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Ventilator-associated lung injury
Abstract
Mechanical ventilation is indispensable in support of patients with respiratory failure who are critically ill. However, use of this technique has adverse effects, including increased risk of pneumonia, impaired cardiac performance, and difficulties associated with sedation and paralysis. Moreover, application of pressure to the lung, whether positive or negative, can cause damage known as ventilator-associated lung injury (VALI). Despite difficulties in distinguishing the effects of mechanical ventilation from those of the underlying disorder, VALI greatly assists patients with the most severe form of lung injury, acute respiratory distress syndrome (ARDS). Moreover, modification of mechanical ventilation so that VALI is kept to a minimum improves survival of patients with ARDS. Here, we outline the effects of mechanical ventilation on injured lungs and explore the underlying mechanisms.
... Patients with pulmonary parenchymal disease have reduced lung compliance and may require more aggressive ventilator settings than patients with ventilatory failure alone (32). PPV is not a benign process and the effects of VILI in pathological and pre-injured lung have been recognized in human medicine (71,72). ...
... Plateau pressures > 30 cmH 2 O, tidal volumes > 10 ml/kg and cyclic alveolar opening and closing are the main determinants of VILI in humans (71)(72)(73). Patients with pulmonary parenchymal disease are more susceptible to VILI due to heterogenous compliance of lung units predisposing to alveolar overdistension, biotrauma secondary to inflammation and decreased surfactant from alveolar flooding necessitating higher driving pressures (71,72). ...
... Plateau pressures > 30 cmH 2 O, tidal volumes > 10 ml/kg and cyclic alveolar opening and closing are the main determinants of VILI in humans (71)(72)(73). Patients with pulmonary parenchymal disease are more susceptible to VILI due to heterogenous compliance of lung units predisposing to alveolar overdistension, biotrauma secondary to inflammation and decreased surfactant from alveolar flooding necessitating higher driving pressures (71,72). ...
Respiratory failure from tick paralysis (TP) is an important cause of mortality in cats and dogs in Australia, occurring from a combination of respiratory muscle paralysis, upper respiratory tract obstruction and pulmonary disease. Patients may require positive-pressure ventilation in management of any combination of hypoxemia, hypoventilation or respiratory fatigue, but may also require airway management due to laryngeal paralysis. No single ventilation strategy is recommended due to the heterogenous disease presentations. Lung protective ventilation should be used in patients with pulmonary disease. Due to local and systemic effects of TP, patients are at higher risk of complications such as aspiration pneumonia and corneal ulceration and may have additional intravenous fluid and nutritional considerations. Treatment with hyperimmune serum is associated with improved outcomes. Prognosis is considered good with documented survival to discharge (STD) of 52.6-77% for animals with TP ventilated with lung disease and 90.5% for animals without lung disease. Median reported duration of ventilation for TP ranges from 23 to 48 h (range 3 h-10 days). The severity of individual neuromuscular signs and the presence of associated conditions such as aspiration pneumonia and laryngeal paralysis may necessitate longer periods of mechanical ventilation. This review aims to summarize the current recommendations regarding indications, management and prognosis of cats and dogs undergoing MV for TP and to identify areas for future research.
... Previous experimental results show that high PEEP levels counteract the adverse respiratory effects of IAH, including lung volumes, respiratory mechanics and oxygenation [8,11,13,20,21]. Furthermore, higher PEEP levels may reduce the risk of ventilation-induced lung injury by preventing cyclic collapsing and reopening of alveoli in the dependent lung regions of patients with IAH [22,23]. ...
... In contrast, we found the "best PEEP", defined as causing the smallest lung elastance [13], with 22 cmH 2 O (healthy and injured lungs) to be higher than the "optimal CT inflation PEEP range". Our results suggest that titrating a PEEP to respiratory mechanics or oxygenation in the presence of IAH is associated with increased alveolar overdistension, which itself increases the risk of ventilator-induced lung injury [18,22,24,40]. ...
... It remains debatable, whether patients with IAH in general may benefit from higher PEEP levels to reduce the risk of atelectotrauma and ventilator-induced lung injury remains unknown [3,19,22]. Experimental and human data suggest that the degree of alveolar overdistension may be a more significant contributor to the release of proinflammatory cytokines than the cyclic nature of the ventilatory pattern [24,40]. ...
Background
Intra-abdominal hypertension (IAH) is common in critically ill patients and is associated with increased morbidity and mortality. High positive end-expiratory pressures (PEEP) can reverse lung volume and oxygenation decline caused by IAH, but its impact on alveolar overdistension is less clear. We aimed to find a PEEP range that would be high enough to reduce atelectasis, while low enough to minimize alveolar overdistention in the presence of IAH and lung injury.
Methods
Five anesthetized pigs received standardized anesthesia and mechanical ventilation. Peritoneal insufflation of air was used to generate intra-abdominal pressure of 27 cmH 2 O. Lung injury was created by intravenous oleic acid. PEEP levels of 5, 12, 17, 22, and 27 cmH 2 O were applied. We performed computed tomography and measured arterial oxygen levels, respiratory mechanics, and cardiac output 5 min after each new PEEP level. The proportion of overdistended, normally aerated, poorly aerated, and non-aerated atelectatic lung tissue was calculated based on Hounsfield units.
Results
PEEP decreased the proportion of poorly aerated and atelectatic lung, while increasing normally aerated lung. Overdistension increased with each incremental increase in applied PEEP. “Best PEEP” (respiratory mechanics or oxygenation) was higher than the “optimal CT inflation PEEP range” (difference between lower inflection points of atelectatic and overdistended lung) in healthy and injured lungs.
Conclusions
Our findings in a large animal model suggest that titrating a PEEP to respiratory mechanics or oxygenation in the presence of IAH is associated with increased alveolar overdistension.
... Previous experimental results of our group show that high PEEP levels counteract the negative respiratory effects of IAH (8,11,15). However, high PEEP levels might cause alveolar over-distension in the non-dependent lung regions, which is associated with ventilatorinduced lung injury (13,16). ...
... In general, we were able to demonstrate that higher PEEP levels reversed the above changes induced by IAH. However, increasing PEEP also increased the proportion of overdistended lung in the ventral non-dependent lung segments, thereby increasing the risk of ventilator-induced lung injury (13,16). ...
... Whether patients with IAH and healthy lungs may benefit from higher PEEP levels to reduce the risk of atelectotrauma and ventilator-induced lung injury remains unknown (3,14,16). ...
Background
Intra-abdominal hypertension (IAH) is common in critically ill patients and is associated with increased morbidity and mortality. High positive end-expiratory pressures (PEEP) can reverse lung volume and oxygenation decline caused by IAH in the setting of injured lungs. The impact of high PEEP levels on alveolar overdistension in IAH and lung injury is unknown. We aimed to define an optimal PEEP range during IAH and lung injury that would be high enough to reduce atelectasis formation while low enough to minimize alveolar overdistention.
Methods
Five anesthetized pigs received standardized anesthesia and mechanical ventilation. Peritoneal insufflation of air was used to generate intra-abdominal pressure of 27cmH2O (20 mmHg). Lung injury was created by intravenous oleic acid. PEEP levels of 5, 12, 17, 22, and 27cmH2O were applied. We performed computed tomography and measured arterial oxygen levels, respiratory mechanics, and cardiac output 5 min after each new PEEP level. The proportion of overdistended, normally aerated, poorly aerated, and non-aerated atelectatic lung tissue was calculated based on Hounsfield units.
Results
PEEP decreased poorly aerated and atelectatic lung whilst increasing normally aerated lung. Overdistension increased with each incremental increase in applied PEEP.
Conclusions
Our findings in a large animal model suggest that an optimal PEEP level which maximally recruits atelectatic lung without causing overdistension or hemodynamic compromise may not exist.
... acute respiratory distress syndrome (ARDS). However, reasoned by the non-physiologic conditions, mechanical ventilation may lead to ventilator-induced lung injury (VILI) [86], respectively post-operative complications [87]. Both, general anesthesia and lung diseases are associated with atelectasis and therefore inhomogeneous lung tissue [88,89]. ...
... controlled expiration provides an improved homogeneity of pressure distribution compared to conventional ventilation modes with passive expiration.Both, during general anesthesia and especially in the presence of a lung disease, lung tissue shows a high inhomogeneity with compartments of different mechanical behavior causing different respiratory responses[86,91], i.e., time constants. Therefore, lung-protective mechanical ventilation during anesthesia as well as in critically ill patients remains a great challenge. ...
Mechanische Beatmung zählt zu den wichtigsten lebenserhaltenden Maßnahmen. Dennoch kann sie mit Komplikationen einhergehen. Deshalb steht die Entwicklung protektiver Beatmungsstrategien im Fokus wissenschaftlicher und medizinischer Forschung. Ein Ansatz setzt sich mit dem zeitlichen Verlauf der Exspiration auseinander. Die Exspiration erfolgt hierbei kontrolliert mit einem entschleunigtem Druckverlauf und reduzierten exspiratorischen Spitzenflüssen und nicht wie bei konventionellen Beatmungsmodi passiv, verbunden mit schnellen Druckabfällen und hohen Spitzenflüssen während der Exspiration. Im ersten Teil der Arbeit werden lungenprotektive Effekte verschiedener exspiratorischen Verläufe und die zu Grunde liegenden Mechanismen sowohl im Tiermodell als auch in physikalischen Modellen im Vergleich zu konventionellen Beatmungsmodi, untersucht. Es zeigte sich, dass die Oxygenierung, die CO2-Eliminierung und auch die Dehnfähigkeit der Lunge höher und der Score für inflammatorische Prozesse geringer bei der Beatmung mit kontrollierter Exspiration waren. Dies lässt sich neben einem höheren Mitteldruck und einem höheren mittleren Volumen, auch auf die höhere Homogenität der Beatmung mit kontrollierter Exspiration zurückführen.
Im zweiten Teil der Arbeit wird auf die Diaphragmadysfunktion, einer weiteren beatmungsassoziierten Komplikation, eingegangen. Diese „Schwächung“ des Diaphragmas kann bei Inaktivierung, wie z.B. bei längeren Operation unter Narkose auftreten. Im Kleintiermodell sind die Effekte von einer periodischen transkutanen elektromagnetischen Stimulation auf das Diaphragma im Vergleich zur konventionellen Beatmung ohne elektromagnetische Stimulation nach neun Stunden Beatmungszeit untersucht wurden. Es zeigte sich, dass durch die elektromagnetische Stimulation die Diaphragmakraft höher war und auch die Dicke des Diaphragmas größer war bei Tieren, die stimuliert wurden im Vergleich zu nicht-stimulierten Tieren.
Diese zwei Ansätze zeigen Strategien zur protektiven Beatmung von Lunge und Diaphragma auf und stellen zugleich die Grundlage für weitere Untersuchungen dar. Zudem wurden Mechanismen der protektiven Effekte bei der Beatmung mit kontrollierter Exspiration offengelegt. So könnten beatmungsassoziierte Komplikationen in Zukunft verringert werden.
... Gaining an in-depth understanding of the interplay between driving pressure and NAVA would have meaningful implications for those clinicians wishing to reduce the risk of ventilator-induced lung injury (VILI) during assisted IMV. VILI is highly dependent on the interaction between what is conveyed by the ventilator machine and the corresponding lung adaptation elicited in response to the ventilator action itself [8,9]. In this regard, being the ventilation a dynamic process, the role played by the respiratory rate in VILI determinism is equally important [10]. ...
