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Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this consensus statement of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: Vibrating-mesh nebulizers should be preferred to jet or ultrasonic nebulizers. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (a) the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (b) the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8 mL/kg, respiratory frequency 12 to 15 bpm, inspiratory:expiratory ratio 50%, inspiratory pause 20% and positive end-expiratory pressure 5 to 10 cm H 2 O and (c) the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patient's flow triggering and episodes of peak decelerating inspiratory flow. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Nebulized antimicrobial agents are increasingly administered for treatment of respiratory infections in mechanically ventilated (MV) patients. A structured online questionnaire assessing the indications, dosages and recent patterns of use for nebulized antimicrobial agents in MV patients was developed. The questionnaire was distributed worldwide and completed by 192 intensive care units. The most common indications for using nebulized antimicrobial agent were ventilator-associated tracheobronchitis (VAT; 58/87), ventilator-associated pneumonia (VAP; 56/87) and management of multidrug-resistant, Gram-negative (67/87) bacilli in the respiratory tract. The most common prescribed nebulized agents were colistin methanesulfonate and sulfate (36/87, 41.3% and 24/87, 27.5%), tobramycin (32/87, 36.7%) and amikacin (23/87, 26.4%). Colistin methanesulfonate, amikacin and tobramycin daily doses for VAP were significantly higher than for VAT (p < 0.05). Combination of parenteral and nebulized antibiotics occurred in 50 (86%) of 58 prescriptions for VAP and 36 (64.2%) of 56 of prescriptions for VAT. The use of nebulized antimicrobial agents in MV patients is common. There is marked heterogeneity in clinical practice, with significantly different in use between patients with VAP and VAT. Randomized controlled clinical trials and international guidance on indications, dosing and antibiotic combinations to improve clinical outcomes are urgently required., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mechanical ventilation-induced air-space enlargement was investigated in a porcine model of multifocal pneumonia. Following the intrabronchial inoculation of Escherichia coli, 9 piglets (22 +/- 2 kg) were ventilated with a tidal volume (VT) of 15 ml/kg for 43 +/- 15 h. Five noninoculated piglets ventilated for 60 h with the same VT served as control animals. Following death, the lungs were fixed and lung morphometry was assessed. In inoculated animals, unventilated infected and normally ventilated noninfected pulmonary lobules coexisted. In normally ventilated lung regions (1) emphysema-like lesions were present, (2) mean alveolar area and mean linear intercept were significantly greater in inoculated than in control animals, and (3) the degree of alveolar distension correlated with the decrease in respiratory compliance. In unventilated lung areas (1) pseudocysts were frequent, (2) alveolar edema was rare, (3) bronchiolectasis was frequent, (4) mean bronchiolar area was greater in inoculated than in control animals, and (5) the degree of bronchiolar distension correlated with the increase in inspiratory plateau pressure. In conclusion, in piglets with severe bronchopneumonia, air-space enlargement rather than pulmonary edema was the major feature of mechanical ventilation-induced lung barotrauma and resembled lesions previously reported in critically ill patients ventilated using high inspiratory pressures.

In critically ill patients measurements of pressure volume curves has been suggested as a method for assessing the severity of lung injury and for monitoring the evolution of the lung disease; it can also guide the ventilatory adjustments to optimize the mechanical ventilation. The static pressure-volume curves are impaired in acute respiratory distress syndrome (ARDS). The evaluation of the lower and upper inflection point on the pressure-volumes curves at the bedside of patients with acute respiratory failure means to apply a "protective ventilatory strategy". The combined application of positive end expiratory pressure (PEEP) to the level of alveolar recruitment and low tidal volume (< 6 ml/kg) ameliorates the lung function and decrease mortality in ARDS patients. Routine monitoring with continuous technique is easy and develops good therapeutic practice.

