Early mechanical ventilation is deleterious after aspiration-induced lung injury in rabbits

We investigated whether mechanical ventilation after aspiration is deleterious when started before surfactant therapy. Gas exchange and lung mechanics were measured in rabbits after aspiration either mechanically ventilated before or after lavage with diluted surfactant or Ringer's solution. Lung injury was induced by intratracheal instillation of 2 mL/kg of a betain/HCl pepsin mixture. After 30 min of spontaneous breathing, ventilation was started in 12 rabbits, which were then treated by lavage with diluted surfactant (15 mL/kg body weight; 5.3 mg/mL, group MVpre S) or with Ringer's solution (1 mL/kg; group MVpre R). Another 12 rabbits were treated by lavage while spontaneously breathing and were then connected to the ventilator (MVpost S and MVpost R). Sham control rabbits were mechanically ventilated for 4 h. At the end of experiment, PaO2/FiO2 ratio in MVpost S was five times higher than in MVpre S (P=0.0043). Lung mechanics measurements showed significant difference between MVpre S and MVpost S (P=0.0072). There was histopathologic evidence of decreased lung injury in MVpost S. Immediate initiation of ventilation is harmful when lung injury is induced by aspiration. Further investigations are needed to clarify whether the timing of lavage with diluted surfactant has an impact on the treatment of patients with aspiration or comparable types of direct lung injury.     

Effect of N-nitroso-N-methylurethane on gas exchange,lung compliance,and surfactant function of rabbits

Objectives To define the effect of N-nitroso-N-methylurethane (NNNMU) on pulmonary gas exchange, compliance and the biochemical and functional properties of the lung surfactant system.Design Four days after inducing lung injury, gas exchange and pulmonary compliance were studied and a bronchoalveolar lavage was taken.Setting Experimental laboratory of a university department of medicine, division of pulmonary and critical care medicine.Animals Ten rabbits after they had received an injection of NNNMU and five control animals.Interventions Controlled mechanical ventilation and bronchoalveolar lavage.Measurements and results Measurements of gas exchange (using the multiple inert gas elimination technique), hemodynamics and pulmonary compliance were performed during ventilatory and hemodynamic steady state. A bronchoalveolar lavage (BAL) was taken after sacrificing the animal. BAL samples were processed for cell count and biochemical and functional surfactant analysis. Animals injected with NNNMU developed mild, but significant reduction in PaO₂, while maintaining eucapnia during spontaneous air breathing. distributions and arterial blood gases were similar in all animals when ventilated mechanically with a fixed tidal volume. Compliance of the lung and phospholipid levels in lavage of NNNMU animals was significantly lower than in control animals (CON). Function of surfactant recovered from animals receiving NNNMU was decreased significantly where compared to CON. Thus, NNNMU resulted in a lowered lavage surfactant phospholipid content, impaired surfactant function, decreased compliance and hypoxemia during spontaneous ventilation. However, gas exchange was similar to that of control animals during mechanical ventilation.Conclusion We conclude that NNNMU-induced gas exchange abnormalities present after 4 days are mild and are reversed by fixed volume mechanical ventilation despite marked alteration in surfactant function and lung compliance. These observations further define properties of a lung injury model that is of value in the study of surfactant replacement.This study was supported by grant-Pa 377/1-11 from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and grant HL23584 from the National Institutes of Health (SCOR Project 1)     

Bronchoalveolar lavage with a diluted surfactant suspension prior to surfactant instillation improves the effectiveness of surfactant therapy in experimental acute respiratory distress syndrome (ARDS)

