Serge Verbrugge

Lung overinflation without positive end-expiratory pressure promotes bacteremia after experimental Klebsiella pneumoniae inoculation

AbstractObjective: To determine the effect of peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) on the development of bacteremia with Klebsiella pneumoniae after mechanical ventilation of intratracheally inoculated rats. Design: Prospective, randomized, animal study. Setting: Experimental intensive care unit of a University. Subjects: Eighty male Sprague Daw-ley rats. Interventions: Intratracheal inoculation with 100 µl of saline containing 3.5−5.0×105 colony forming units (CFUs) K. pneumoniae/ml. Pressure-controlled ventilation (frequency 30 bpm; I/E ratio=1:2; FIO2=1.0) for 180 min at the following settings (PIP/PEEP in cmH2O): 13/3 (n=16); 13/0 (n=16); 30/10 (n=16) and 30/0 (n=16), starting 22 h after inoculation. Arterial blood samples were obtained and cultured before and 180 min after mechanical ventilation and immediately before sacrifice in two groups of non-ventilated control animals (n=8 per group). After sacrifice, the lungs were homogenized to determine the number of CFUs K. pneumoniae. Measurements and results: The number of CFUs recovered from the lungs was comparable in all experimental groups. After 180 min, 11 animals had positive blood cultures for K. pneumoniae in group 30/0, whereas only 2,0 and 2 animals were positive in 13/3,13/0 and 30/10, respectively (p<0.05 group 30/0 versus all other groups). Conclusions: These data show that 3 h of mechanical ventilation with a PIP of 30 cmH2O without PEEP in rats promotes bacteremia with K. pneumoniae. The use of 10 cmH2O PEEP at such PIP reduces ventilation-induced K. pneumoniae bacteremia.

Different Ventilation Strategies Affect Lung Function but Do Not Increase Tumor Necrosis Factor-α and Prostacyclin Production in Lavaged Rat Lungs In Vivo

BACKGROUND Using an in vivo animal model of surfactant deficiency, the authors compared the effect of different ventilation strategies on oxygenation and inflammatory mediator release from the lung parenchyma. METHODS In adult rats that were mechanically ventilated with 100% oxygen, acute lung injury was induced by repeated lung lavage to obtain an arterial oxygen partial pressure < 85 mmHg (peak pressure/positive end-expiratory pressure [PEEP] = 26/6 cm H2O). Animals were then randomly assigned to receive either exogenous surfactant therapy, partial liquid ventilation, ventilation with high PEEP (16 cm H2O), ventilation with low PEEP (8 cm H2O), or ventilation with an increase in peak inspiratory pressure (to 32 cm H2O; PEEP = 6 cm H2O). Two groups of healthy nonlavaged rats were ventilated at a peak pressure/PEEP of 32/6 and 32/0 cm H2O, respectively. Blood gases were measured. Prostacyclin (PGI2) and tumor necrosis factor-alpha (TNF-alpha) concentrations in serum and bronchoalveolar lavage fluid (BALF) as well as protein concentration in BALF were determined after 90 and 240 min and compared with mechanically ventilated and spontaneously breathing controls. RESULTS Surfactant, partial liquid ventilation, and high PEEP improved oxygenation and reduced BALF protein levels. Ventilation with high PEEP at high mean airway pressure levels increased BALF PGI2 levels, whereas there was no difference in BALF TNF-alpha levels between groups. Serum PGI2 and TNF-alpha levels did not increase as a result of mechanical ventilation when compared with those of spontaneously breathing controls. CONCLUSIONS Although alveolar protein concentration and oxygenation markedly differed with different ventilation strategies in this model of acute lung injury, there were no indications of ventilation-induced systemic PGI2 and TNF-alpha release, nor of pulmonary TNF-alpha release. Mechanical ventilation at high mean airway pressure levels increased PGI2 levels in the bronchoalveolar lavage-accessible space.

The open lung concept: pressure-controlled ventilation is as effective as high-frequency oscillatory ventilation in improving gas exchange and lung mechanics in surfactant-deficient animals.