Physiological background concerning mechanics of the respiratory system, techniques of measurement and clinical implications of pressure-volume curve measurement in mechanically ventilated patients are discussed in the present review. The significance of lower and upper inflection points, the assessment of positive end-expiratory pressure (PEEP)-induced alveolar recruitment and overdistension and rationale for optimizing ventilatory settings in patients with acute lung injury are presented. Evidence suggests that the continuous flow method is a simple and reliable technique for measuring pressure-volume curves at the bedside. In patients with acute respiratory failure, determination of lower and upper inflection points and measurement of respiratory compliance should become a part of the routine assessment of lung injury severity, allowing a bedside monitoring of the evolution of the lung disease and an optimization of mechanical ventilation.

The aim of this study was to compare three ventilatory techniques for reducing PaCO2 in patients with severe acute respiratory distress syndrome treated with permissive hypercapnia: (1) expiratory washout alone at a flow of 15 L/min, (2) optimized mechanical ventilation defined as an increase in the respiratory frequency to the maximal rate possible without development of intrinsic positive end- expiratory pressure (PEEP) combined with a reduction of the instrumental dead space, and (3) the combination of both methods. Tidal volume was set according to the pressure-volume curve in order to obtain an inspiratory plateau airway pressure equal to the upper inflection point minus 2 cm H2O after setting the PEEP at 2 cm H2O above the lower inflection point and was kept constant throughout the study. The three modalities were compared at the same inspiratory plateau airway pressure through an adjustment of the extrinsic PEEP. During conventional mechanical ventilation using a respiratory frequency of 18 breaths/min, respiratory acidosis (PaCO2 = 84 +/- 24 mm Hg and pH = 7.21 +/- 0.12) was observed. Expiratory washout and optimized mechanical ventilation (respiratory frequency of 30 +/- 4 breaths/min) had similar effects on CO2 elimination (DeltaPaCO2 = -28 +/- 11% versus -27 +/- 12%). A further decrease in PaCO2 was observed when both methods were combined (DeltaPaCO2 = -46 +/- 7%). Extrinsic PEEP had to be reduced by 5.3 +/- 2.1 cm H2O during expiratory washout and by 7.3 +/- 1.3 cm H2O during the combination of the two modes, whereas it remained unchanged during optimized mechanical ventilation alone. In conclusion, increasing respiratory rate and reducing instrumental dead space during conventional mechanical ventilation is as efficient as expiratory washout to reduce PaCO2 in patients with severe ARDS and permissive hypercapnia. When used in combination, both techniques have additive effects and result in PaCO2 levels close to normal values.

Measurement of respiratory compliance is advocated for assessing the severity of acute respiratory failure (ARF). Recently, the administration of an automated constant flow of 15 L/min was proposed as a method easier to implement at the bedside than supersyringe or inspiratory occlusions methods. However, pressure-volume (P-V) curves were shifted to the right because of the resistive properties of the respiratory system. The aim of this study was to compare the P-V curves obtained using two constant flows-3 and 9 L/min-during volume-controlled mechanical ventilation with those obtained with the supersyringe and the inspiratory occlusions methods. Fourteen paralyzed patients with ARF were studied. The supersyringe and the inspiratory occlusions methods were performed according to usual recommendations. The new automated method was performed during volume-controlled mechanical ventilation by setting the inspiratory:expiratory ratio at 80%, the respiratory frequency at 5 breaths/min, and the tidal volume at 500 or 1,500 ml. These peculiar ventilatory settings were equivalent to administering a constant flow of 3 or 9 L/min during a 9.6-s inspiration. Esophageal and airway pressures were recorded. P-V curves obtained by the 3-L/min constant-flow method were identical to those obtained by the reference methods, whereas the P-V curve obtained by the 9-L/min constant flow was slightly shifted to the right. The slopes of the P-V curves and the lower inflection points were not different between all methods, indicating that the resistive component induced by administering a constant flow equal to or less than 9 L/min is not of clinical relevance. Because the 3-L/min constant-flow method is not artifacted by the resistive properties of the respiratory system and does not require any other equipment than a ventilator, it is an easy-to-implement, inexpensive, safe, and reliable method for measuring the thoracopulmonary P-V curve at the bedside.