Objective: To assess whether bronchoalveolar lavage (BAL) with a diluted surfactant suspension prior to surfactant instillation prevents the only transient improvement in lung function as reported after surfactant instillation in severe acute respiratory distress syndrome (ARDS). Design: Randomized, prospective, experimental study. Setting: Laboratory and animal facility of a large university. Materials: Adult male Sprague-Dawley rats (280 ± 30 g). Interventions: All animals underwent repetitive whole lung saline lavage to induce acute lung injury. Then, animals were randomly divided into seven study groups: the first group received surfactant (150 mg/kg) within 10 min after the last lavage (early treatment), whereas in the other six groups mechanical ventilation was continued for 3 h before treatment (late treatment). Treatment consisted of: surfactant instillation at a dose of 150 mg/kg; at a dose of 250 mg/kg; BAL with saline; BAL with a diluted surfactant suspension (2.5 mg/ml); BAL with saline, immediately followed by surfactant instillation (150 mg/kg) and BAL with a diluted surfactant suspension (2.5 mg/kg), immediately followed by surfactant instillation (150 mg/kg). Measurements and results: Blood gases were measured for 6 h and then BAL was performed to measure the protein concentration and surface tension properties. Mean PaO₂ values increased immediately after surfactant instillation to pre-lavage values but remained stable only in the group that received surfactant immediately after the lavage procedure and the group that underwent BAL with a diluted surfactant suspension prior to surfactant instillation. Conclusion: BAL with a diluted surfactant suspension prior to surfactant instillation at a later time point in lung injury resulted in a stable improvement of lung function. This improvement is comparable with the results seen after surfactant instillation immediately after lung lavage.     

Effects of a catecholamine-induced increase in cardiac output on lung injury after experimental unilateral pulmonary acid instillation

OBJECTIVES: Increasing pulmonary blood flow aggravated ventilation-associated lung injury in ex vivo animal experiments, but data were less consistent in an in vivo animal model and do not reflect redistributed lung perfusion seen in clinical acute lung injury. We sought to determine the effects of increased cardiac output on markers of lung injury in an in vivo model of inhomogeneous lung perfusion and injury. DESIGN: Prospective, controlled animal study. SETTING: Experimental research laboratory of a university hospital. SUBJECTS: A total of 50 anesthetized, mechanically ventilated, male Wistar rats. INTERVENTIONS: Unilateral lung injury was induced in rats by left lung acid instillation. After 24 hrs, animals were anesthetized and subjected to mechanical ventilation (tidal volume, 8 mL/kg; positive end-expiratory pressure, 7 cm H2O; FIO2, 0.4) and continuous infusion of either 10 microg x kg x min dobutamine or isotonic saline (control) for 4 hrs. MEASUREMENTS AND MAIN RESULTS: Cardiac output and differential lung perfusion were recorded throughout the ventilation period. Right and left lung wet-to-dry weight ratio, cytokines and inflammatory cells in lung lavage, and histologic lung injury were measured postmortem. After acid injury, lung perfusion was preferentially distributed to the noninjured lung. Dobutamine increased baseline cardiac output (>70%) and perfusion of both lungs (left, acid-instilled lung: from 16 +/- 2 to 29 +/- 6 mL/min; right, non-acid-instilled lung: from 54 +/- 3 to 98 +/- 7 mL/min). There was no difference in left lung injury between dobutamine- and saline-infused animals, but right lung injury was aggravated in dobutamine-infused animals, as indicated by increased lung edema, histologic lung injury, and cell counts in lavage. CONCLUSIONS: In the setting of unilateral lung injury and uneven lung perfusion, a dobutamine-induced increase in cardiac output has potentially detrimental effects on the opposite lung.     

Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep

Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40 degrees C) were inflated into the airway. Afterwards, live Pseudomonas aeruginosa (5 x 10(11) CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2 and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.     

Non-invasive radiation-free monitoring of regional lung ventilation in critically ill infants

OBJECTIVE: Established techniques used to examine lung function in critically ill infants cannot continuously follow regional aspects of lung ventilation although this information would be beneficial for proper therapy planning. We have studied the applicability and clinical relevance of a relatively new non-invasive radiation-free imaging method, electrical impedance tomography (EIT), in monitoring regional lung function in paediatric intensive care patients. DESIGN: Prospective study. SETTING: Neonatal and paediatric intensive care unit (ICU) at a university hospital. PATIENTS: Eight infants (1 day-7 years old) suffering from miscellaneous diseases requiring intensive care therapy. INTERVENTIONS: Adjustment of ventilator settings, surfactant administration, and postural changes. MEASUREMENTS AND RESULTS: Repeated EIT measurements were performed with the intention to monitor regional lung ventilation in mechanically ventilated and spontaneously breathing infants. The follow-up time ranged between 1 and 11 days. During individual EIT measurements of 100-s duration electrical voltages resulting from repetitive injection of small electrical currents were continuously measured on the thoracic circumference using conventional surface electrodes. Acquired data were used to generate functional cross-sectional thoracic images of regional lung ventilation. A total of 638 EIT measurements were performed. The redistribution of lung ventilation and changes in regional ventilation magnitude resulting from adjusted positive end-expiratory pressure, peak inspiratory pressure, inspiration-expiration ratio, surfactant instillation, and prone or supine positioning were identified. CONCLUSIONS: Provided that EIT hardware and software are further developed to guarantee stable and undisturbed measurements in the ICU and that practical handling is improved, this non-invasive method may become a useful bedside monitoring tool of regional lung ventilation in critically ill infants.     