Objective: To demonstrate in experimental animals with respiratory insufficiency that under well-defined conditions, commercially available ventilators allow settings which are as effective as high frequency oscillatory ventilators (HFOV), with respect to the levels of gas exchange, protein infiltration, and lung stability. Design: Prospective, randomized, animal study. Setting: Experimental laboratory of a university. Subjects: 18 adult male Sprague-Dawley rats. Interventions: Lung injury was induced by repeated whole-lung lavage. Thereafter, the animals were assigned to pressure-controlled ventilation (PCV) plus The Open Lung Concept (OLC) or HFOV plus OLC (HFOOLC). In both groups, an opening maneuver was performed by increasing airway pressures to improve the arterial oxygen tension/fractional inspired oxygen (PaO2/FIO2) ratio to L 500 mm Hg; thereafter, airway pressures were reduced to minimal values, which kept PaO2/FIO2 L 500 mm Hg. Pressure amplitude was adjusted to keep CO2 as close as possible in the normal range. Measurements and results: Airway pressure, blood gas tension, and arterial blood pressure were recorded every 30 min. At the end of the 3-h study period, a pressure-volume curve was recorded and bronchoalveolar lavage was performed to determine protein content. After the recruitment maneuver, the resulting mean airway pressure to keep a PaO2/FIO2 L 500 mm Hg was 25 ± 1.3 cm H2O during PCVOLC and 25 ± 0.5 cm H2O during HFOVOLC. Arterial oxygenation in both groups was above L 500 mm Hg and arterial carbon dioxide tension was kept close to the normal range. No differences in mean arterial pressure, lung mechanics and protein influx were found between the two groups. Conclusions: This study shows that in surfactant-deficient animals, PCV, in combination with a recruitment maneuver, opens atelectatic lung areas and keeps them open as effectively as HFOV.

Hemodynamic effects of partial liquid ventilation with perfluorocarbon in acute lung injury

ObjectiveTo assess the effect of partial liquid ventilation with perfluorocarbons on hemodynamics and gas exchange in large pigs with induced acute lung injury (ALI).DesignRandomized, prospective, double-control, experimental study.SettingExperimental intensive care unit of a university.MaterialsEighteen large pigs (50±5 kg body weight) with an average anterior posterior thoracic diameter of 24 cm and induced acute lung injury.InterventionsAll animals were surfactant depleted by lung lavage to aPaO2 below 100 mmHg and randomized to receive either perflubron (n=6) or saline (n=6) in five intratracheal doses of 5 ml/kg at 20-min intervals, or no instillation (n=6).Measurements and resultsIn all animals heart rate, arterial pressures, pulmonary pressures, cardiac output and blood gases were recorded at 20-min intervals. There was no deleterious effect on any hemodynamic parameter in the perflubron group, whereas systolic and mean pulmonary arterial pressure values showed a persistent decrease after the first 5 ml/kg of perflubron, from 48.7±14.1 to 40.8±11.7 mmHg and from 39.7±13.2 to 35.2±12.0 mmHg, respectively. Perflubron resulted in a significant (ANOVAP<0.01), dose-dependent increase inPaO2 values from 86.3±22.4 to a maximum of 342.4±59.4 mmHg at a dose of 25 ml/kg; the other groups showed no significant increase inPaO2.ConclusionsTracheal instillation of perflubron in induced ALI results in a dose-dependent increase inPaO2 and has no deleterious effect on hemodynamic parameters.

Exogenous surfactant preserves lung function and reduces alveolar Evans blue dye influx in a rat model of ventilation-induced lung injury

