lower reintubation rate. Clinical trial registered with www.clinicaltrials.gov (NCT 01575353).

The T cell activation molecule H4 and the CD28-like molecule ICOS are identical.

The recently cloned CD28‐like molecule ICOS displays striking similarities with H4, characterized some years ago in the mouse and recently in humans. Both molecules are selectively expressed by activated and germinal center T cells, display similar structure, and display co‐stimulatory activities. H4 displays lateral association with the CD3/TCR and is expressed by mature thymocytes. In the mouse, H4 is also expressed at high levels by thymic NKT cells that are resistant to negative selection. The aim of this work was to evaluate whether H4 and ICOS are the same molecule using the C398.4A (binding human and mouse H4) and F44 (binding human ICOS) monoclonal antibody (mAb) in parallel experiments on human T cells. ICOS and H4 displayed the same expression pattern in a panel of T cell lines and the same expression kinetics in phytohemagglutinin‐activated T cells. C398.4A completely blocked cell staining by F44, whereas F44 partially blocked C398.4A. H4 and ICOS immunoprecipitates displayed identical SDS‐PAGE patterns and H4 immunoprecipitation completely removed ICOS from cell lysates. Finally, the C398.4A mAb specifically stained cells transfected with the human or mouse ICOS. These data prove that H4 and ICOS are the same molecule and that F44 and C398.4A bind partially different epitopes.

Inhibition of Poly(Adenosine Diphosphate-Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

Background:Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate–ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate–ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods:Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results:The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate–ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor &agr; and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion:The pharmacologic inhibition of poly(adenosine diphosphate–ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

Effects of propofol on patient-ventilator synchrony and interaction during pressure support ventilation and neurally adjusted ventilatory assist.

Objectives:Evaluating the physiologic effects of varying depths of propofol sedation on patient-ventilator interaction and synchrony during pressure support ventilation and neurally adjusted ventilatory assist. Design:Prospective crossover randomized controlled trial. Setting:University hospital ICU. Patients:Fourteen intubated patients mechanically ventilated for acute respiratory failure. Interventions:Six 25-minute trials randomly performed applying both pressure support ventilation and neurally adjusted ventilatory assist during wakefulness and with two doses of propofol, administered by Target Control Infusion, determining light (1.26 ± 0.35 &mgr;g/mL) and deep (2.52 ± 0.71 &mgr;g/mL) sedation, as defined by the bispectral index and Ramsay Sedation Scale. Measurements and Main Results:We measured electrical activity of the diaphragm to assess neural drive and calculated its integral over time during 1 minute (∫electrical activity of the diaphragm/min) to estimate diaphragm energy expenditure (effort), arterial blood gases, airway pressure, tidal volume and its coefficient of variation, respiratory rate, neural timing components, and calculated the ineffective triggering index. Increasing the depth of sedation did not cause significant modifications of respiratory timing, while determined a progressive significant decrease in neural drive (with both modes) and effort (in pressure support ventilation only). In pressure support ventilation, the difference in ineffective triggering index between wakefulness and light sedation was negligible (from 5.9% to 7.6%, p = 0.97); with deep sedation, however, ineffective triggering index increased up to 21.8% (p < 0.0001, compared to both wakefulness and light sedation). With neurally adjusted ventilatory assist, ineffective triggering index fell to 0%, regardless of the depth of sedation. With both modes, deep sedation caused a significant increase in PaCO2, which resulted, however, from different breathing patterns and patient-ventilator interactions. Conclusions:In pressure support ventilation, deep propofol sedation increased asynchronies, while light sedation did not. Propofol reduced the respiratory drive, while breathing timing was not significantly affected. Gas exchange and breathing pattern were also influenced by propofol infusion to an extent that varied with the depth of sedation and the mode of ventilation.

Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways.

H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4+ Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti‐H4/ICOS antibodies strongly enhanced CD3‐mediated tyrosine phosphorylation of ZAP‐70, ζ, or Vav, as well as extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3‐kinase (PI‐3K) to H4/ICOS was enhanced by H4/ICOS cross‐linking, and PI‐3K inhibitors inhibited ERK and JNK activation andIL‐4/IL‐10 secretion, but not p38 MAP kinase or ZAP‐70 activation. H4/ICOS‐mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP‐70, MAP kinase activation, or IL‐4/IL‐10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP‐70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL‐4, but not IL‐10 secretion. ERK or JNKinhibitors partially inhibited IL‐4 and IL‐10 secretion, while PKC or p38 inhibitors had no significant effects on IL‐4 or IL‐10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.