... If, on the one hand, these computations refer to the elastic energy and power applied to the respiratory system, on the other hand they miss to account for the resistive component and the PEEP contribution. As a matter of fact, driving pressure and V T are pointed by clinical data as key variables for VILI [1,9]. Hence, here we can provide only a partial computation of the energy and power expenditure in our patients during assisted ventilation. ...
... Gaining an in-depth understanding of the interplay between driving pressure and NAVA would have meaningful implications for those clinicians wishing to reduce the risk of ventilator-induced lung injury (VILI) during assisted IMV. VILI is highly dependent on the interaction between what is conveyed by the ventilator machine and the corresponding lung adaptation elicited in response to the ventilator action itself [8,9]. In this regard, being the ventilation a dynamic process, the role played by the respiratory rate in VILI determinism is equally important [10]. ...
... If, on the one hand, these computations refer to the elastic energy and power applied to the respiratory system, on the other hand they miss to account for the resistive component and the PEEP contribution. As a matter of fact, driving pressure and V T are pointed by clinical data as key variables for VILI [1,9]. Hence, here we can provide only a partial computation of the energy and power expenditure in our patients during assisted ventilation. ...
Background:
Driving pressure can be readily measured during assisted modes of ventilation such as pressure support ventilation (PSV) and neurally adjusted ventilatory assist (NAVA). The present prospective randomized crossover study aimed to assess the changes in driving pressure in response to variations in the level of assistance delivered by PSV vs NAVA.
Methods:
16 intubated adult patients, recovering from hypoxemic acute respiratory failure (ARF) and undergoing assisted ventilation, were randomly subjected to six 30-min-lasting trials. At baseline, PSV (PSV100) was set with the same regulation present at patient enrollment. The corresponding level of NAVA (NAVA100) was set to match the same inspiratory peak of airway pressure obtained in PSV100. Therefore, the level of assistance was reduced and increased by 50% in both ventilatory modes (PSV50, NAVA50; PSV150, NAVA150). At the end of each trial, driving pressure obtained in response to four short (2-3 s) end-expiratory and end-inspiratory occlusions was analyzed.
Results:
Driving pressure at PSV50 (6.6 [6.1-7.8] cmH2O) was lower than that recorded at PSV100 (7.9 [7.2-9.1] cmH2O, P = 0.005) and PSV150 (9.9 [9.1-13.2] cmH2O, P < 0.0001). In NAVA, driving pressure at NAVA50 was reduced compared to NAVA150 (7.7 [5.1-8.1] cmH2O vs 8.3 [6.4-11.4] cmH2O, P = 0.013), whereas there were no changes between baseline and NAVA150 (8.5 [6.3-9.8] cmH2O vs 8.3 [6.4-11.4] cmH2O, P = 0.331, respectively). Driving pressure at PSV150 was higher than that observed in NAVA150 (P = 0.011).
Conclusions:
NAVA delivers better lung-protective ventilation compared to PSV in hypoxemic ARF patients.
Trial registration number and date of registration:
The present trial was prospectively registered at www.clinicatrials.gov (NCT03719365) on 24 October 2018.
... Use of mechanical ventilation in patients with pulmonary deficiencies may produce overdistension and injuries in lung epithelia because of excessive pressure [107]. Tas et al. [104,108] recently reported a lung-on-a-chip model that mimics a ventilator-induced lung injury. ...
Tissue engineering approaches, including those to functional lung tissues, are finely honed by the inclusion of upgraded devices that mimic biophysical and biochemical features in vivo. Perfusion culture is one of these essential biophysical characteristics enabled by the introduction of microfluidic devices in recent years. This review links the importance of dynamic culture for in vitro maintenance of functional lung cells to the modeling of respiratory disease. We identify and discuss different parameters for fabricating the requisite microfluidic models for lung cells, as well as their application in modeling lung diseases caused by external factors such as smoking and pollution. The possibility of creating a multi-organ-on-a-chip to establish a more physiologically relevant model is highlighted. Overall, the focus is on different prospects for the in vitro modeling approach and for lungs-on-a-chip for developing advanced, reliable technology to analyze the pathophysiology of respiratory diseases and screen potential treatments.Graphic abstract
... There is evidence that ECMO was applied differently during the COVID-19 pandemic. The longer period of mechanical ventilation prior to ECMO initiation raises concern that ventilator induced lung injury could be a contributing factor (25). Relatedly, prolonged use of noninvasive ventilation prior to endotracheal intubation has also been observed during the COVID-19 pandemic and has been associated with worse ECMO outcomes (26,27). ...
Unlabelled:
To compare complications and mortality between patients that required extracorporeal membrane oxygenation (ECMO) support for acute respiratory distress syndrome (ARDS) due to COVID-19 and non-COVID-19 viral pathogens.
Design:
Retrospective observational cohort study.
Setting:
Adult patients in the Extracorporeal Life Support Organization registry.
Patients:
Nine-thousand two-hundred ninety-one patients that required ECMO for viral mediated ARDS between January 2017 and December 2021.
Interventions:
None.
Measurements and main results:
The primary outcomes of interest were mortality during ECMO support and prior to hospital discharge. Time-to-event analysis and logistic regression were used to compare outcomes between the groups. Among 9,291 included patients, 1,155 required ECMO for non-COVID-19 viral ARDS and 8,136 required ECMO for ARDS due to COVID-19. Patients with COVID-19 had longer duration of ECMO (19.6 d [interquartile range (IQR), 10.1-34.0 d] vs 10.7 d [IQR, 6.3-19.7 d]; p < 0.001), higher mortality during ECMO support (44.4% vs 27.5%; p < 0.001), and higher in-hospital mortality (50.2% vs 34.5%; p < 0.001). Further, patients with COVID-19 were more likely to experience mechanical and clinical complications (membrane lung failure, pneumothorax, intracranial hemorrhage, and superimposed infection). After adjusting for pre-ECMO disease severity, patients with COVID-19 were more than two times as likely to die in the hospital compared with patients with non-COVID-19 viral ARDS.
Conclusions:
Patients with COVID-19 that require ECMO have longer duration of ECMO, more complications, and higher in-hospital mortality compared with patients with non-COVID-19-related viral ARDS. Further study in patients with COVID-19 is critical to identify the patient phenotype most likely to benefit from ECMO and to better define the role of ECMO in the management of this disease process.
... As mentioned above, in the case of IAH, alveolar collapse occurs at higher closing pressures during expiration. Existing lung injury may deteriorate due to increased atelectasis formation and atelectotrauma due to inadequate PEEP administration in IAH (21). Therefore, high PEEP levels may be necessary to keep lungs open. ...
... In the intensive care unit (ICU), intubation with mechanical ventilators necessarily saves the lives of critically ill patients immediately fighting for their lives and gaining extra time to treat and recover. However, clinical reports provide evidence that prolonged mechanical ventilation can lead to the impairment of diaphragmatic or lung function [1][2][3]. Similarly, respiratory failure requiring reintubation occurs in approximately 15-20% of patients after extubation [4]. Delayed extubation or reintubation tends to increase mortality risk in critically ill patients. ...
Predicting the correct timing for extubation is pivotal for critically ill patients with mechanical ventilation support. Evidence suggests that extubation failure occurs in approximately 15–20% of patients, despite their passing of the extubation evaluation, necessitating reintubation. For critically ill patients, reintubation invariably increases mortality risk and medical costs. The numerous parameters that have been proposed for extubation decision-making, which constitute the key predictors of successful extubation, remains unclear. In this study, an extended classifier system capable of processing real-value inputs was proposed to select features of successful extubation. In total, 40 features linked to clinical information and variables acquired during spontaneous breathing trial (SBT) were used as the environmental inputs. According to the number of “don’t care” rules in a population set, Probusage, the probability of the feature not being classified as above rules, can be calculated. A total of 228 subjects’ results showed that Probusage was higher than 90% for minute ventilation at the 1st, 30th, 60th, and 90th minutes; respiratory rate at the 90th minute; and body weight, indicating that the variance in respiratory parameters during an SBT are critical predictors of successful extubation. The present XCSR model is useful to evaluate critical factors of extubation outcomes. Additionally, the current findings suggest that SBT duration should exceed 90 min, and that clinicians should consider the variance in respiratory variables during an SBT before making extubation decisions.
... As a consequence, these individuals have a reduced functional tidal volume (Gattinoni et al., 1987) and heterogeneous lung emptying (Pelosi et al., 1996). Mechanical ventilation is often required to support oxygenation in ARDS (Henderson & Sheel, 2012;Pinhu et al., 2003). ...
Acute respiratory distress syndrome (ARDS) is a lung injury characterized by non-cardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypo-thermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in in-flammatory cytokines observed in the HI group compared to the I group. Changes
... As a consequence, these individuals have a reduced functional tidal volume (Gattinoni et al., 1987) and heterogeneous lung emptying (Pelosi et al., 1996). Mechanical ventilation is often required to support oxygenation in ARDS (Henderson & Sheel, 2012;Pinhu et al., 2003). ...
Acute respiratory distress syndrome (ARDS) is a lung injury characterized by noncardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in inflammatory cytokines observed in the HI group compared to the I group. Changes to respiratory system mechanics in the injured groups were due to increases in lung elastance (E) and resistance (R) (ΔE from pre-injury = 46 ± 14 cmH2 O L-1 , p < 0.0001; ΔR from pre-injury: 3 ± 2 cmH2 O L-1 s- , p = 0.30) rather than changes to the chest wall (ΔE from pre-injury: 0.7 ± 1.6 cmH2 O L-1 , p = 0.99; ΔR from pre-injury: 0.6 ± 0.1 cmH2 O L-1 s- , p = 0.01). Both control groups had no change in respiratory mechanics. In conclusion, therapeutic hypothermia can reduce markers of injury and inflammation associated with experimentally induced short-term ARDS.
... However, the use of this strategy can exacerbate or initiate lung injury, referred to as ventilator-associated lung injury (VALI) or ventilator-induced lung injury (VILI) (Gattinoni et al., 2010). VILI causes cell damage and inflammatory responses and VALI is an important component of ARDS mortality (Han et al., 2005;Pinhu et al., 2003;Curley et al., 2016). ...
Mechanical ventilation is an essential supportive therapy in the treatment of critical patients, and it aims to maintain adequate gas exchange; however, it can also contribute to inflammation and oxidative stress, thus leading to lung injury. We tested the hypothesis that exogenous surfactant administration will be protective against ventilator-induced lung injury in adult healthy Wistar rats both because of its anti-inflammatory properties as well as its role in preventing alveolar collapse at end-expiration. Thus, the effect of intranasal instillation of a bovine exogenous surfactant was tested in Wistar rats submitted to mechanical ventilation. The animals were divided into four groups: (1) CONTROL; (2) SURFACTANT; (3) Mechanical ventilation (MV); (4) MV with pre-treatment with surfactant (MVSURFACTANT). The MV and MVSURFACTANT were submitted to MV with high tidal volume (12 mL/kg) for 1 h. After the experimental protocol, all animals were euthanized and the arterial blood, bronchoalveolar lavage fluid and lungs were collected for biochemical, immunoenzymatic assay, arterial blood gases, and morphometric analyzes. The Wistar rats that received exogenous surfactant (Survanta®) by intranasal instillation before MV demonstrated reduced levels of leukocytes, inflammatory biomarkers such as CCL2, IL-1, IL-6 and TNF-α. Furthermore, it prevented oxidative damage by reducing lipid peroxidation and protein carbonylation as well as histological pattern changes of pulmonary parenchyma. Our data indicate that exogenous surfactant attenuated lung inflammation and redox imbalance induced by mechanical ventilation in healthy adult rats suggesting a preventive effect on ventilator-induced lung injury.