Surfactant and corticosteroid effects on lung function in a rat model of acute lung injury.

OBJECTIVES: To evaluate pulmonary responses to intratracheal administration of surfactant with and without dexamethasone in rats with paraquat-induced lung injury. DESIGN: Prospective, randomized, controlled study. SETTING: University research facility. SUBJECTS: Adult male Sprague Dawley rats. INTERVENTIONS: Rats were anesthetized and underwent a tracheostomy and arterial catheter insertion 3 days after intraperitoneal injection of paraquat (35 mg/kg). The rats were ventilated for 90 mins after sequential designation as controls or as recipients of intratracheal surfactant alone (50 or 100 mg/kg) or surfactant (50 or 100 mg/kg) plus dexamethasone (0.5 mg/kg). MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were determined at 15, 30, 60, and 90 mins. After 90 mins of ventilation, a static pressure-volume curve was performed, and inflammatory cells, total protein content, and cytokines were measured in bronchoalveolar lavage fluid. Postmortem histology was then examined. Treatment with 50 mg/kg dexamethasone/Survanta and 100 mg/kg Survanta with and without dexamethasone significantly increased oxygenation shortly after instillation when compared with the control group, with the response maintained throughout the study period. Static pressure-volume curves showed that the group receiving 100 mg/kg dexamethasone/Survanta had significantly higher lung volumes than the control group. Total cell, neutrophil, and macrophage counts were decreased significantly in the animals treated with 100 mg/kg dexamethasone/Survanta compared with untreated control rats. Total protein recovered from bronchoalveolar lavage fluid in the animals treated with 100 mg/kg Survanta with and without dexamethasone was decreased significantly compared with control animals. The histologic appearance of the lungs was markedly better in the groups treated with surfactant with or without dexamethasone. CONCLUSIONS: Results suggest that the combined administration of high doses of intratracheal surfactant and dexamethasone improves gas exchange, ameliorates lung inflammation, and alleviates lung damage after paraquat-induced lung injury. Surfactant alone and lower doses of surfactant plus dexamethasone had a lesser effect on these measures.     

High-frequency oscillation and exogenous surfactant administration in lung-injured adult sheep

OBJECTIVE: To evaluate the effects of high-frequency oscillation on the response to exogenous surfactant in lung-injured adult sheep. DESIGN: A prospective, controlled, in vivo, animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Twenty-eight adult sheep. INTERVENTIONS: Animals were anesthetized and instrumented with a tracheostomy and vascular catheters. Following whole lung saline lavage, animals were randomized to one of four groups: Group S-CMV received surfactant and was ventilated for 4 hrs using a conventional mechanical ventilation strategy, group S-HFOV/CMV received surfactant and was ventilated with a high-frequency oscillation technique for 2 hrs and a conventional mechanical strategy for 2 hrs, group HFOV/CMV underwent the latter ventilatory strategies without receiving surfactant, and group HFOV was ventilated with high-frequency oscillation only for 4 hrs. At the end of the ventilatory period, the distributions of ventilation and surfactant were evaluated in animals that received surfactant. MEASUREMENTS AND MAIN RESULTS: Animals in the S-CMV group had a significantly greater mean PaO2 value at the end of the experimental period than animals in the S-HFOV/CMV or HFOV/CMV groups. Evaluation of the distribution of ventilation relative to surfactant demonstrated that animals ventilated with high-frequency oscillation followed by conventional mechanical ventilation had a significantly greater disproportionate distribution of ventilation relative to surfactant compared with the CMV-only group. CONCLUSIONS: A period of high-frequency oscillation, as used in this study, immediately following exogenous surfactant administration mitigates the host's response to surfactant when subsequently switched to conventional mechanical ventilation.     