Serum levels of osteopontin are increased in SIRS and sepsis

ObjectiveIn sepsis, dysregulation of the immune response leads to rapid multiorgan failure and death. Accurate and timely diagnosis is lifesaving and should discriminate sepsis from the systemic inflammatory response syndrome (SIRS) caused by non-infectious agents. Osteopontin acts as an extracellular matrix component or a soluble cytokine in inflamed tissues. Its exact role in immune response and sepsis remains to be elucidated. Therefore, we investigated the role of osteopontin in SIRS and sepsis.DesignProspective, observational study.SettingIntensive care unit of a university hospital.Patients and participantsFifty-six patients with SIRS or sepsis and 56 healthy subjects were enrolled.InterventionsWe analyzed the serum levels of osteopontin and TH1–TH2 cytokines and investigated the role of osteopontin on interleukin 6 secretion by monocytes.Measurements and main resultsSerum osteopontin levels were strikingly higher in patients than in controls and in sepsis than in SIRS, and decreased during the resolution of both the disorders. Receiver operating characteristic curves showed that osteopontin levels have discriminative power between SIRS and sepsis with an area under the curve of 0.796. Osteopontin levels directly correlated with those of interleukin 6 and in vitro, recombinant osteopontin increased interleukin 6 secretion by monocytes in both the absence and presence of high doses of lipopolysaccharide.ConclusionThese data suggest that osteopontin might be a mediator involved in the pathogenesis of SIRS and sepsis, possibly by supporting interleukin 6 secretion.Descriptor45. SIRS/Sepsis: clinical studies.

Role of human neutrophil peptides in the initial interaction between lung epithelial cells and CD4+ lymphocytes.

Human neutrophil peptides (HNP) exert immune‐modulating effects. We hypothesized that HNP link innate and adaptive immunity through activation of costimulatory molecules. Human lung epithelial cells and CD4+ lymphocytes were treated with HNP separately or in coculture. Stimulation with HNP induced an increase in cell surface expression of CD54 (ICAM‐1), CD80, and CD86 on lung epithelial cells and the corresponding major ligands, CD11a (LFA‐1), CD152 (CTLA‐4), and CD28 on CD4+ lymphocytes. There was an increased nuclear expression of the transcription factor p53 in human alveolar A549 cells and an elevated NF‐κB (p50) and a degradation of I‐κB protein in CD4+ lymphocytes following HNP stimulation. HNP enhanced the interaction between A549 cells and CD4+ lymphocytes by increasing cell adhesion and release of IFN‐γ, IL‐2, and IL‐8. This was attenuated by using an α1‐proteinase inhibitor to neutralize HNP. We conclude that HNP play an important role in linking innate to acquired immunity by activation of costimulatory molecules in lung epithelial cells and CD4+ lymphocytes.

Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway

IntroductionMechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.MethodsAnesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining.ResultsHigh tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes.ConclusionsThe peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.

Thoracic epidural analgesia in post-thoracotomy patients: comparison of three different concentrations of levobupivacaine and sufentanil

BACKGROUND Relative effects of dosage, volume and concentration of local anaesthetics used for postoperative thoracic epidural analgesia are still under debate. In this randomized, prospective, double-blinded study, we evaluated the incidence of side-effects such as changes in arterial pressure, postoperative nausea, vomiting, and pruritus in patients admitted for thoracic surgery during continuous thoracic epidural infusion using levobupivacaine and sufentanil mixture in three different volumes. METHODS We studied 150 patients who underwent thoracotomy with a thoracic epidural catheter placed between T4 and T7. The patients were randomized into three groups which received 10 mg h(-1) of levobupivacaine at three different concentrations (0.5%, 0.25%, and 0.15%), in combination with sufentanil at 2.6 microg h(-1). Haemodynamic effects, pruritus, nausea, vomiting, sensory and motor block, pain score, additional analgesic requirement, sedation, and patient satisfaction were registered immediately after the surgical operation and on the first, second, and third postoperative days. RESULTS We did not detect any differences in the incidence of side-effects such as changes in arterial pressure, and also postoperative nausea, vomiting, and pruritus. The three groups were also similar with regard to patient characteristics, sensory and motor block, pain score, analgesic rescue dose, sedation, and patient satisfaction. CONCLUSIONS The same dose of a mixture of levobupivacaine and sufentanil administered in three different volumes and concentrations during continuous thoracic epidural infusion for thoracotomy provided an equal incidence of adverse haemodynamic effects, nausea, vomiting, or pruritus.

Oronasal mask versus helmet in acute hypercapnic respiratory failure

The choice of the interface for noninvasive ventilation (NIV) is a key factor in NIV success. We hypothesised that a new helmet specifically design to improve performance in hypercapnic patients would be clinically equivalent to a standard oronasal mask. In a multicentre, short-term, physiological, randomised trial in chronic obstructive pulmonary disease patients facing an acute hypercapnic respiratory failure episode, we compared the changes in arterial blood gases (ABGs) and tolerance score obtained using the helmet or mask, and, as secondary end-points, dyspnoea, vital signs, early NIV discontinuation and rate of intubation. 80 patients were randomly assigned to receive NIV either with the helmet (n=39) or mask (n=41), using an intensive care unit ventilator. Compared with baseline, in the first 6 h, NIV improved ABGs, dyspnoea and respiratory rate (p<0.05) in both groups. Changes in ABGs and discomfort were similar with the two groups, while dyspnoea decreased more (p<0.005) using the mask. The rate of intubation and the need for interface change during the whole period of NIV were very low and not different between groups. The new helmet may be a valid alternative to a mask in improving ABGs and achieving a good tolerance during an episode of acute hypercapnic respiratory failure. In COPD patients undergoing NIV, an oronasal mask and a helmet equally improved ABGs and tolerance score http://ow.ly/DMVIg