Objectives: The concentrations of nitric oxide (NO) in the ventilatory circuits and the patient's airways were compared between sequential (SQA) and continuous (CTA) administration during inspiratory limb delivery., Design: Prospective controlled study., Setting: 14-bed Surgical Intensive Care Unit of a teaching University hospital., Patients and Participants: Eleven patients with acute lung injury on mechanical ventilation and two healthy volunteers., Interventions: A prototype NO delivery device (Opti-NO) and César ventilator were set up in order to deliver 1, 3 and 6 parts per million (ppm) of NO into the bellows of a lung model in SQA and CTA. Using identical ventilatory and Opti-NO settings, NO was administered to the patients with acute lung injury., Measurements and Results: NO concentrations measured from the inspiratory limb [INSP-NOMeas] and the trachea [TRACH-NOMeas] using fast response chemiluminescence were compared between the lung model and the patients using controlled mechanical ventilation with a constant inspiratory flow. INSP-NOMeas were stable during SQA and fluctuated widely during CTA (fluctuation at 6 ppm = 61% in the lung model and 58 +/- 3% in patients). In patients, [TRACH-NOMeas] fluctuated widely during both modes (fluctuation at 6 ppm = 55 +/- 3% during SQA and 54 +/- 5% during CTA). The NO flow requirement was significantly lower during SQA than during CTA (74 +/- 0.5 vs 158 +/- 2.2 ml.min-1 to attain 6 ppm, p = 0.0001). INSP-NOMeas were close to the values predicted using a classical formula only during SQA (bias = -0.1 ppm, precision = +/-1 ppm during SQA; bias = 2.93 ppm and precision = +/-3.54 ppm during CTA). During SQA, INSP-NOMeas varied widely in healthy volunteers on pressure support ventilation., Conclusions: CTA did not provide homogenous mixing of NO with the tidal volume and resulted in fluctuating INSP-NOMeas. In contrast, SQA delivered stable and predictable NO concentrations during controlled mechanical ventilation with a constant inspiratory flow and was economical compared to CTA. However, SQA did not provide stable and predictable NO concentrations during pressure support ventilation.

Background: Permissive hypercapnia is a ventilatory strategy aimed at avoiding lung volutrauma in patients with severe acute respiratory distress syndrome (ARDS). Expiratory washout (EWO) is a modality of tracheal gas insufflation that enhances carbon dioxide removal during mechanical ventilation by reducing dead space. The goal of this prospective study was to determine the efficacy of EWO in reducing the partial pressure of carbon dioxide (PaCO2) in patients with severe ARDS treated using permissive hypercapnia., Methods: Seven critically ill patients with severe ARDS (lung injury severity score, 3.1 +/- 0.3) and no contraindications for permissive hypercapnia were studied. On the first day, hemodynamic and respiratory parameters were measured and the extent of lung hyperdensities was assessed using computed tomography. A positive end-expiratory pressure equal to the opening pressure identified on the pressure-volume curve was applied. Tidal volume was reduced until a plateau airway pressure of 25 cm H2O was reached. On the second day, after implementation of permissive hypercapnia, EWO was instituted at a flow of 15 l/min administered during the entire expiratory phase into the trachea through the proximal channel of an endotracheal tube using a ventilator equipped with a special flow generator. Cardiorespiratory parameters were studied under three conditions: permissive hypercapnia, permissive hypercapnia with EWO, and permissive hypercapnia., Results: During permissive hypercapnia, EWO decreased PaCO2 from 76 +/- 4 mmHg to 53 +/- 3 mmHg (-30%; P < 0.0001), increased pH from 7.20 +/- 0.03 to 7.34 +/- 0.04 (P < 0.0001), and increased PaO2 from 205 +/- 28 to 296 +/- 38 mmHg (P < 0.05). The reduction in PaCO2 was accompanied by an increase in end-inspiratory plateau pressure from 26 +/- 1 to 32 +/- 2 cm H2O (P = 0.001). Expiratory washout also decreased cardiac index from 4.6 +/- 0.4 to 3.7 +/- 0.3 l.min-1.m-2 (P < 0.01), mean pulmonary arterial pressure from 28 +/- 2 to 25 +/- 2 mmHg (P < 0.01), and true pulmonary shunt from 47 +/- 2 to 36 +/- 3% (P < 0.01)., Conclusions: Expiratory washout is an effective and easy-to-use ventilatory modality to reduce PaCO2 and increase pH during permissive hypercapnia. However, it significantly increases airway pressures and lung volume through expiratory flow limitation, reexposing some patients to a risk of lung volutrauma if the extrinsic positive end-expiratory pressure is not substantially reduced.