At surfactant deficiency, application of "the open lung concept" prevents protein leakage and attenuates changes in lung mechanics

OBJECTIVE: To evaluate whether mechanical ventilation using "the open lung concept" during surfactant depletion can attenuate the deterioration in pulmonary function. DESIGN: Experimental, comparative study. SETTING: Research laboratory of a large university. SUBJECTS: Eighteen adult male Sprague-Dawley rats, weighing 280-340 g. INTERVENTIONS: Twelve rats were anesthetized, mechanically ventilated with 100% oxygen, and randomly divided into two groups (n = 6 each). The open lung group underwent six saline lavages at different ventilator settings that prevented alveolar collapse. The settings (expressed as frequency/peak inspiratory pressure/positive end-expiratory pressure/inspiratory:expiratory ratio) were 30/26/6/1:2 during the first lavage, 100/27/10/1:1 during the next two lavages, and 100/33/15/1:1 during the last three lavages and during the remaining ventilation period. The ventilated control group underwent six saline lavages with settings at 30/26/6/1:2. After the lavages, peak inspiratory pressure and positive end-expiratory pressure were increased in this group by 2 cm H2O each for the remaining study period. An additional group of six animals were killed immediately after induction of anesthesia and served as healthy controls. Blood gases were measured before lavage, immediately after the last lavage, and thereafter hourly. At the end of the 4-hr study period, we constructed pressure-volume curves from which we determined total lung capacity at a distending pressure of 35 cm H2O (TLC35). Subsequently, total lung volume at a distending pressure of 5 cm H2O (V5) was determined, followed by bronchoalveolar lavage. RESULTS: In the ventilated control group, PaO2, V5, and TLC35 were significantly decreased and protein concentration of bronchoalveolar lavage was significantly increased compared with the healthy control group. In the open lung group, PaO2 did not decrease after the lavage procedure, and V5, TLC35, and the protein concentration of bronchoalveolar lavage were comparable with the healthy controls. CONCLUSION: We conclude that application of the open lung concept during surfactant depletion attenuates deterioration in pulmonary function.     

Comparative effects of proportional assist and variable pressure support ventilation on lung function and damage in experimental lung injury*

OBJECTIVE:: To investigate the effects of proportional assist ventilation, variable pressure support, and conventional pressure support ventilation on lung function and damage in experimental acute lung injury. DESIGN:: Randomized experimental study. SETTING:: University hospital research facility. SUBJECTS:: Twenty-four juvenile pigs. INTERVENTIONS:: Pigs were anesthetized, intubated, and mechanically ventilated. Acute lung injury was induced by saline lung lavage. After resuming of spontaneous breathing, animals were randomly assigned to 6 hrs of assisted ventilation with pressure support ventilation, proportional assist ventilation, or variable pressure support (n = 8 per group). Mean tidal volume was kept at ≈6 mL/kg in all modes. MEASUREMENTS AND MAIN RESULTS:: Lung functional parameters, distribution of ventilation by electrical impedance tomography, and breathing patterns were analyzed. Histological lung damage and pulmonary inflammatory response were determined postmortem. Variable -pressure support and proportional assist ventilation improved oxygenation and venous admixture compared with pressure support ventilation. Proportional assist ventilation led to higher esophageal pressure time product than variable pressure support and pressure support ventilation, and redistributed ventilation from central to dorsal lung regions compared to pressure support ventilation. Variable pressure support and proportional assist ventilation yielded higher tidal volume variability than pressure support ventilation. Such pattern was deterministic (self-organized) during proportional assist ventilation and stochastic (random) during variable pressure support. Subject-ventilator synchrony as well as pulmonary inflammatory response and damage did not differ among groups. CONCLUSIONS:: In a lung lavage model of acute lung injury, both variable pressure support and proportional assist ventilation increased the variability of tidal volume and improved oxygenation and venous admixture, without influencing subject-ventilator synchrony or affecting lung injury compared with pressure support ventilation. However, variable pressure support yielded less inspiratory effort than proportional assist ventilation at comparable mean tidal volumes of 6 mL/kg.     