... 11,12 Such patients may require IMV, which is linked to a wide variety of complications and a high mortality rate. 7,13,14 Regardless of whether or not IMV is used, the need for it can be a sign of more serious acute disease. In this part of the world, however, no prospective studies have been performed on the predictive factors and outcomes have not been well investigated among patients with SCAP who are in respiratory failure. ...
Objectives: To explore the risk factors, pathogens and outcomes of severe community-acquired pneumonia (SCAP) in patients with respiratory failure. Methods: A prospective observational study was conducted at Northwest General Hospital & Research Centre, Peshawar, Pakistan from February 2016 to October 2018. All patients with Community-acquired pneumonia (CAP) who fulfilled the inclusion criteria were recorded consecutively. Diagnosis of SCAP was made following the criteria established by the IDSA/ATS in the consensus guidelines on the management of CAP in adults published in 2007. In-hospital mortality was the main outcome. Results: The final analysis comprised a total of 100 patients with SCAP. The mean age was 60.0±18.01 years, and 54.0% were female patients. Afghani patients represented 22.0% of the total patients. The most common comorbidity associated with SCAP was hypertension (42.0%). The most commonly isolated etiological agents were Acinetobacter baumannii, followed by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. In-hospital mortality was 45%. On multivariate analysis, factors associated with in-hospital mortality were age (OR 1.054; 95%Cl 1.01-1.10; p=0.021), presence of two
or more complications (OR 4.51; 95%Cl 1.18-17.28; p=0.028), septic shock (OR 6.44; 95%Cl 1.55-26.803;p=0.010), length of mechanical ventilation (OR 1.17; 95%Cl 1.01-1.40; p=0.043), and paO2(OR 4.51; 95%Cl 1.18-17.28; p=0.004). Conclusion: A high mortality rate was observed in our study. Age, presence of two or more complications, septic shock, length of mechanical ventilation, and low paO2 were identified to be independent predictors of mortality for patients with SCAP.
... In these patients, flow limitation and air trapping result from caliber reductions of small airways in response to high local flow rates. 18 Flow-controlled expiration (FLEX) ventilation is a new procedure that modulates the otherwise passive expiration phase. By reducing the initial highexpiratory peak flow to a more linear flow, it causes an expiratory gas flow to persist throughout the complete expiratory phase. ...
Objective:
Mechanical ventilation is usually achieved by active lung inflation during inspiration and passive lung emptying during expiration. By contrast, flow-controlled expiration (FLEX) ventilation actively reduces the rate of lung emptying by causing linear gas flow throughout the expiratory phase. Our aim was to evaluate the effects of FLEX on lung compliance and gas exchange in anesthetized horses in dorsal recumbency.
Animals:
8 healthy horses.
Procedures:
All animals were anesthetized twice and either ventilated beginning with FLEX or conventional volume-controlled ventilation in a randomized, crossover design. Total anesthesia time was 3 hours, with the ventilatory mode being changed after 1.5 hours. During anesthesia, cardiac output (thermodilution), mean arterial blood pressures, central venous pressure, and pulmonary arterial pressure were recorded. Further, peak, plateau, and mean airway pressures and dynamic lung compliance (Cdyn) were measured. Arterial blood gases were analyzed every 15 minutes. Data were analyzed using ANOVA (P < 0.05).
Results:
FLEX ventilation resulted in significantly higher arterial oxygen partial pressures (521 vs 227 mm Hg) and Cdyn (564 vs 431 mL/cm H2O) values compared to volume-controlled ventilation. The peak and plateau airway pressure were lower, but mean airway pressure was significantly higher (4.8 vs 9.2 cm H2O) in FLEX ventilated horses. No difference for cardiovascular parameters were detected.
Clinical relevance:
The results of this study showed a significant improvement of the Pao2 and Cdyn without compromising the cardiovascular system when horses were ventilated by use of FLEX compared to conventional ventilation.
... The disease is characterised by massive pulmonary inflammation, alterations in surfactant homeostasis and ventilation/perfusion mismatching leading to severe hypoxemia and multiple organ dysfunction [2]. Mechanical ventilation (MV) has added significantly to the survival of PARDS patients but also induces a pulmonary inflammation (biotrauma) that aggravates pre-existing lung injury (double-hit), a concept known as ventilator-induced lung injury (VILI) [3][4][5]. ...
Background
Paediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe, life-threatening lung injury necessitating mechanical ventilation with mortality rates ranging up to 40–50%. Neuromuscular blockade agents (NMBAs) may be considered to prevent patient self-inflicted lung injury in PARDS patients, but two trials in adults with severe ARDS yielded conflicting results. To date, randomised controlled trials (RCT) examining the effectiveness and efficacy of NMBAs for PARDS are lacking. We hypothesise that using NMBAs for 48 h in paediatric patients younger than 5 years of age with early moderate-to-severe PARDS will lead to at least a 20% reduction in cumulative respiratory morbidity score 12 months after discharge from the paediatric intensive care unit (PICU).
Methods
This is a phase IV, multicentre, randomised, double-blind, placebo-controlled trial performed in level-3 PICUs in the Netherlands. Eligible for inclusion are children younger than 5 years of age requiring invasive mechanical ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H 2 O for moderate-to-severe PARDS occurring within the first 96 h of PICU admission. Patients are randomised to continuous infusion of rocuronium bromide or placebo for 48 h. The primary endpoint is the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out, day-care and parental smoking. Secondary outcomes include respiratory mechanics, oxygenation and ventilation metrics, pulmonary and systemic inflammation markers, prevalence of critical illness polyneuropathy and myopathy and metrics for patient outcome including ventilator free days at day 28, length of PICU and hospital stay, and mortality
Discussion
This is the first paediatric trial evaluating the effects of muscular paralysis in moderate-to-severe PARDS. The proposed study addresses a huge research gap identified by the Paediatric Acute Lung Injury Consensus Collaborative by evaluating practical needs regarding the treatment of PARDS. Paediatric critical care practitioners are inclined to use interventions such as NMBAs in the most critically ill. This liberal use must be weighed against potential side effects. The proposed study will provide much needed scientific support in the decision-making to start NMBAs in moderate-to-severe PARDS.
Trial registration
ClinicalTrials.gov NCT02902055 . Registered on September 15, 2016.
... Indeed, MV has been associated with greater risk of kidney failure [9], and diminished neurocognitive function in the brain [10]. Pinhu et al. [11] suggested two possible mechanisms through which MV induces multiple organ failure that are related to VAP and lung injuries that reduce the rate of organ perfusion. Better understanding of the pathophysiology leading to the development of MODS in patients on MV should help in the development of approaches to interrupt the cascades leading to the syndrome [8]. ...
Background
Mechanical ventilation (MV) is a lifesaving therapy used for patients with respiratory failure. Nevertheless, MV is associated with numerous complications and increased mortality. The aim of this study is to define the effects of MV on gene expression of direct and peripheral human tissues.
Methods
Classification models were applied to Genotype-Tissue Expression Project (GTEx) gene expression data of six representative tissues– liver, adipose, skin, nerve-tibial, muscle and lung, for performance comparison and feature analysis. We utilized 18 prediction models using the Random Forest (RF), XGBoost (eXtreme Gradient Boosting) decision tree and ANN (Artificial Neural Network) methods to classify ventilation and non-ventilation samples and to compare their prediction performance for the six tissues. In the model comparison, the AUC (area under receiver operating curve), accuracy, precision, recall, and F1 score were used to evaluate the predictive performance of each model. We then conducted feature analysis per each tissue to detect MV marker genes followed by pathway enrichment analysis for these genes.
Results
XGBoost outperformed the other methods and predicted samples had undergone MV with an average accuracy for the six tissues of 0.951 and average AUC of 0.945. The feature analysis detected a combination of MV marker genes per each tested tissue, some common across several tissues. MV marker genes were mainly related to inflammation and fibrosis as well as cell development and movement regulation. The MV marker genes were significantly enriched in inflammatory and viral pathways.
Conclusion
The XGBoost method demonstrated clear enhanced performance and feature analysis compared to the other models. XGBoost was helpful in detecting the tissue-specific marker genes for identifying transcriptomic changes related to MV. Our results show that MV is associated with reduced development and movement in the tissues and higher inflammation and injury not only in direct tissues such as the lungs but also in peripheral tissues and thus should be carefully considered before being implemented.
... The respiratory failure may occur if too early to remove the artificial airway support. However, prolonged mechanical ventilation also results in diaphragmatic or lung function impairment [1][2][3]. The previous evidence reported that approximately 15% to 20% of patients would occur respiratory failure after extubation and need reintubation. ...
Mechanical ventilation is necessary to maintain patients' life in intensive care units. However, too early or too late extubation may injure the muscles or lead to respiratory failure. Therefore, the spontaneous breathing trial (SBT) is applied for testing whether the patients can spontaneously breathe or not. However, previous evidence still reported 15%~20% of the rate of extubation fail. The monitor only considers the ventilation variables during SBT. Therefore, this study measures the asynchronization between thoracic and abdomen wall movement (TWM and AWM) by using instantaneous phase difference method (IPD) during SBT for 120 minutes. The respiratory inductive plethysmography were used for TWM and AWM measurement. The preliminary result recruited 31 signals for further analysis. The result showed that in successful extubation group can be classified into two groups, IPD increase group, and IPD decrease group; but in extubation fail group, the IPD value only increase. Therefore, the IPD decrease group can almost perfectly be discriminated with extubation fail group, especially after 70 minutes (Area under curve of operating characteristic curve was 1). These results showed IPD is an important key factor to find whether the patient is suitable for extubation or not. These finding suggest that the asynchronization between TWM and AWM should be considered as a predictor of extubation outcome. In future work, we plan to recruit 150 subjects to validate the result of this preliminary result. In addition, advanced machine learning method is considered to apply for building effective models to discriminate the IPD increase group and extubation fail group.Clinical Relevance- The finding of this study is that the patients whose average IPD of 95 to 100 minutes was smaller than average IPD of first 5 minutes of SBT could be 100% successful extubation. In addition, ability of discrimination of average IPD after 70 minutes presents AUC 1.
... In recent years, 2D electrical impedance tomography (EIT) has emerged as a modality capable of fast, non-ionizing, and non-invasive functional bedside imaging for patients undergoing mechanical ventilation. While mechanical ventilation is an important life-saving intervention for patients experiencing respiratory failure, it may result in ventilator-associated lung injury and other complications which are detrimental to patient outcomes [22,46]. The ability to quickly assess changes in regional ventilation distribution, lung volume, and other dynamic respiratory processes in the ICU setting is therefore highly desirable, and 2D EIT shows great potential for use in these and other pulmonary imaging and monitoring applications. ...