A good knowledge of histological and bacteriological characteristics of experimental and human ventilator-associated bronchopneumonias (BPN) is of critical importance for the intensivist. BPN can be experimentally produced by intratracheal inoculation of microorganisms in high concentrations and ventilator-associated BPN by ventilating baboons with oleic-acid lung injury. Experimental ventilator-associated BPN is frequently polymicrobial, and bacterial lung burden increases with the severity of lung infection. In human ventilator-associated BPN, gross examination is of poor value for diagnosing lung infection. Four histologic categories of increasing severity have been described: bronchiolitis, focal bronchopneumonia, confluent bronchopneumonia, and lung abscess. Nonspecific inflammatory lesions are always associated with histologic lung infection: primary lung infection causes secondary inflammatory lung damage, whereas non-specific alveolar injury is rapidly superinfected when the lungs are mechanically ventilated. Infectious pulmonary lesions are disseminated within all pulmonary segments but preferentially found in the dependent segments. This fact suggests that ventilator-associated BPN has a bronchogenic origin and that gravity plays an important role in the dissemination of microorganisms within lung parenchyma. Ventilator-associated BPN is a nosocomial infection with a predominance of gram-negative bacteria, staphylococci species, and yeasts. It is frequently polymicrobial, and the lung bacterial burden depends on the histologic grade, the administration of topical and intravenous antibiotics, and the host's local antibacterial defenses. The bacterial complexity of human lung infection does not support the concept of a threshold for the diagnosis of nosocomial BPN. Intensivists should always keep in mind that human ventilator-associated BPN is a complex and rapidly changing entity.

Objective: To describe histologically pulmonary barotrauma in mechanically ventilated patients with severe acute respiratory failure., Design: Assessment of histologic pulmonary barotrauma., Setting: A 14-bed surgical intensive care unit (SICU) PATIENTS: The lungs of 30 young critically ill patients (mean age 34 +/- 10 years) were histologically examined in the immediate post-mortem period. None of them were suspected of pre-existing emphysema., Measurements and Results: Clinical events and ventilatory settings used during mechanical ventilation were compared with lung histology. Airspace enlargement, defined as the presence of either alveolar overdistension in aerated lung areas or intraparenchymal pseudocysts in nonaerated lung areas, was found in 26 of the 30 lungs examined (86%). Patients with severe airspace enlargement (2.6-40 mm internal diameter) had a significantly greater incidence of pneumothorax (8 versus 2, p < 0.05), were ventilated using higher peak airway pressures (56 +/- 18 cmH2O versus 44 +/- 10 cmH2O, p < 0.05) and tidal volumes (12 +/- 3 ml/kg versus 9 +/- 2 ml/kg, p < 0.05), were exposed significantly longer to toxic levels of oxygen (8.6 +/- 9.4 days versus 1.9 +/- 2 days at FIO2 > 0.6, p < 0.05) and lost more weight (6.3 +/- 9.2 kg versus 0.75 +/- 5.8 kg, p < 0.05) than patients with mild airspace enlargement (1-2.5 mm internal diameter)., Conclusion: Underlying histologic lesions responsible for clinical lung barotrauma consist of pleural cysts, bronchiolar dilatation, alveolar overdistension and intraprenchymal pseudocysts. Mechanical ventilation appears to be an aggravating factor, particularly when high peak airway pressures and large tidal volumes are delivered by the ventilator.