Effect of combined high-frequency oscillatory ventilation on rabbit alveolar type-2 cells

The effects on lung tissue of high-frequency oscillatory ventilation combined with intermittent mandatory ventilation (HFO-IMV) were compared with those of conventional mechanical ventilation (CMV) by matching the mean tracheal pressure. Pulmonary alveolar type-2 cells and subcellular organelles from rabbit lung were morphometrically examined by electron microscopy. The volume and surface densities of lamellar bodies in alveolar type-2 cells from the animals ventilated with HFO-IMV were decreased significantly compared with those from the animals either ventilated with CMV or breathing spontaneously (control group). The cell surface to volume ratio in the HFO-IMV group showed a significant increase compared with the CMV groups, whereas other variables showed no differences between the three groups. These results suggest that the secretion of surfactant from alveolar type-2 cells was enhanced in HFO-IMV-treated animals compared with CMV-treated and control groups.     

The inhibition of inducible nitric oxide synthase in ovine sepsis model

Excessive NO has been shown to play a major role in the pathogenesis of multiple organ dysfunctions in septic condition. Burn injury, especially if it is associated with smoke inhalation, is often complicated by subsequent development of pneumonia or sepsis that determine the outcome. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that closely mimics human sepsis and pneumonia. We hypothesized that the inhibition of iNOS-derived excessive NO might be beneficial in treating the cardiopulmonary derangement in this model. Female sheep (n = 18) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (< 40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa (5 x 10(11) colony forming units) into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of BBS-2 (100 microg/kg/h), an iNOS inhibitor, was started 1 h after insult. The administration of BBS-2 improved pulmonary gas exchange (PaO2/FiO2 and pulmonary shunt fraction) and partially reduced airway obstruction and an increase in ventilatory pressures. The lung water content was not affected by iNOS inhibition. The hypotension seen in nontreated animals was not ameliorated either. The increase in plasma concentration of nitrate and nitrite was inhibited by BBS-2. The results of present study show that iNOS may be partially involved in the pathogenesis of acute lung injury induced by smoke inhalation followed by bacterial instillation in the airway.     

Open lung ventilation preserves the response to delayed surfactant treatment in surfactant-deficient newborn piglets

OBJECTIVE: Delayed surfactant treatment (>2 hrs after birth) is less effective than early treatment in conventionally ventilated preterm infants with respiratory distress syndrome. The objective of this study was to evaluate if this time-dependent efficacy of surfactant treatment is also present during open lung ventilation. DESIGN: Prospective, randomized controlled animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Thirty-eight newborn piglets. INTERVENTIONS: Following repeated whole-lung lavage, animals were randomly allocated to conventional positive pressure ventilation (PPVCON) using a positive end-expiratory pressure (PEEP) of 5 cm H2O and a tidal volume of 7 mL/kg or open lung positive pressure ventilation (PPVOLV). During PPVOLV, collapsed alveoli were actively recruited and thereafter stabilized with sufficient PEEP. Within each ventilation group, animals received surfactant (25 mg/kg) either after 2 hrs (PPVCON-2 and PPVOLV-2) or after 4 hrs (PPVCON-4 and PPVOLV-4) of ventilation. A control group received surfactant immediately after lung lavage. Following surfactant administration, all animals were conventionally ventilated for an additional 2 hrs. MEASUREMENTS AND MAIN RESULTS: Two hours after surfactant treatment, both oxygenation and lung mechanics showed a clear deterioration in the PPVCON-4 group compared with PPVCON-2 and the control group. However, this deterioration of the surfactant response over time was not observed during PPVOLV. Analysis of the bronchoalveolar lavage fluid obtained at the end of the experiment showed that the protein concentration and the conversion of large to small aggregate surfactant was significantly higher in the PPVCON-4 group compared with the PPVCON-2 group while comparable in both PPVOLV groups. In addition, interleukin-8 and myeloperoxidase levels tended to be higher in the PPVCON-4 group compared with the PPVOLV-4 group. CONCLUSIONS: In contrast to conventional ventilation, open lung ventilation preserves the response to delayed surfactant treatment in surfactant-deficient newborn piglets. This sustained response is accompanied by an attenuation of secondary lung injury.     