For patients undergoing mechanical ventilation due to respiratory failure, 2D electrical impedance tomography (EIT) is emerging as a means to provide functional monitoring of pulmonary processes. In EIT, electrical current is applied to the body, and the internal conductivity distribution is reconstructed based on subsequent voltage measurements. However, EIT images are known to often suffer from large systematic artifacts arising from various limitations and exacerbated by the ill-posedness of the inverse problem. The direct D-bar reconstruction method admits a nonlinear Fourier analysis of the EIT problem, providing the ability to process and filter reconstructions in the nonphysical frequency regime. In this work, a technique is introduced for automated Fourier-domain filtering of known systematic artifacts in 2D D-bar reconstructions. The new method is validated using three numerically simulated static thoracic datasets with induced artifacts, plus two experimental dynamic human ventilation datasets containing systematic artifacts. Application of the method is shown to significantly reduce the appearance of artifacts and improve the shape of the lung regions in all datasets.
... • Beatmungsassoziierte Lungenschädigung [35,36] • Beatmungsinduzierte Zwerchfelldysfunktion [37][38][39] • Sauerstofftoxizität [40][41][42] Bereits nach zwei bis drei Tagen [67,68]. ...
Hintergrund der vorliegenden Arbeit war die Erforschung der Ursachen für die im Tiermodel des akuten Lungenversagens unter der mechanischen Beatmung beobachteten lungenprotektiven Effekte der kontrollierten Exspiration. In einer Vorstudie an einem physikalischen Lungenmodell mit voneinander unabhängigen Kompartimenten konnte gezeigt werden, dass die kontrollierte Exspiration zu einem homogeneren Druckabfall in Arealen mit heterogenen mechanischen Eigenschaften führt.
In dieser Arbeit sollte untersucht werden, ob eine solche Homogenisierung auch im atemmechanischen Modell des gesamten respiratorischen Systems, also der funktionellen Einheit aus inhomogenen Lungenkompartimenten und gemeinsamem Brustkorb, zu finden ist.
Daher wurde ein geeignetes physikalisches Modell entwickelt und Druck- und Flussmessungen unter der mechanischen Beatmung mit passiver und kontrollierter Exspiration durchgeführt. Anhand von Atem-Zeit-Kurven wurde die Atemmechanik des Modells charakterisiert und zur Beurteilung der exspiratorischen Druckverteilung wurden Homogenitätsindikatoren bestimmt.
Es konnten vier Lungenkompartimente mit jeweils unterschiedlichen Zeitkonstanten simuliert werden, deren Compliances sich bei Parallelschaltung additiv verhielten. Unter Reihenschaltung der Lungen- und Thoraxcompliance war die Gesamtcompliance geringer als die isolierte Lungencompliance und es zeigten sich Effekte der Volumenkonkurrenz zwischen den Lungenkompartimenten. Die Kontrolle der Exspiration führte durch Begrenzung des Spitzenflusses zu einem linearisierten Druckabfall. Im Vergleich zur passiven Exspiration waren Druckdifferenzen zwischen verschiedenen Kompartimenten des Modells während der Exspiration erheblich reduziert. Zudem ergaben sich höhere Mitteldrücke bei geringeren Differenzen der Mitteldrücke verschiedener Kompartimente.
Zusammenfassend führte die kontrollierte Exspiration bei inhomogener Atemmechanik zu einer Homogenisierung der exspiratorischen Druckverteilung. Dieser Mechanismus könnte im akuten Lungenversagen eine Reduktion intrapulmonaler Scherkräfte bewirken und damit eine beatmungsinduzierte Lungenschädigung attenuieren.
... As a consequence, these individuals have a reduced functional tidal volume (Gattinoni et al., 1987) and heterogeneous lung emptying (Pelosi et al., 1996). Mechanical ventilation is often required to support oxygenation in ARDS (Henderson & Sheel, 2012;Pinhu et al., 2003). ...
... Invasive MV is associated with high rates of serious complications and mortality. 12 To avoid invasive mechanical ventilation associated complications, NIV has been used for acute respiratory failure. The most important rationale for using NIV is to overcome an episode of severe ARF without the need for MV. ...
BACKGROUND Community-Acquired Pneumonia (CAP) is defined as “an acute infection of the pulmonary parenchyma. The most important complication of CAP is Acute Respiratory Failure (ARF) and some of them may require Invasive Mechanical Ventilation (IMV) to manage hypoxia and hypoventilation along with appropriate antibiotic therapy. A number of studies, however, indicate that IMV is associated with high rates of serious complications and mortality in patients with ARF. For this reason Non-Invasive Ventilation (NIV) has been used for ARF of diverse aetiologies.The most important rationale for using NIV in early stages of respiratory failure is to decrease the workload on respiratory muscles and improve ventilation by applying positive airway pressure. This may help to overcome an episode of severe ARF without the need for MV. In this study we evaluated the efficacy of NIV in patients with ARF and compare the outcome of using NIV in CAP with ARF patients with and without comorbidities. METHODS This prospective observational study was done on 150 CAP patients in acute respiratory failure who received NIV. It was conducted in the Department of Respiratory Medicine in Gandhi Hospital, Secunderabad, for a period of one year and six months. A comparative analysis of the outcome of using NIV in CAP with ARF patients with and without co-morbidities was carried out. RESULTS In the current study 150 CAP patients with ARF who needed NIV, were treated initially with NIV, antibiotic therapy and other supportive measures as per the American Thoracic Society (ATS) guidelines 32. 95 (63.3 %) of 150 patients were continuously treated with NIV. Apart from these, 55 (36.7 %) patients required MV. In patients with continued NIV, 93 (98 %) recovered, remaining 2 died with sudden cardiac arrest. In patients who were gone for MV, 12 (22 %) survived. CONCLUSIONS Early intervention by NIV in CAP patients suffering from acute respiratory failure secondary to community acquired pneumonia was found to be successful in avoiding mechanical ventilation and its attendant morbidity and mortality31. Early intervention with NIV, identifying risk factors for NIV failure, addressing associated co-morbid conditions will go in a long way in effectively managing these patients by significantly minimizing the ICU and hospital stay. Patients with co-morbidities have more chances of NIV failures. Patients with co morbidities on NIV stayed significantly more number of days in the hospital than patients without co-morbidities. The current study suggests that co morbid patients require more monitoring as compared to patients without co morbidities on NIV. KEY WORDS Community-Acquired Pneumonia (CAP), Non-Invasive Ventilation (NIV), Mechanical Ventilation (MV), Acute Respiratory Failure (ARF), Arterial Blood Gas Analysis (ABG), Intensive Care Unit (ICU), Intubation
... Consistent with previous studies [19,20], we reported that the intraoperative bleeding volume of MIE group was significantly lower than OE group, because of the clearer operative vision on vascular anatomy due to the magnifying effect thoracoscope. The incidence of postoperative pneumonia in MIE group patients was lower than OE group in both our study and previous studies [19,20], due to the use of single-lumen endotracheal intubation which could decrease lung edema induced by prolonged one-lung ventilation with positive end-expiratory pressure [21][22][23]. Otherwise, the less pain and less effect on chest wall and diaphragm in MIE group could alleviate symptoms of postoperative pneumonia by the less effect on cough and expectoration after MIE. ...
This study investigates whether minimally invasive esophagectomy (MIE) is a safe and effective way for patients with resectable esophageal cancer by comparing the short-term quality of life (QOL) after minimally invasive esophagectomy and open esophagectomy (OE). A total number of 104 patients who underwent esophagectomy from January 2013 to March 2014 were enrolled in this study. These patients were divided into two groups (MIE and OE group). Three scoring scales of quality of life were used to evaluate QOL before the operation and at the first, third, sixth and twelfth months after MIE or OE, which consist of Karnofshy performance scale (KPS), the European Organization for Research and Treatment questionnaire QLQC-30 (EORTC QLQC-30) and esophageal cancer supplement scale (OES-18). The MIE group was higher than the OE group in one-year survival rate (92.54% vs. 72.00%). Significant differences between the two groups were observed in intraoperative bleeding volume (158.53 ± 91.07 mL vs. 228.97 ± 109.33 mL, p = 0.001), and the incidence of postoperative pneumonia (33.33% vs. 58.62%, p = 0.018). The KPS of MIE group was significantly higher than the OE group at the first (80 vs. 70, p = 0.004 < 0.05), third (90 vs. 80, p = 0.006 < 0.05), sixth (90 vs. 80, p = 0.007 < 0.05) and twelfth months (90 vs. 80, p = 0.004 < 0.05) after surgery. The QLQC-30 score of MIE group was better than OE group at first and twelfth months after the operation. The OES-18 score of MIE group was significantly better than OE group at first, sixth and twelfth months after surgery. The short-term quality of life in MIE group was better than OE group.
... При угрожающей жизни ОДН, а также в случаях несостоятельности функций нескольких органов и систем ИВЛ остается основным методом интенсивной терапии. Однако его применение может стать причиной как легочных, так и внелегочных осложнений [11]. ...
Introduction. In patients with spontaneous breathing and respiratory failure, various methods of delivering the gas mixture to the respiratory tract have been developed. The use of high-flow oxygen therapy is alternative standard oxygen therapy. Objectives. Experimental study of the effects of high-flow oxygen therapy and evaluation of its clinical effectiveness in comparison with traditional oxygen therapy in patients with severe community-acquired pneumonia. Materials and methods. During the experimental stage of the study, the level of mean airway pressure was determined depending on the flow of the gas mixture using a lung model with parameters of biomechanics of respiration. During the clinical stage, a comparative analysis of the effectiveness of respiratory support in groups of patients with severe community-acquired pneumonia using high-flow and traditional oxygen therapy was carried out. Results. During experimental study, flow of gas mixture 30 l/min was determined, at which mean airway pressure registered on models of healthy lungs and lungs with modified respiratory biomechanics significantly increases. During the clinical phase of the study, a statistically significant decrease in the frequency of initiation of artificial (invasive and non-invasive) lung ventilation, an increase in oxygenation (saturation hemoglobin with oxygen, partial pressure oxygen in arterial blood) and partial pressure carbon dioxide with simultaneous decrease in respiratory rate. Conclusion. The value of gas flow over 30 l/min has significant effect on the recorded mean airway pressure calculated using models of lungs in experiment. However, clinical significance of this indicator is not clinically significant. The use of high-flow oxygen therapy in patients with severe community-acquired pneumonia in comparison with standard method reduces the frequency use of ventilation (invasive and non-invasive) with a significant increase in oxygenation indicators. This reduces hyperventilation, which is confirmed by a significant increase in partial pressure carbon dioxide and a decrease in respiratory rate.
... Cellular pathology includes physical disruption of cells and tissues and activation of cytotoxic responses. Leucocytes are raised to likely interact with the endothelium as the increasing intra-alveolar pressure fastens the transit time of them [83]. Inferences for current medical practices involve lung-protective ventilation. ...
Lung injury is characterized by inflammatory processes demonstrated as loss of function of the pulmonary capillary endothelial and alveolar epithelial cells. Autophagy is an intracellular digestion system that work as an inducible adaptive response to lung injury which is a resultant of exposure to various stress agents like hypoxia, ischemia-reperfusion and xenobiotics which may be manifested as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic lung injury (CLI), bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), asthma, ventilator-induced lung injury (VILI), ventilator-associated lung injury (VALI), pulmonary fibrosis (PF), cystic fibrosis (CF) and radiation-induced lung injury (RILI). Numerous regulators like LC3B-II, Beclin 1, p62, HIF1/BNIP3 and mTOR play pivotal role in autophagy induction during lung injury possibly for progression/inhibition of the disease state. The present review focuses on the critical autophagic mediators and their potential cross talk with the lung injury pathophysiology thereby bringing to limelight the possible therapeutic interventions.