Background Changes in pulmonary edema infiltration and surfactant after intermittent positive pressure ventilation with high peak inspiratory lung volumes have been well described. To further elucidate the role of surfactant changes, the authors tested the effect of different doses of exogenous surfactant preceding high peak inspiratory lung volumes on lung function and lung permeability. Methods Five groups of Sprague‐Dawley rats (n = 6 per group) were subjected to 20 min of high peak inspiratory lung volumes. Before high peak inspiratory lung volumes, four of these groups received intratracheal administration of saline or 50, 100, or 200 mg/kg body weight surfactant; one group received no intratracheal administration. Gas exchange was measured during mechanical ventilation. A sixth group served as nontreated, nonventilated controls. After death, all lungs were excised, and static pressure‐volume curves and total lung volume at a transpulmonary pressure of 5 cm H2 O were recorded. The Gruenwald index and the steepest part of the compliance curve (Cmax) were calculated. A bronchoalveolar lavage was performed; surfactant small and large aggregate total phosphorus and minimal surface tension were measured. In a second experiment in five groups of rats (n = 6 per group), lung permeability for Evans blue dye was measured. Before 20 min of high peak inspiratory lung volumes, three groups received intratracheal administration of 100, 200, or 400 mg/kg body weight surfactant; one group received no intratracheal administration. A fifth group served as nontreated, nonventilated controls. Results Exogenous surfactant at a dose of 200 mg/kg preserved total lung volume at a pressure of 5 cm H2 O, maximum compliance, the Gruenwald Index, and oxygenation after 20 min of mechanical ventilation. The most active surfactant was recovered in the group that received 200 mg/kg surfactant, and this dose reduced minimal surface tension of bronchoalveolar lavage to control values. Alveolar influx of Evans blue dye was reduced in the groups that received 200 and 400 mg/kg exogenous surfactant. Conclusions Exogenous surfactant preceding high peak inspiratory lung volumes prevents impairment of oxygenation, lung mechanics, and minimal surface tension of bronchoalveolar lavage fluid and reduces alveolar influx of Evans blue dye. These data indicate that surfactant has a beneficial effect on ventilation‐induced lung injury.

Combining partial liquid ventilation with nitric oxide to improve gas exchange in acute lung injury

Objective: To assess the effects of increasing concentrations of inhaled nitric oxide (NO) during incremental dosages of partial liquid ventilation (PLV) on gas exchange, hemodynamics, and oxygen transport in pigs with induced acute lung injury (ALI). Design: Prospective experimental study. Setting: Experimental intensive care unit of a university. Subjects: 6 pigs with induced ALI. Interventions: Animals were surfactant-depleted by lung lavage to a partial pressure of oxygen in arterial blood (PaO2) < 100 mmHg. They then received four incremental doses of 5 ml/kg perflubron (LiquiVent). Between each dose the animals received 0, 10, 20, 30, 40, and 0 parts per million (ppm) NO. Measurements and main results: Blood gases, hemodynamic parameters, and oxygen delivery were measured after each dose of perflubron as well as after each NO concentration. Perflubron resulted in a dose-dependent increase in PaO2. At each perflubron dose, additional NO inhalation resulted in a further significant (ANOVA, p < 0.05) increase in PaO2, with a maximum effect at 30 ± 10 ppm NO. The 5 ml/kg perflubron dose led to a significant decrease in mean pulmonary artery pressure, which decreased further with higher NO concentrations. Conclusions: PLV can be combined with NO administration and results in a cumulative effect on arterial oxygenation and to a decrease in pulmonary artery pressure, without having any deleterious effect on measured systemic hemodynamic parameters.

ROLE OF CHEMOTACTIC FACTORS IN NEUTROPHIL ACTIVATION AFTER THERMAL INJURY IN RATS

Acute thermal trauma is well known to produce evidence of a “systemic inflammatory response” in vivo, as manifested by evidence of complement activation, appearance in plasma of a variety of inflammatory factors, and development of multi-organ injury. The current studies were focused on acute thermal injury of rat skin and factors responsible for accompanying activation of blood neutrophils. Acute thermal injury of rat skin resulted in a time-dependent loss of L-selectin and up-regulation of Mac-1 (CD11b/CD18) on blood neutrophils, with no changes in LFA-1 (CD11a/CD18). The loss of L-selectin was prevented by blockade of C5a but not by blockade of the α-chemokine, macrophage inflammatory protein-2 (MIP-2). C5a, the α chemokines, MIP-2 and keratinocyte-derived cytokine (KC), and platelet activating factor (PAF) contributed to up-regulation of blood neutrophil Mac-1. Blocking interventions against these mediators also blunted the degree of neutropenia developing after thermal trauma. These data suggest that activation of blood neutrophils after thermal trauma is related to the role of several chemotactic mediators. These studies may provide clues regarding factors responsible for development of the “systemic inflammatory response syndrome” after thermal injury in the experimental model employed.