High positive end-expiratory pressure levels promote bacterial translocation in experimental pneumonia

Objective A previous study in piglets with experimental pneumonia showed that reducing atelectasis by means of open lung ventilation attenuated bacterial translocation compared to conventional ventilation settings. This study examined the effect of open lung ventilation with higher than necessary positive end-expiratory pressures (PEEP) on bacterial translocation. Design and setting Prospective animal study in a university-affiliated research laboratory. Subjects Thirty piglets. Interventions Animals were surfactant-depleted by whole-lung lavage and infected with group B streptococci. Thereafter the animals were ventilated for 5 h according to either a conventional ventilation strategy, open lung strategy, or open lung/high-PEEP strategy. Blood samples for blood gas analysis and blood bacterial counts were taken every hour. After 5 h of ventilation surviving animals were killed, and lung colony forming units and lung mechanics parameters were determined. Results All animals in both open lung groups survived but only 30% of those in the conventional ventilation group. Open lung ventilation resulted in significantly less bacterial translocation than either conventional or high-PEEP ventilation. Lung function in the conventional ventilated group was significantly less than in the two open lung groups. Conclusions The lowest level of bacterial translocation was observed during optimal ventilation (open lung) which was achieved by using individually tailored settings. Deviation to either side can be harmful, as shown by the increased bacterial translocation during conventional and high-PEEP ventilation. This work was performed at the Department of Anesthesiology, Erasmus Medical Center, Rotterdam, and was financially supported by the International Foundation for Clinically Oriented Research (IFCOR). This article is discussed in the editorial available at:     

Response to exogenous surfactant is different during open lung and conventional ventilation

OBJECTIVE: Previous studies have shown that the efficacy of exogenous surfactant is dose-dependent during conventional positive pressure ventilation (PPVCON). The present study aimed to determine whether this dose-dependent relationship is also present during open lung (OLC) ventilation. We also explored the effect of exogenous surfactant on the ventilation pressures applied during ventilation. DESIGN: Animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Seventy-two newborn piglets. INTERVENTIONS: After repeated whole lung lavage, animals were randomly allocated to two surfactant groups receiving either 100 mg/kg surfactant (S100) or 25 mg/kg surfactant (S25) or to a control group receiving a bolus of air. Within each group, animals were randomly assigned to either PPVCON, open lung PPV (PPVOLC), or open lung high-frequency oscillatory ventilation (HFOVOLC) and ventilated for 5 hrs. MEASUREMENTS AND MAIN RESULTS: The ventilation pressures decreased in a dose-dependent way, showing the largest reduction in the S100 group. In both OLC groups, oxygenation, lung mechanics, and polymorphonuclear neutrophils analyzed in bronchoalveolar lavage were independent of the surfactant dose. In the PPVCON group, however, there was a clear dose-dependency, resulting in a deterioration of oxygenation and lung mechanics and an increase in polymorphonuclear neutrophils as the surfactant dose decreased. Although comparable between the three ventilation groups, bronchoalveolar lavage interleukin-8 concentrations significantly increased in all ventilation groups as the surfactant dose increased. Alveolar protein influx and conversion of large to small aggregate surfactant were higher during PPVCON compared with both OLC groups. There were no differences in the surfactant treatment response between PPVOLC and HFOVOLC. CONCLUSION: Exogenous surfactant enables a reduction in ventilation pressures. Compared with PPVCON, the efficacy of surfactant treatment is less dose-dependent during open lung ventilation. Surfactant conversion during open lung ventilation is reduced compared with PPVCON. Exogenous surfactant seems to up-regulate bronchoalveolar lavage interleukin-8 concentrations, independent of the ventilation strategy.     

Ventilator-induced lung injury leads to loss of alveolar and systemic compartmentalization of tumor necrosis factor-α