... Inflammation is also a major risk factor for POD [10][11][12]. Mechanical ventilation can cause ventilator-associated lung injury, which can promote the release of inflammatory factors in the lungs and throughout the body [13][14][15]. Because respiratory function and lung compliance are generally reduced in elderly patients, mechanical ventilation under general anesthesia is more likely to cause lung injury such as barotraumas and induce peripheral inflammatory responses. ...
Background
Postoperative delirium (POD) is a frequent complication in elderly patients, usually occurring within a few days after surgery. This study investigated the effect of lung-protective ventilation (LPV) on POD in elderly patients undergoing spinal surgery and the mechanism by which LPV suppresses POD.
Material/Methods
Seventy-one patients aged ≥65 years were randomized to receive LPV or conventional mechanical ventilation (MV), consisting of intermittent positive pressure ventilation following induction of anesthesia. The tidal volume in patients who received MV was 8 ml/kg predicted body weight (PBW), and the ventilation frequency was 12 times/min. The tidal volume in patients who received LPV was 6 ml/kg PBW, the positive end-expiratory pressure was 5 cmH2O, and the ventilation frequency was 15 times/min, with a lung recruitment maneuver performed every 30 min. Blood samples were collected immediately before anesthesia induction (T0), 10 min (T1) and 60 min (T2) after turning over, immediately after the operation (T3), and 15 min after extubation (T4) for blood gas analysis. Simultaneous cerebral oxygen saturation (rSO2) and cerebral desaturation were recorded. Preoperative and postoperative serum concentrations of interleukin (IL)-6, IL-10 and glial fibrillary acidic protein (GFAP) were measured by ELISA. POD was assessed by nursing delirium screening score.
Results
Compared with the MV group, pH was lower and PaCO2 higher in the LPV group at T2. In addition PaO2, SaO2, and PaO2/FiO2 were higher at T1, and T4, and rSO2 was higher at T3, and T4 in the LPV than in the MV group (P<0.05 each). Postoperative serum GFAP and IL-6 were lower and IL-10 higher in the LPV group. The incidences of cerebral desaturation and POD were significantly lower in the LPV group (P<0.05).
Conclusions
LPV may reduce POD in elderly patients undergoing spinal surgery by inhibiting inflammation and improving cerebral oxygen metabolism.
... In patients with severe hypoxemia, particularly those with acute respiratory distress syndrome (ARDS), the loss of alveolar ventilation capacity due to alveolar consolidation, edema and/or collapse contributes to the need for ventilatory support [3]. The discovery that high tidal and minute ventilation strategies can cause harm-termed "ventilator-induced lung injury" (VILI ) [4][5][6]-has led to the use of lung "protective" ventilation (LPV) strategies, where low tidal volumes (4-8 mL/kg of per body weight [PBW ] [7] versus 10-15 mL/kg of PBW in conventional mechanical ventilation [MV ] [6]) decrease lung stretch, reduce VILI [8], and can potentially improve survival and reduce mortality in patients with acute lung injury and ARDS [6,9]. Amato et al. showed that lower driving pressure was the physical variable that best correlated with survival in patients with ARDS [10]; higher positive end-expiratory pressure (PEEP), lower peak and plateau pressures, and lower respiratory rate, may also be associated with improved survival [11,12]. ...
Background:
Invasive mechanical ventilation is lifesaving in the setting of severe acute respiratory failure but can cause ventilation-induced lung injury. Advances in extracorporeal CO2 removal (ECCO2R) technologies may facilitate more protective lung ventilation in acute respiratory distress syndrome, and enable earlier weaning and/or avoid invasive mechanical ventilation entirely in chronic obstructive pulmonary disease exacerbations. We evaluated the in vitro CO2 removal capacity of the novel PrismaLung+ ECCO2R device compared with two existing gas exchangers.
Methods:
The in vitro CO2 removal capacity of the PrismaLung+ (surface area 0.8 m2, Baxter) was compared with the PrismaLung (surface area 0.35 m2, Baxter) and A.L.ONE (surface area 1.35 m2, Eurosets) devices, using a closed-loop bovine blood-perfused extracorporeal circuit. The efficacy of each device was measured at varying pCO2 inlet (pinCO2) levels (45, 60, and 80 mmHg) and blood flow rates (QB) of 200-450 mL/min; the PrismaLung+ and A.L.ONE devices were also tested at a QB of 600 mL/min. The amount of CO2 removed by each device was assessed by measurement of the CO2 infused to maintain circuit equilibrium (CO2 infusion method) and compared with measured CO2 concentrations in the inlet and outlet of the CO2 removal device (blood gas analysis method).
Results:
The PrismaLung+ device performed similarly to the A.L.ONE device, with both devices demonstrating CO2 removal rates ~ 50% greater than the PrismaLung device. CO2 removal rates were 73 ± 4.0, 44 ± 2.5, and 72 ± 1.9 mL/min, for PrismaLung+, PrismaLung, and A.L.ONE, respectively, at QB 300 mL/min and pinCO2 45 mmHg. A Bland-Altman plot demonstrated that the CO2 infusion method was comparable to the blood gas analysis method for calculating CO2 removal. The resistance to blood flow across the test device, as measured by pressure drop, varied as a function of blood flow rate, and was greatest for PrismaLung and lowest for the A.L.ONE device.
Conclusions:
The newly developed PrismaLung+ performed more effectively than PrismaLung, with performance of CO2 removal comparable to A.L.ONE at the flow rates tested, despite the smaller membrane surface area of PrismaLung+ versus A.L.ONE. Clinical testing of PrismaLung+ is warranted to further characterize its performance.
... The relationship between mechanical ventilation and lung injury has long been known, 150 and the favorable effect on clinically relevant outcomes, including mortality, of lung-protective ventilation strategies involving the use of low tidal volume (V T ) and moderate-to-high levels of positive end-expiratory pressure (PEEP), with or without recruitment maneuvers, is well-documented in the ICU setting, particularly in patients with ARDS. 100 More recently, data are accumulating in support of intraoperative lung-protective ventilation strategies to reduce the risk of pulmonary complications after both cardiac and noncardiac surgery. 151,152 Despite the lack of clear evidence in this regard in the specific setting of cardiac surgery, intraoperative lung-protective ventilation strategies are widely adopted during cardiac procedures. ...
Despite the improvements in surgical techniques and perioperative care, cardiac surgery is still burdened by relatively high mortality and frequent major postoperative complications, including myocardial dysfunction, pulmonary complications, neurologic injury, and acute kidney injury. Although the surgeon's skills and volume as well as patient-related and procedure-related risk factors play a major role in the success of cardiac surgery, there is growing evidence that also optimizing perioperative care may significantly improve outcomes. In this review, we focus on those aspects of perioperative care which are strictly related to the anesthesia regimen, with special reference to volatile anesthetics and neuraxial anesthesia, whose impact on outcome in adult cardiac surgery has been extensively investigated.
Brain dysfunction during critical illness (ie, delirium and coma) is extremely common, and its lasting effect has only become increasingly understood in the last two decades. Brain dysfunction in the intensive care unit (ICU) is an independent predictor of both increased mortality and long-term impairments in cognition among survivors. As critical care medicine has grown, important insights regarding brain dysfunction in the ICU have shaped our practice including the importance of light sedation and the avoidance of deliriogenic drugs such as benzodiazepines. Best practices are now strategically incorporated in targeted bundles of care like the ICU Liberation Campaign's ABCDEF Bundle.
Zu den Kernthemen der Intensivmedizin gehören die maschinelle Beatmung und das Weaning. Die maschinelle Beatmung mit positivem Atemwegsdruck dient der Übernahme oder Unterstützung der Ventilation und der Aufrechterhaltung eines ausreichenden pulmonalen Gasaustauschs bei der akuten respiratorischen Insuffizienz. Bei physiologischer Atmung wird von der Atemmuskulatur ein negativer Druckgradient aufgebaut, dem entlang inspiratorisch Gas in die Lungen fließt. Bei der Beatmung resultiert demgegenüber der inspiratorische Druckgradient aus einem positiven Atemwegsdruck. Die Umkehrung der intrathorakalen Druckverhältnisse hat zahlreiche pathophysiologische Konsequenzen. Dementsprechend ist mit der maschinellen Beatmung ein Überwachungsaufwand verbunden, der lediglich auf einer Intensivstation gewährleistet werden kann.
Objectives:
Major observational studies report that the mortality rate of acute respiratory distress syndrome (ARDS) is close to 40%. Different treatment strategies are required for each patient, according to the degree of ARDS. Early prediction of ARDS is helpful to implement targeted drug therapy and mechanical ventilation strategies for patients with different degrees of potential ARDS. In this paper, a new dynamic prediction machine learning model for ARDS incidence and severity is established and evaluated based on 28 parameters from ordinary monitors and ventilators, capable of dynamic prediction of the incidence and severity of ARDS. This new method is expected to meet the clinical practice requirements of user-friendliness and timeliness for wider application.
Methods:
A total of 4738 hospitalized patients who required ICU care from 159 hospitals are employed in this study. The models are trained by standardized data from electronic medical records. There are 28 structured, continuous non-invasive parameters that are recorded every hour. Seven machine learning models using only continuous, non-invasive parameters are developed for dynamic prediction and compared with methods trained by complete parameters and the traditional risk adjustment method (i.e., oxygenation saturation index method).
Results:
The optimal prediction performance (area under the curve) of the ARDS incidence and severity prediction models built using continuous noninvasive parameters reached0.8691 and 0.7765, respectively. In terms of mild and severe ARDS prediction, the AUC values are both above 0.85. The performance of the model using only continuous non-invasive parameters have an AUC of 0.0133 lower, in comparison with that employing a complete feature set, including continuous non-invasive parameters, demographic information, laboratory parameters and clinical natural language text.
Conclusions:
A machine learning method was developed in this study using only continuous non-invasive parameters for ARDS incidence and severity prediction. Because the continuous non-invasive parameters can be easily obtained from ordinary monitors and ventilators, the method presented in this study is friendly and convenient to use. It is expected to be applied in pre-hospital setting for early ARDS warning.
The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P–P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.
Purpose
In the COVID-19 outbreak periods, people's life has been deranged, leading to disrupt the world. Firstly, the number of deaths is growing and has the potential to surpass the highest level at any time. Secondly, the pandemic broke many countries' fortified lines of epidemic prevention and gave people a more honest view of its seriousness. Finally, the pandemic has an impact on life, and the economy led to a shortage in medical, including a lack of clinicians, facilities and medical equipment. One of those, a simple ventilator is a necessary piece of medical equipment since it might be useful for a COVID-19 patient's treatment. In some cases, the COVID-19 patients require to be treated by modern ventilators to reduce lung damage. Therefore, the addition of simple ventilators is a necessity to relieve high work pressure on medical bureaucracies. Some low-income countries aim to build a simple ventilator for primary care and palliative care using locally accessible and low-cost components. One of the simple principles for producing airflow is to squeeze an artificial manual breathing unit (AMBU) iterative with grippers, which imitates the motion of human fingers. Unfortunately, the squeezing angle of grippers is not proportional to the exhaust air volume from the AMBU bag. This paper aims to model the AMBU bag by a mathematical equation that enables to implement on a simple controller to operate a bag-valve-mask (BVM) ventilator with high accuracy performance.
Design/methodology/approach
This paper provides a curvature function to estimate the air volume exhausting from the AMBU bag. Since the determination of the curvature function is sophisticated, the coefficients of the curvature function are approximated by a quadratic function through the experimental identification method. To obtain the high accuracy performance, a linear regression model and a least square method are employed to investigate the characteristic of the BVM ventilator's grippers angle with respect to the airflow volume produced by the AMBU bag.