Fifteen critically ill patients with acute respiratory failure were ventilated with high-frequency jet ventilation (HFJV; frequency 100 breaths/min; I/E ratio 0.43; 1.8-mm internal diameter injector cannula). The patients were divided into two groups according to their initial PaO2 during intermittent positive pressure ventilation at FIO21: in eight patients (group I) the mean PaO2 was 141 +/- 34 mm Hg, and in seven patients (group II) mean PaO2 was 376 +/- 75 mm Hg. During HFJV three different operating pressures were used at random: 1.3, 1.8, and 2.3 bars. Increase in operating pressures significantly decreased PaCO2 and significantly increased mean lung volume above apneic FRC, mean airway pressure, and mean alveolar pressure in both groups. A close relationship was found between variations in mean airway pressure and mean alveolar pressure (r = 0.99, P less than 0.001). Significant increases in PaO2 with increasing operating pressures were observed only in group I. In group II, PaCO2 was significantly lower than in group I for a given operating pressure. We conclude that operating pressure is a main determinant of arterial oxygenation during HFJV because of the concomitant increases in intrathoracic pressures and lung volume. Operating pressure also influences carbon dioxide clearance, PaCO2 varies inversely with operating pressure.

In ten patients after recovery from general anesthesia for major vascular surgery, we compared continuous positive airway pressure (CPAP) and high-frequency jet ventilation (HFJV) at the same fractional concentration of oxygen in the inspired gas, both being superimposed on spontaneous breathing. The HFJV was delivered by a ventilator ( Acutronic VS-600) through the lateral lumen of a three-lumen endotracheal tube. Mean airway pressure was increased (3, 8, and 11 mm Hg) by adjusting the driving pressure during HFJV and by the setting of the expiratory valve during CPAP. During HFJV, the frequency (10 Hz) and inspiratory-expiratory ratio (0.25) were kept constant. Control values were measured when patients breathed spontaneously without positive end-expiratory pressure. Cardiac output and transmural filling pressures remained unchanged throughout the study. Neither the arterial oxygen pressure (PaO2) nor intrapulmonary shunt (Qs/Qt) changed significantly during CPAP. The 20- to 30-percent increase in PaO2 and the 5- to 10-percent decrease in Qs/Qt during HFJV when compared to control reflected a slightly but significantly (p less than 0.05) better oxygenation. The increase in arterial carbon dioxide tension was significantly greater during CPAP than during HFJV.

Seven hypoxaemic patients with acute respiratory failure were ventilated with HFJV (Ventilator VS 600). Arterial oxygenation was improved in each patient by the increases induced in mean airway pressure (PAW) (to 20 cm H2O) using three different ventilatory settings applied in a random order: technique A: I:E ratio 0.43, driving pressure 2.9 bar, no PEEP; technique B: I:E ratio 1.0, driving pressure 1.9 bar, no PEEP; technique C: I:E ratio 0.43, driving pressure 1.8 bar, PEEP 11 cm H2O. Respiratory frequency was maintained at 250 b.p.m. throughout the study. There were no significant differences in PaO2 (FlO2 = 1) or Qs/Qt between the three techniques. In contrast, carbon dioxide elimination was markedly affected by the method used to increase PAW:PaCO2 was significantly higher during technique C (8.5 +/- 3.6 kPa) and technique B (6.6 +/- 2.1 kPa) than during technique A (4.8 +/- 0.9 kPa). Significant increases in cardiac index, heartrate, mean pulmonary arterial pressure and a decrease in the arterio-venous oxygen content difference were observed when PaCO2 increased. We conclude that, to obtain the PAW necessary to improve pulmonary oxygen exchange, more effective carbon dioxide elimination is achieved by increasing the driving pressure, rather than by increasing the I:E ratio, or using a PEEP valve.