OBJECTIVES: To determine the effect on compartmentalization of the tumor necrosis factor (TNF)-alpha response in the lung and systemically after ventilation with high peak inspiratory pressure with and without positive end-expiratory pressure (PEEP). DESIGN AND SETTING: Prospective, randomized, animal study in an experimental laboratory of a university. SUBJECTS AND INTERVENTIONS: 85 male Sprague-Dawley rats. Lipopolysaccharide was given intratracheally or intraperitoneally to stimulate TNF-alpha production; control animals received a similar amount of saline. Animals were subsequently ventilated for 20 min in a pressure control mode with peak inspiratory pressure/PEEP ratio of either 45/0 or 45/10 (frequency 30 bpm, I/E ratio 1:2, FIO2 = 1). MEASUREMENTS AND RESULTS: Blood gas tension and arterial pressures were recorded at 1, 10, and 20 min after start of mechanical ventilation. After killing of the animals pressure-volume curves were recorded, and bronchoalveolar lavage (BAL) was performed for assessment of protein content and the small/large surfactant aggregate ratio. TNF-alpha was determined in serum and BAL. TNF-alpha levels were significantly increased after lipopolysaccharide stimulation; furthermore ventilation without PEEP resulted in a significant shift of TNF-alpha to the nonstimulated compartment as opposed to ventilation with a PEEP level of 10 cmH2O. CONCLUSIONS: Ventilation strategies which are known to induce ventilation-induced lung injury (VILI) disturb the compartmentalization of the early cytokines response in the lung and systemically. Furthermore, the loss of compartmentalization is a two-way disturbance, with cytokines shifting from the vascular side to the alveolar side and vice versa. A ventilation strategy (PEEP level of 10 cmH2O) which prevents VILI significantly diminished this shift in cytokines.     

Influence of positive end-expiratory pressure (PEEP) on histopathological and bacteriological aspects of pneumonia during low tidal volume mechanical ventilation

Objective Ventilatory strategies combining low tidal volume (V_T) with positive end-expiratory pressure (PEEP) are considered to be lung protective. The influence of the PEEP level was investigated on bacteriology and histology in a model of ventilator-associated pneumonia.Subjects Nineteen New Zealand rabbits.Interventions The animals were mechanically ventilated with a positive inspiratory pressure of 15 cmH₂O and received either a zero end-expiratory pressure (ZEEP, n=6), a 5 cmH₂O PEEP (n=5) or a 10 cmH₂O PEEP (n=4). An inoculum of Enterobacter aerogenes was then instilled intrabronchially. The non-ventilated pneumonia group (n=4) was composed of spontaneously breathing animals which received the same inoculum. Pneumonia was assessed 24 h later.Main results The lung bacterial burden was higher in mechanically ventilated animals compared with spontaneously breathing animals. All animals from the latter group had negative spleen cultures. The spleen bacterial concentration was found to be lower in the 5 cmH₂O PEEP group when compared to the ZEEP and 10 cmH₂O PEEP groups (3.1±1.5 vs 4.9±1.1 and 5.0±1.3 log₁₀ cfu/g, respectively; p<0.05). Lung weight and histological score values were lower in the spontaneously breathing animals as well as in the 5 cmH₂O PEEP group compared with the ZEEP and 10 cmH₂O groups.Conclusions Mechanical ventilation substantially increased the lung bacterial burden and worsened the histological aspects of pneumonia in this rabbit model. Variations in terms of lung injury and systemic spreading of infection were noted with respect to the ventilatory strategy.Presented in January 2004 at the Congress of the French Society of Critical Care Medicine.     

Partial liquid ventilation in severely surfactant-depleted, spontaneously breathing rabbits supported by proportional assist ventilation

OBJECTIVE: We hypothesized that partial liquid ventilation (PLV) would improve oxygenation in nonparalyzed, surfactant-deficient rabbits breathing spontaneously while supported by proportional assist ventilation (PAV). This ventilation mode compensates for low pulmonary compliance and high resistance and thereby facilitates spontaneous breathing. DESIGN: Randomized trial. SETTING: University animal research facility. SUBJECTS: Twenty-six anesthetized New Zealand white rabbits weighing 2592 +/- 237g (mean +/- sd). INTERVENTIONS: After pulmonary lavage (target Pao2 <100 mm Hg on mechanical ventilation with 6 cm H2O of positive end-expiratory pressure [PEEP] and an Fio2 of 1.0), rabbits were randomized to PAV (PEEP of 8 cm H2O) with or without PLV. PLV rabbits received 25 mL/kg of perfluorocarbon by intratracheal infusion (1 mL/kg/min). Pao2, Paco2, tidal volume, respiratory rate, minute ventilation, mean airway pressure, arterial blood pressure, heart rate, pulmonary compliance, and airway resistance were measured. Evaporated perfluorocarbon was refilled every 30 mins in PLV animals. After 5 hrs, animals were killed and lungs were removed. Lung injury was evaluated using a histologic score. MAIN RESULTS: Pao2 and compliance were significantly higher in PLV rabbits compared with controls (p <.05, analysis of variance for repeated measures). All other parameters were similar in both groups. CONCLUSIONS: PLV improved oxygenation and pulmonary compliance in spontaneously breathing, severely surfactant-depleted rabbits supported by PAV. The severity of lung injury by histology was unaffected.     