Findings
This paper investigates the correlation between the exhausting airflow of the AMBU bag and the grippers angle of the BVM ventilator.
Originality/value
The experimental results validated that the regression model of the characteristic of the exhausting airflow of the AMBU bag with respect to the grippers' angle has been fitted with a coefficient over 98% within the range of 350–750 ml.
Objective: High stretch (strain >10%) can alter the biomechanical behaviors of airway smooth muscle cells which may play important roles in diverse lung diseases such as asthma and ventilator-induced lung injury. However, the underlying modulation mechanisms for high stretch-induced mechanobiological responses in ASMCs are not fully understood. Here, we hypothesize that ASMCs respond to high stretch with increased expression of specific microRNAs (miRNAs) that may in turn modulate the biomechanical behaviors of the cells. Thus, this study aimed to identify the miRNA in cultured ASMCs that is most responsive to high stretch, and subsequently investigate in these cells whether the miRNA expression level is associated with the modulation of cell biomechanics.
Methods: MiRNAs related to inflammatory airway diseases were obtained via bioinformatics data mining, and then tested with cultured ASMCs for their expression variations in response to a cyclic high stretch (13% strain) simulating in vivo ventilator-imposed strain on airways. Subsequently, we transfected cultured ASMCs with mimics and inhibitors of the miRNA that is most responsive to the high stretch, followed by evaluation of the cells in terms of morphology, stiffness, traction force, and mRNA expression of cytoskeleton/focal adhesion-related molecules.
Results: 29 miRNAs were identified to be related to inflammatory airway diseases, among which let-7a-5p was the most responsive to high stretch. Transfection of cultured human ASMCs with let-7a-5p mimics or inhibitors led to an increase or decrease in aspect ratio, stiffness, traction force, migration, stress fiber distribution, mRNA expression of α -smooth muscle actin (SMA), myosin light chain kinase, some subfamily members of integrin and talin. Direct binding between let-7a-5p and ItgαV was also verified in classical model cell line by using dual-luciferase assays.
Conclusion: We demonstrated that high stretch indeed enhanced the expression of let-7a-5p in ASMCs, which in turn led to changes in the cells’ morphology and biomechanical behaviors together with modulation of molecules associated with cytoskeletal structure and focal adhesion. These findings suggest that let-7a-5p regulation is an alternative mechanism for high stretch-induced effect on mechanobiology of ASMCs, which may contribute to understanding the pathogenesis of high stretch-related lung diseases.
Background
Mechanical ventilation (MV) is a lifesaving therapy used for patients with respiratory failure. Nevertheless, MV is associated with numerous complications and increased mortality. The aim of this study is to define the effects of MV on gene expression of direct and peripheral human tissues.
Methods
Classification models were applied to Genotype-Tissue Expression Project (GTEx) gene expression data of six representative tissues–liver, adipose, skin, nerve-tibial, muscle and lung, for performance comparison and feature analysis. We utilized 18 prediction models using the Random Forest (RF), XGBoost (eXtreme Gradient Boosting) decision tree and ANN (Artificial Neural Network) methods to classify ventilation and non-ventilation samples and to compare their prediction performance for the six tissues. In the model comparison, the AUC (area under receiver operating curve), accuracy, precision, recall, and F1 score were used to evaluate the predictive performance of each model. We then conducted feature analysis per each tissue to detect MV marker genes followed by pathway enrichment analysis for these genes.
Results
XGBoost outperformed the other methods and predicted samples had undergone MV with an average accuracy for the six tissues of 0.951 and average AUC of 0.945. The feature analysis detected a combination of MV marker genes per each tested tissue, some common across several tissues. MV marker genes were mainly related to inflammation and fibrosis as well as cell development and movement regulation. The MV marker genes were significantly enriched in inflammatory and viral pathways.
Conclusion
The XGBoost method demonstrated clear enhanced performance and feature analysis compared to the other models. XGBoost was helpful in detecting the tissue-specific marker genes for identifying transcriptomic changes related to MV. Our results show that MV is associated with reduced development and movement in the tissues and higher inflammation and injury not only in direct tissues such as the lungs but also in peripheral tissues and thus should be carefully considered before being implemented.
Objective:
Flow-controlled expiration (FLEX) has been shown to attenuate ventilator induced lung injury in animal models. It has also shown to homogenize compartmental pressure distribution in a physical model of the inhomogeneous respiratory system having independent compartments. We hypothesized that the homogenizing effects of FLEX are also effective in this regard when the independence of compartments is suspended by simulated chest wall compliance.
Approach:
A four compartment physical model of the respiratory system having chest wall compliance (137 ml/cmH2O) was developed. Two of the four compartments had high compliance (18 ml/cmH2O) and two had low compliance (10 ml/cmH2O). These compartments were each combined with either high (6.8 cmH2O·s/l) or low resistance (3.5 cmH2O·s/l). The model was ventilated in the volume-controlled ventilation (VCV) mode with either passive expiration or with FLEX. The maximal pressure differences (ΔPmax) and the maximal differences of mean pressure (ΔPmean) between the compartments during expiration were determined.
Main results:
With passive expiration ΔPmax reached up to 3.4 ± 0.03 cmH2O but only 0.9 ± 0.01 cmH2O with FLEX (p < 0.001). Maximal differences of ΔPmean were significantly lower with FLEX as compared to passive expiration (extending up to 0.4 ± 0.04 cmH2O vs. 2.0 ± 0.15 cmH2O, p < 0.001).
Significance:
The homogenizing effects of FLEX on compartmental pressure distribution could be reproduced in a more complex physical model of the inhomogeneous respiratory system having chest wall compliance and might be a mechanism underlying the lung protective effects of ventilation with FLEX.
Background
Children with CHD carry an additional burden of pulmonary insufficiency, often necessitating prolonged ventilatory support, especially in the peri-operative phase. There has been an increase in the utilisation of non-invasive ventilatory support for these children. The objective of this study was to evaluate the utilisation, safety, and outcomes of RAM cannula as a tool for escalation and de-escalation of respiratory support in paediatric cardiac patients less than one year of age.
Methods
A single-centre retrospective cohort study of patients supported with RAM cannula.
Results
A total of 275 instances of RAM use were included in the study, 81.1% being post-operative. Patients were stratified into escalation and de-escalation cohorts based on the indication of non-invasive ventilation. The success rate of using RAM cannula was 69.5% overall, 66.1% in the escalation group, and 72.8% in the de-escalation group. At baseline, age at cardiac ICU admission >30 days, FiO2 ≤ 40%, PaCO2 ≤ 50 mmHg; and after 12 hours of non-invasive ventilation support respiratory rate ≤ 60/min, PaO2 ≥ 50 mmHg, PaCO2 ≤ 50 mmHg; and absence of worsening on follow-up chest X-ray predicted the success with a sensitivity of 95% in the logistic regression model. Successful support was associated with a significantly shorter unit stay.
Conclusions
RAM cannula can be safely used to provide non-invasive support to infants in the cardiac ICU for escalation and de-escalation of respiratory support. Factors associated with success can be used to make decisions about candidacy and appropriate timing of non-invasive ventilation use to maximise effectiveness.
Objectives:
Negative pressure ventilation may be more physiologic than positive pressure ventilation, but data describing negative pressure ventilation use in the PICU are limited. We aimed to describe the epidemiology and outcomes of PICU patients receiving negative pressure ventilation.
Design:
Descriptive analysis of a large, quality-controlled multicenter database.
Setting:
Fifty-six PICUs in the Virtual Pediatric Systems database who reported use of negative pressure ventilation.
Patients:
Children admitted to a participating PICU between 2009 and 2019 who received negative pressure ventilation.
Interventions:
None.
Measurements and main results:
Among 788 subjects, 71% were less than 2 years old, and 45% had underlying health conditions. Two concurrent aspiration events were the only adverse events reported. After excluding one over-represented center, the 3 years with the most negative pressure ventilation usage were 2017-2019 (all > 25 cases/yr and ≥ 13 centers reporting usage). Among those 187 children, the most common primary diagnoses were bronchiolitis and cardiac disease (both 15.5%), 24.1% required endotracheal intubation after negative pressure ventilation, and 9.1% died.
Conclusions:
Negative pressure ventilation is being used in many PICUs, most commonly for pulmonary infections or cardiac disease, in children with high rates of subsequent intubation and mortality and with few documented adverse events. Use at individual centers is rare but increasing, suggesting need for prospective collaboration to better evaluate the role of negative pressure ventilation in the PICU.
Introduction:
Coronavirus disease-19 (COVID-19) is a new type of epidemic pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The population is generally susceptible to COVID-19, which mainly causes lung injury. Some cases may develop severe acute respiratory distress syndrome (ARDS). Currently, ARDS treatment is mainly mechanical ventilation, but mechanical ventilation often causes ventilator-induced lung injury (VILI) accompanied by hypercapnia in 14% of patients. Extracorporeal carbon dioxide removal (ECCO2R) can remove carbon dioxide from the blood of patients with ARDS, correct the respiratory acidosis, reduce the tidal volume and airway pressure, and reduce the incidence of VILI.
Case report:
Two patients with critical COVID-19 combined with multiple organ failure undertook mechanical ventilation and suffered from hypercapnia. ECCO2R, combined with continuous renal replacement therapy (CRRT), was conducted concomitantly. In both cases (No. 1 and 2), the tidal volume and positive end-expiratory pressure (PEEP) were down-regulated before the treatment and at 1.5 hours, one day, three days, five days, eight days, and ten days after the treatment, together with a noticeable decrease in PCO2 and clear increase in PO2, while FiO2 decreased to approximately 40%. In case No 2, compared with the condition before treatment, the PCO2 decreased significantly with down-regulation in the tidal volume and PEEP and improvement in the pulmonary edema and ARDS after the treatment.
Conclusion:
ECCO2R combined with continuous blood purification therapy in patients with COVID-19 who are criti-cally ill and have ARDS and hypercapnia might gain both time and opportunity in the treatment, down-regulate the ventilator parameters, reduce the incidence of VILI and achieve favorable therapeutic outcomes.