Nineteen critically ill patients with acute respiratory failure were studied to compare the hemodynamic effects of continuous positive-pressure ventilation (CPPV) and high-frequency jet ventilation (HFJV) at comparable levels of alveolar ventilation. Patients were divided into three groups: Group 1 included seven patients without circulatory shock in whom mean airway pressure (Paw) was slightly higher during CPPV than during HFJV (17.3 +/- 3.0 vs. 13.0 +/- 2.9 mmHg); Group 2 included six patients without circulatory shock in whom HFJV and CPPV were compared at the same level of Paw (19.2 +/- 5.0 mmHg); Group 3 included seven patients with circulatory shock in whom HFJV and CPPV were compared at the same level of Paw (16.0 +/- 3.9 mmHg). The following respiratory frequencies were used in HFJV: Group 1, 200 +/- 76 beats/min; Group 2, 238 +/- 103 beats/min; Group 3, 286 +/- 149 beats/min. In all patients comparable levels of PaCO2 were obtained with CPPV and HFJV. In Group 1 patients, mean arterial pressure, cardiac index, and stroke index were significantly higher during HFJV. In Group 2 patients, no significant difference was found between HFJV and CPPV. In Group 3 patients, the following hemodynamic variables were significantly higher during HFJV: mean arterial pressure (71 +/- 24 vs. 84 +/- 23 mmHg), cardiac index (3.6 +/- 1 vs. 4.1 +/- 1.41 X min-1 X m-2), and oxygen delivery (403 +/- 93 vs. 471 +/- 124 ml X min-1 X m-2).(ABSTRACT TRUNCATED AT 250 WORDS)

Six critically ill patients with acute respiratory failure were ventilated using high-frequency jet ventilation (HFJV)-frequency 100.min-1, driving pressure 35 psi, 1.8 mm inside diameter injector cannula. Hemodynamic measurements using radial artery and Swan-Ganz catheters, esophageal pressure (EP), and mean airway pressure (Paw) were measured at four different I:E ratios: 0.25, 0.43, 0.67 and 1.0. Static respiratory compliance, using the super syringe method, was measured during intermittent positive pressure ventilation (IPPV) and during HFJV. The results suggested that decreased venous return, increased right ventricular afterload, and decreased PaCO2 accounted for the decrease in cardiac index observed during HFJV using elevated I:E ratios. These variations, related to marked increases in intrathoracic pressures, are very similar to those observed during conventional ventilation with PEEP.

An external spirometric method using a differential linear transformer was used to measure tidal volume (VT) and to determine factors influencing CO2 elimination and HFJV-induced "PEEP effect" in 15 critically ill patients under HFJV. VT increased with increasing driving pressure (DP) and decreasing frequency (f) and was influenced little by changes in I/E ratio. CO2 elimination, as reflected by the measurement of PaCO2, was mainly influenced by the absolute level of VT rather than by the product VT X frequency (PaCO2 = 5715/VT, r = 0.75, P less than 0.05). The primary phenomenon explaining HFJV-induced "PEEP effect" was intrapulmonary gas trapping due to incomplete exhalation of the first VT administered: the spontaneous relaxation times of these first VT were longer than expiratory time allotted to the ventilatory settings. HFJV-induced "PEEP effect" increased with I/E ratio, DP, and f and was markedly influenced by the mechanical properties of the total respiratory system. At given ventilatory settings, HFJV-induced "PEEP effect" was greater in patients with a normal or elevated time constant of the total respiratory system (tau RS) than in patients with a low tau RS. These results suggest that HFJV should not be used in patients with chronic obstructive pulmonary disease and asthma, and should be preferentially administered to patients having stiff lungs or decreased chest wall compliance.