Mechanical ventilation with high positive end-expiratory pressure and small driving pressure amplitude is as effective as high-frequency oscillatory ventilation to preserve the function of exogenous surfactant in lung-lavaged rats

ObjectiveTo demonstrate that under well-defined conditions, pressure-controlled ventilators (PCV) allow settings that are as good as high-frequency oscillatory ventilators (HFOV) at preserving the function of exogenous surfactant in lung-lavaged rats. DesignExperimental, comparative study. SettingResearch laboratory of a large university. SubjectsSixteen adult male Sprague-Dawley rats (280–310 g). InterventionsLung injury was induced by repeated lavage. After last lavage, all animals received exogenous surfactant and were then randomly assigned to two groups (n = 8 per group). The first group received PCV with small pressure amplitudes and high positive end-expiratory pressure. The second group received HFOV. In both groups, an opening maneuver was performed by increasing airway pressure to improve Pao2/Fio2 to ≥500 torr. Measurements and Main ResultsBlood gases were measured every 30 mins for 3 hrs. Airway pressures were measured with a tip catheter pressure transducer. At the end of the study period, a pressure-volume curve was recorded and a broncho-alveolar lavage was performed to determine protein content and surfactant composition. The results showed that arterial oxygenation in both groups could be kept >500 torr during the 3-hr study period by using a mean airway pressure of 13 ± 3 cm H2O in PCV and 13 ± 2 cm H2O in HFOV. Further, there were no differences in the Gruenwald index, protein influx, or ratio of small to large aggregates between the study groups. ConclusionPCV with sufficient level of positive end-expiratory pressure and small driving pressure amplitudes is as effective as HFOV to maintain optimal gas exchange, to improve lung mechanics, and to prevent protein influx and conversion of large into small aggregates after exogenous surfactant therapy in lung-lavaged rats.

Injurious ventilation strategies- cause systemic release of IL-6 and MIP-2 in rats in vivo

In vivo experiments showed no increased production of tumour necrosis factor (TNF) in response to injurious ventilation strategies in otherwise untreated animals. Because interleukin‐6 (IL‐6) and macrophage inflammatory protein‐2 (MIP‐2) are more sensitive markers of ventilation‐induced cytokine release, serum and bronchoalveolar lavage (BAL) samples were examined for these mediators. Eighty‐five adult rats were randomized to three different ventilation strategies. Rats were ventilated with low pressures and low tidal volumes [13/3; peak inspiratory pressure (PIP)/positive end‐expiratory pressure (PEEP) in cmH2O], the second group of rats was ventilated with high pressures and low PEEP resulting in high tidal volumes (32/6), and the third group was ventilated with the same high pressures but without PEEP (32/0). Animals were ventilated either for 90 or 240 min, subsequently serum and BAL were collected for analyses on IL‐6 and MIP‐2 content. Non‐ventilated animals served as healthy controls. Ventilation with 32/0 for 90 or 240 min, led to increased serum IL‐6 levels. Serum MIP‐2 levels were increased by ventilation with 32/6 (90 min) and 32/0 (240 min). Ventilation under any condition, even at 13/3, resulted in elevated MIP‐2 levels in the BAL fluid. Even at normal pressures pulmonary MIP‐2 levels were increased, suggesting that ventilation may promote pro‐inflammatory responses in healthy subjects.

Partial liquid ventilation improves lung function in ventilation-induced lung injury

Disturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish lung function after ventilation-induced lung injury. Adult rats were exposed to high PIP without PEEP for 20 min. Thereafter, the animals were randomly divided into five groups. The first group was killed immediately after randomization and used as an untreated control. The second group received only sham treatment and ventilation, and three groups received treatment with perfluorocarbon (10 mL x kg(-1), 20 mL x kg(-1), and 20 ml x kg(-1) plus an additional 5 mL x kg(-1) after 1 h). The four groups were maintained on mechanical ventilation for a further 2-h observation period. Blood gases, lung mechanics, total protein concentration, minimal surface tension, and small/large surfactant aggregates ratio were determined. The results show that in ventilation-induced lung injury, partial liquid ventilation with different amounts of perflubron improves gas exchange and pulmonary function, when compared to a group of animals treated with standard respiratory care. These effects have been observed despite the presence of a high intra-alveolar protein concentration, especially in those groups treated with 10 and 20 mL of perflubron. The data suggest that replacement of perfluorocarbon, lost over time, is crucial to maintain the constant effects of partial liquid ventilation.