Près de la moitié des patients ventilés artificiellement en réanimation présentent un inconfort respiratoire (ou dyspnée). Les difficultés de communication entre patients et soignants rendent complexes l’évaluation et la prise en charge de cette dyspnée. L’objectif de ce travail était de développer des interfaces cerveau-ordinateur (BCI) permettant d’aider les soignants à détecter la dyspnée sous ventilation mécanique (VM) en réanimation. Dans l’étude DYSVENT, des patients dyspnéiques sous VM en réanimation ont été inclus. Un électroencéphalogramme (EEG) était enregistré à l’état basal puis après optimisation des réglages du respirateur à la recherche d’un potentiel pré-inspiratoire (PPI) signe d’une activité corticale liée à la ventilation (ACLV), habituellement absente au cours de la ventilation spontanée. Dans l’étude DYSPEV, deux BCI basées sur des potentiels évoqués visuels en régime permanent (PEVRP) ont été testés chez des volontaires sains : une BCI de détection de la dyspnée (D-BCI) et une BCI de quantification prenant la forme d’une échelle visuelle analogique (EVA) virtuelle (LAS). Les volontaires sains ont été étudiés sous diverses conditions respiratoires : ventilation spontanée (VS), charge inspiratoire à seuil (ITL) et résistive (IRL), inhalation de CO2 (CO2) et retour en VS (VSWO). Différentes fréquences ont été testées pour les stimulus visuels : 12/15Hz, 15/20Hz et 20/30Hz pour la D-BCI et basses fréquences (13, 17, 19, 23 et 29 Hz) et hautes fréquences (41,43,47, 53 et 59 Hz) pour la LAS. Dans l’étude DYSVENT, les patients inclus (n = 47) présentaient un inconfort respiratoire dans 73% à 89% des cas selon la méthode d’évaluation utilisée (EVA ou score d’hétéro-évaluation IC-RDOS ou RDOS). L’optimisation de la ventilation a permis d’améliorer cet inconfort de manière significative. A l’état basal, 38% des patients présentaient un PPI contre 19% après la phase d’optimisation des réglages du respirateur (p < 10-4). Dans l’étude DYSPEV, les volontaires sains inclus (n = 50) présentaient un inconfort respiratoire lors des conditions IRL, ITL et CO2 dans le groupe D-BCI (30 sujets) et lors des conditions ITL et CO2 dans le groupe LAS (20 sujets, condition ITL non testée dans ce groupe) avec des EVA significativement plus élevées comparativement à la VS. Pour la D-BCI, le meilleur réglage de fréquence était 20-30Hz avec une AUC à 0.89 (IC95 [0.80-0.90]) et les basses fréquences pour la LAS avec une AUC à 0.84 (IC95 [0.83-0.85]). Dans l’étude DYSVENT, la détection d’une ACLV était insuffisante pour mettre en évidence des situations à risque d’inconfort respiratoire sous ventilation mécanique. L’étude DYSPEV a permis de faire la preuve de concept chez le volontaire sain de la détection et la quantification d’une dyspnée expérimentale à l’aide d’une BCI basée sur les PEVRP. Une BCI globale combinant ces 2 techniques pourrait être développée pour assister les soignants au quotidien dans la reconnaissance et la prise de l’inconfort respiratoire sous VM en réanimation.
Drugs tested on animal models do not always produce the same results in humans; a reliable in vitro lung model can bridge the divide between the two. Because the alveolus is a target for several drugs, an alveolar model can be a platform for both designing drugs and studying lung diseases. A model should allow for gas exchange, growth of primary alveolar epithelial cells, extracellular matrix production, and have similar mechanical properties to alveoli, creating an environment conducive to normal metabolic activity and cellular responses. Existing artificial alveolar models that use polymeric membranes to sustain lung cells are limited by the necessary strain profile and the ability to maintain primary human alveolar cells. We are engineering an alveolus-on-a-chip device that simulates complex functional human alveoli, including the thin microporous alveolar barrier and the three-dimensional cyclic stretch induced by breathing movements. The design of this platform is optimized for robust fabrication, ease in cell culture manipulation, fluidic management and stretch activity. Furthermore, we are investigating two main types of primary alveolar cells culture in the alveoli which truly mimic the alveolar population. Our results suggest a use of this artificial alveolus in the development of an effective platform for rapid drug screening and pulmonary disease research.
Many chapters in this book on severe traumatic brain injury (TBI) deal with the monitoring of the injured brain. Although there are controversies surrounding the use of many of the available monitoring tools, most neurosurgeons and neurointensivists argue for invasive monitoring including intracranial (ICP) and cerebral perfusion pressures (CPP). Furthermore, continuous sedation is a standard therapy for endotracheal tube tolerance, ICP control, and stress reduction. The use of repeated neurological evaluations—wake-up tests—for clinical monitoring is highly controversial, since sedation must be interrupted, which potentially leads to increased ICP and may elicit a stress response. In this chapter, the scarce evidence for the use of NWTs in TBI management is summarized, providing the reader with arguments for and against their use. It is concluded that while the NWT (Neurological Wake-up Test) provides an excellent clinical monitoring tool, it also results in increased ICP and CPP as well as elicits a biochemical stress response. Its use should be individualized and the test applied with caution, carefully evaluating the response of the patient.
Purpose of review:
We briefly review post-intensive care syndrome (PICS) and the morbidities associated with critical illness that led to the intensive care unit (ICU) liberation movement. We review each element of the ICU liberation bundle, including pediatric support data, as well as tips and strategies for implementation in a pediatric ICU (PICU) setting.
Recent findings:
Numerous studies have found children have cognitive, physical, and psychiatric deficits after a PICU stay. The effects of the full ICU liberation bundle in children have not been published, but in adults, bundle implementation (even partial) resulted in significant improvement in survival, mechanical ventilation use, coma, delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition.
Summary:
Although initially described in adults, children also suffer from PICS. The ICU liberation bundle is feasible in children and may ameliorate the effects of a PICU stay. Further studies are needed to characterize the benefits of the ICU liberation bundle in children.
We have previously shown that mechanical strain-induced fetal rat lung cell proliferation is transduced via the phospholipase C--protein kinase C pathway. In the present study, we found that protein-tyrosine kinase activity of fetal lung cells increased after a short period of strain, which was accompanied by tyrosine phosphorylation of proteins of 110-130 kDa. Several components of this complex were identified as pp60substrates. Strain increased pp60 activity in the cytoskeletal fraction, which coincided with a shift in subcellular distribution of pp60 from the Triton-soluble to the cytoskeletal fraction. Strain-induced pp60 translocation did not appear to be mediated via the focal adhesion kinase-paxillin pathway. In contrast, strain increased the association between pp60 and the actin filament-associated protein of 110 kDa. Preincubation of cells with herbimycin A, a tyrosine kinase inhibitor, abolished strain-induced phospholipase C-1 tyrosine phosphorylation and its coimmunoprecipitation with pp60. It also inhibited strain-induced DNA synthesis. These results suggest that activation of pp60 is an upstream event of the phospholipase C--protein kinase C pathway that may represent an important mechanism by which mechanical perturbations are converted to biological reactions in fetal lung cells.
This study was carried out to discriminate between two alternative hypotheses as to how cells sense mechanical forces and transduce them into changes in gene transcription. Do cells sense mechanical signals through generalized membrane distortion1,2 or through specific transmembrane receptors, such as integrins3? Here we show that mechanical stresses applied to the cell surface alter the cyclic AMP signalling cascade and downstream gene transcription by modulating local release of signals generated by activated integrin receptors in a G-protein-dependent manner, whereas distortion of integrins in the absence of receptor occupancy has no effect.
{BACKGROUND: Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. METHODS: Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. RESULTS: The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent
The objective of this study was to determine whether the permeability characteristics of the nuclear envelope vary during different phases of cellular activity. Both passive diffusion and signal-mediated transport across the envelope were analyzed during the HeLa cell cycle, and also in dividing, confluent (growth-arrested), and differentiated 3T3-L1 cultures. Colloidal gold stabilized with BSA was used to study diffusion, whereas transport was investigated using gold particles coated with nucleoplasmin, a karyophilic Xenopus oocyte protein. The gold tracers were microinjected into the cytoplasm, and subsequently localized within the cells by electron microscopy. The rates of diffusion in HeLa cells were greatest during the first and fifth hours after the onset of anaphase. These results correlate directly with the known rates of pore formation, suggesting that pores are more permeable during or just after reformation. Signal-mediated transport in HeLa cells occurs through channels that are located within the pore complexes and have functional diameters up to 230-250 A. Unlike diffusion, no significant differences in transport were observed during different phases of the cell cycle. A comparison of dividing and confluent 3T3-L1 cultures revealed highly significant differences in the transport of nucleoplasmin-gold across the envelope. The nuclei of dividing cells not only incorporated larger particles (230 A versus 190 A in diameter, including the protein coat), but the relative uptake of the tracer was about seven times greater than that in growth-arrested cells. Differentiation of confluent cells to adipocytes was accompanied by an increase in the maximum diameter of the transport channel to approximately 230 A.
The respective roles of high pressure and high tidal volume to promote high airway pressure pulmonary edema are unclear. Positive end-expiratory pressure (PEEP) was shown to reduce lung water content in this type of edema, but its possible effects on cellular lesions were not documented. We compared the consequences of normal tidal volume ventilation in mechanically ventilated rats at a high airway pressure (HiP-LoV) with those of high tidal volume ventilation at a high (HiP-HiV) or low (LoP-HiV) airway pressure and the effects of PEEP (10 cm H2O) on both edema and lung ultrastructure. Pulmonary edema was assessed by extravascular lung water content and microvascular permeability by the drug lung weight and the distribution space of 125I-labeled albumin. HiP-LoV rat lungs were not different from those of controls (7 cm H2O peak pressure ventilation). By contrast, the lungs from the groups submitted to high volume ventilation had significant permeability type edema. This edema was more pronounced in LoP-HiV rats. It was markedly reduced by PEEP, which, in addition, preserved the normal ultrastructural aspect of the alveolar epithelium. This was in striking contrast to the diffuse alveolar damage usually encountered in this type of edema. To our knowledge, this constitutes the first example of a protective effect of PEEP during permeability edema.
To investigate the relationship between lung anatomy and pulmonary mechanics in acute respiratory failure (ARF), 20 patients with ARF underwent computerized tomography (CT) at 3 levels of positive end-expiratory pressure (PEEP) (5, 10, and 15 cm H2O). The static pressure-volume curve of the total respiratory system and the lung volumes (helium dilution method) were also measured. By knowing the lung volumes and analyzing the CT number frequency distribution, a quantitative estimate of normally aerated, poorly aerated, and nonaerated lung tissue was obtained at each level of PEEP. The recruitment was defined as the percent increase of normally aerated tissue from 5 to 15 cm H2O. We found that the different compliances (starting compliance, inflation compliance, and deflation compliance) were correlated only with the amount of normally aerated tissue present in the range of pressures explored by a given compliance (5 cm H2O for starting compliance and 15 cm H2O for inflation and deflation compliances). No relationship was found between the compliances and the poorly aerated and nonaerated tissue. The specific compliance was in the normal range, whereas the amount of recruitment was related to the ratio of inflation compliance to starting compliance. Our data suggest that (1) the pressure-volume curve parameters in ARF investigate only the residual healthy zones of the lung and do not directly estimate the "amount" of disease (poorly or nonaerated tissue), (2) the pressure-volume curve may allow an estimate of the anatomic recruitment, and (3) the residual normally aerated zones of the ARF lung seem to maintain a normal intrinsic elasticity.
Lung lav age was performed in 16 anaesthetized rabbits to produce surfactant-deficient lungs. This resulted in alveolar collapse,
an arterial Po2 of less than 15kPa on 100% oxygen and an inflection point on the inspirator/ limb of the pressure-volume curve at an airway
pressure of 8–10 mm Hg. One group of eight animals was then ventilated with a positive end-expiratory pressure (PEEP) equal
to the pressure at the inflection point, whilst the second group of eight was ventilated with a PEEP 5 mm Hg less than the
inflection point. Animals in the high PEEP group had a significantly greater arterial P02 than those in the low PEEP group,
but the mean survival time for each group was similar. However, there was a significantly greater incidence of hyaline membranes
in the low PEEP group. Various mechanisms to explain these findings are discussed.