Methylprednisolone does not enhance the surfactant effects on oxygenation and histology in paraquat-induced rat lung injury

OBJECTIVE: To investigate whether exogenous surfactant would improve gas exchange and lung histology and methylprednisolone pretreatment would enhance the surfactant effect in a rat model of paraquat-induced lung injury. SETTING: University research facility. SUBJECTS: Thirty-three adult male Sprague-Dawley rats. INTERVENTIONS: All rats received intraperitoneal paraquat injection (35 mg/kg) and were assigned randomly to one of four groups: the control group received no further treatment; the methylprednisolone group received a concomitant intraperitoneal methylprednisolone injection (30 mg/kg); the surfactant group received intratracheal Survanta (100 mg/kg) at the start of ventilation; and the methylprednisolone + surfactant group received both methylprednisolone and surfactant treatments. MEASUREMENTS AND MAIN RESULTS: Three days after paraquat injection, every rat was ventilated for 90 min, a static pressure-volume curve and bronchoalveolar lavage were performed and postmortem histology was examined. Treatment with surfactant and methylprednisolone + surfactant improved oxygenation relative to the control group and produced significantly higher lung volumes than the control and methylprednisolone groups. Treatment with surfactant resulted in a significant decrease in total cell and neutrophil counts relative to the control group. Surfactant with methylprednisolone pretreatment significantly decreased total cell, macrophage and neutrophil counts when compared with the surfactant group. The histological appearance of the lungs was better in the two surfactant-treated groups. CONCLUSION: Intratracheal instillation of surfactant improves gas exchange, ameliorates lung inflammation and results in less lung damage in paraquat-induced rat lung injury. Surfactant with methylprednisolone pretreatment decreases inflammatory cell infiltration, but cannot further improve oxygenation and lung histology.     

Standardized lung recruitment during high frequency and conventional ventilation: similar pathophysiologic and inflammatory responses in an animal model of respiratory distress syndrome

Objective To evaluate standardized lung recruitment strategy during both high frequency oscillation (HFO) and volume-targeted conventional ventilation (CV+V) in spontaneously breathing piglets with surfactant washout on pathophysiologic and inflammatory responses.Design Prospective animal study.Setting Research laboratory.Subjects Twenty-four newborn piglets.Interventions We compared pressure support and synchronized intermittent mandatory ventilation, both with targeted tidal volumes, (PSV+V, SIMV+V) to HFO. Animals underwent saline lavage to produce lung injury, received artificial surfactant and were randomized to one of the three treatment groups (each n=8). After injury and surfactant replacement, lung volumes were recruited in all groups using a standard protocol. Ventilation continued for 6 h.Measurements and main results Arterial and central venous pressures, heart rates, blood pressure and arterial blood gases were continuously monitored. At baseline, post lung injury and 6 h we collected serum and bronchoalveolar lavage samples for proinflammatory cytokines: IL 6, IL 8 and TNF-, and performed static pressure-volume (P/V) curves. Lungs were fixed for morphometrics and histopathologic analysis. No physiologic differences were found. Analysis of P/V curves showed higher opening pressures after lung injury in the HFO group compared to the SIMV+V group (p<0.05); no differences persisted after treatment. We saw no differences in change in proinflammatory cytokine levels. Histopathology and morphometrics were similar. Mean airway pressure (P_aw) was highest in the HFO group compared to SIMV+V (p<0.002).Conclusions Using a standardized lung recruitment strategy in spontaneously breathing animals, CV+V produced equivalent pathophysiologic outcomes without an increase in proinflammatory cytokines when compared to HFO.This study was supported in part by a grant from the Research and Education Fund of Childrens Hospitals and Clinics–St. Paul, Minnesota. Dräger Babylog supplied by Dräger Critical Care Systems, Survanta provided by Ross laboratories.