Mechanical ventilation may promote overdistension-induced pulmonary lesions in patients with acute respiratory distress syndrome (ARDS). The static pressure-volume (P-V) curve of the respiratory system can be used to determine the lung volume and corresponding static airway pressure at which lung compliance begins to diminish (the upper inflection point, or UIP). This fall in compliance may indicate overdistension of lung units. We prospectively studied 42 patients receiving mechanical ventilation with an FIO2 of 0.5 or more for at least 24 h. According to the Lung Injury Score (LIS), 25 patients were classified as having ARDS (LIS > 2.5), while 17 patients constituted a non-ARDS control group. The P-V curve was obtained every 2 d. Mechanical ventilation initially used standard settings (volume-control mode, a positive end-expiratory pressure [PEEP] adjusted to the lower inflection point on the P-V curve, and a tidal volume [VT] of 10 ml/kg). The end-inspiratory plateau pressure (Pplat) was compared to the UIP, and VT was lowered when the Pplat was above the UIP. In the range of lung volume studied on the P-V curves (up to 1600 ml), a UIP could be shown in only one control patient (at 23 cm H2O). By contrast, a UIP was present on the P-V curve obtained from all patients with ARDS, corresponding to a mean airway pressure of 26 +/- 6 cm H2O, a lung volume of 850 +/- 200 ml above functional residual capacity and 610 +/- 235 ml above PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)
Intermittent positive pressure ventilation with large tidal volumes and high peak airway pressures can result in pulmonary barotrauma. In the present study, we examined the hypothesis that ventilation at very low lung volumes can also worsen lung injury by repeated opening and closing of airway and alveolar duct units as ventilation occurs from below to above the infection point (Pinf) as determined from the inspiratory pressure-volume curve. We ventilated isolated, nonperfused, lavaged rat lungs with physiologic tidal volumes (5 to 6 ml/kg) at different end-expiratory pressures (above and below Pinf) and studied the effect on compliance and lung injury. In the groups ventilated with positive end-expiratory pressure (PEEP) below Pinf compliance fell dramatically after ventilation. It did not change in either the control group or the group ventilated with PEEP above Pinf. Lung injury assessed morphologically was significantly greater in the groups ventilated with a PEEP below Pinf, and in these groups the site of injury was dependent on the level of PEEP. The group ventilated without PEEP had significantly greater respiratory and membranous injury to bronchioles, while the group ventilated with PEEP of 4 cm H2O had significantly greater alveolar duct injury. In conclusion, ventilation at lung volumes below those found at Pinf caused a significant decrease in lung compliance and progression of lung injury. Therefore, in addition to high airway pressures, end-expiratory lung volume is an important determinant of the degree and site of lung injury during positive-pressure ventilation.
Integrins are cell adhesion receptors that mediate cell-extracellular matrix and cell-cell interactions. Each integrin consists of two glycoprotein subunits (alpha and beta). We have previously described a novel integrin beta-subunit, beta 6, which is expressed in cultured epithelial cells. beta 6 can associate with alpha v to form the fibronectin-binding heterodimer alpha v beta 6. Here we report the tissue distribution of beta 6 integrin mRNA determined by in situ hybridization of a beta 6 cRNA probe with representative frozen tissue sections from a rhesus monkey tissue bank. We detected beta 6 mRNA exclusively in epithelial cells. However, beta 6 mRNA expression varied greatly among different epithelia. High levels of beta 6 mRNA were found only in two very specialized epithelial cell types: a portion of the kidney tubule epithelium, termed macula densa, and the endometrial epithelium of secretory phase uterus. In the endometrium, beta 6 expression was highest in the differentiated epithelium of functional layer glands, suggesting that beta 6 expression can be regulated in a differentiation-dependent manner. beta 6 expression may also depend on the stage in the estrous cycle, since we found much lower beta 6 mRNA levels in a specimen of proliferative phase endometrium. Epithelium in several other tissues, including salivary gland ducts, gall bladder, and epididymis, contained detectable levels of beta 6 mRNA, albeit much lower than in macula densa and endometrium. In other epithelia, including skin and lung, beta 6 mRNA was undetectable. Taken together, these results suggest that in normal adult primates beta 6 expression is regulated in a cell type-specific manner, restricted to a few epithelial tissues.
The type II alveolar epithelial cell has important metabolic and biosynthetic functions but also serves as the stem cell of the alveolar epithelium. Much of the evidence underlying this premise was obtained before 1980 and provided the basis for a working model that has not been reconsidered for more than fifteen years. With the exceptions to be discussed below, little evidence has accumulated in the interim to suggest that the model requires significant alteration. Important questions remain unanswered, however, and some components of the model need to be supplemented, particularly in light of recent investigations that have provided insights not possible in earlier work. In particular, in vitro studies have suggested that the relationship between the parent type II cell and its progeny may not be as straightforward as originally thought. In addition, the rate of epithelial cell loss was recognized long ago to be an important factor in the regulation of this system, but its kinetics and mechanisms have received little attention. These and other unresolved issues are critical to our understanding of the homeostasis of the alveolar epithelium under normal and pathological conditions.
Deformation of the alveolar epithelial basement membrane with lung inflation has been implicated in blood-gas barrier breakdown during the development of ventilator-induced lung injury. To determine the vulnerability of alveolar epithelial cells to deformation-induced injury, we developed a cell-stretching device that subjects cells to cyclic, equibiaxial strains. Alveolar epithelial type II cells from primary culture were tested 1 and 5 days after seeding, during which time the cells underwent major morphological and phenotypic changes. Cells were subjected to changes in surface area of 12, 24, 37, and 50%, which corresponded to lung inflation of similar to 60, 80, 100, and >100% of total lung capacity. Deformation-induced injury of alveolar epithelial cells, assessed with a fluorescent cell viability assay, increased with deformation magnitude and decreased with time elapsed after seeding. In cells stretched after 1 day in culture, the percentage of dead cells after a single deformation ranged from 0.5 to 72% over the range of deformations used. In cells stretched at 5 days, the percentage of dead cells ranged from 0 to 9% when exposed to identical deformation protocols. These results suggest that morphological and phenotypic changes with time in culture fundamentally change the vulnerability of alveolar epithelial cells to deformation.
Ventilator-induced lung injury in children and adults is characterized by an initial inflammatory phase. To investigate whether the inflammatory cytokine, IL-I, plays a role in this process, a rabbit model of ventilator-induced injury was created. Animals maintained under pentobarbital anesthesia were primed for injury by undergoing lung lavage with 22 mL/kg of saline and then ventilated for 8 h with either F102 0.21 and normal pressures or F102 1.0 and high ventilator pressures. The animals exposed to hyperoxial/hyperventilation demonstrated a greater increase in lung lavage neutrophil counts and a higher histological injury score, as well as a faster decline in oxygenation compared to the control animals. A third group of rabbits 800 μg of recombinant IL-1 receptor antagonist after lung lavage and prior to the exposure to F102 1.0 and high ventilator pressures. These animals had significantly lower concentrations of albumin and elastase and lower neutrophil counts in their lungs after the 8-h ventilatory period compared to hyperoxia/hyperventilation rabbits. IL-1 blockade had no effect on the decline in dynamic compliance and oxygenation seen in saline-treated hyperoxic/ hyperventilated rabbits. IL-1 is a mediator of acute inflammation due to ventilator-induced lung injury.
immune system, as could be the case in the patient with end-stage renal failure implicated in the Amoy Gardens outbreak and another with renal failure at the centre of an outbreak in Singapore. Subclinical infections may also occur and will not be recognisable until reliable diagnostic tests are available. Procedures causing high risk to medical personnel include nasopharyngeal aspiration, bronchoscopy, endotracheal intubation, airway suction, cardiopulmonary resuscitation, and non-invasive ventilation procedures. Cleaning the patient and the bedding after faecal incontinence also appears to be a high-risk procedure. Treatments have been empirical. Initial patients were given broad-spectrum antibiotics but, after failing to respond for 2 days, were given ribavirin and corticosteroids. Patients who continued to deteriorate with progression of chest radiographic changes or oxygen desaturation, or both, were given pulsed methylprednisolone. 1 Steroids were used on the rationale that progression of the pulmonary disease may be mediated by the host inflammatory response, similar to that seen in acute respiratory distress syndrome, and produced by a cytokine or chemokine "storm". The clinical impression is that pulsed steroids sometimes produce a dramatic response. However, apparent benefits of steroid treatment have proven to be incorrect before, as in infection with respiratory syncytial virus. 12 Lack of knowledge of SARS' natural history adds to the difficulty of determining the effectiveness of therapy. Some patients have a protracted clinical course with potential for relapses continuing into the second or third week, or beyond. Long hospital stays, even in less ill patients, are required, and the high proportion of patients requiring lengthy intensive care, with or without ventilation (23% in the 138 cases from
Transforming growth factor β (TGF β) family members are secreted in inactive complexes with a latency-associated peptide (LAP), a protein derived from the N-terminal region of the TGF β gene product. Extracellular activation of these complexes is a critical but incompletely understood step in regulation of TGF β function in vivo. We show that TGF β 1 LAP is a ligand for the integrin α vβ 6 and that α vβ 6-expressing cells induce spatially restricted activation of TGF β 1. This finding explains why mice lacking this integrin develop exaggerated inflammation and, as we show, are protected from pulmonary fibrosis. These data identify a novel mechanism for locally regulating TGF β 1 function in vivo by regulating expression of the α vβ 6 integrin.
Mechanical stresses are important environmental cues for both normal cellular functions and pathophysiological changes in conditions such as cardiac hypertrophy and atherosclerosis. There is increasing evidence that mechanotransduction processes in response to mechanical stresses share many common features with processes in cell adhesion, such as an increase in tyrosine phosphorylation of proteins in the focal adhesion sites. Recent findings suggest that integrins may function as mechanotransducers in cells.
To determine the initial signaling event in the vascular permeability increase after high airway pressure injury, we compared groups of lungs ventilated at different peak inflation pressures (PIPs) with (gadolinium group) and without (control group) infusion of 20 microM gadolinium chloride, an inhibitor of endothelial stretch-activated cation channels. Microvascular permeability was assessed by using the capillary filtration coefficient (Kfc), a measure of capillary hydraulic conductivity. Kfc was measured after ventilation for 30-min periods with 7, 20, and 30 cmH2O PIP with 3 cmH2O positive end-expiratory pressure and with 35 cmH2O PIP with 8 cmH2O positive end-expiratory pressure. In control lungs, Kfc increased significantly to 1.8 and 3.7 times baseline after 30 and 35 cmH2O PIP, respectively. In the gadolinium group, Kfc was unchanged from baseline (0.060 +/- 0.010 ml . min-1 . cmH2O-1 . 100 g-1) after any PIP ventilation period. Pulmonary vascular resistance increased significantly from baseline in both groups before the last Kfc measurement but was not different between groups. These results suggest that microvascular permeability is actively modulated by a cellular response to mechanical injury and that stretch-activated cation channels may initiate this response through increases in intracellular calcium concentration.
We previously showed that when pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to test whether stress failure occurred more frequently at high than at low lung volumes for the same Ptm. Lungs of anesthetized rabbits were inflated to a transpulmonary pressure of 20 cmH2O, perfused with autologous blood at 32.5 or 2.5 cmH2O Ptm, and fixed by intravascular perfusion. Samples were examined by both transmission and scanning electron microscopy. The results were compared with those of a previous study in which the lung was inflated to a transpulmonary pressure of 5 cmH2O. There was a large increase in the frequency of stress failure of the capillary walls at the higher lung volume. For example, at 32.5 cmH2O Ptm, the number of endothelial breaks per millimeter cell lining was 7.1 +/- 2.2 at the high lung volume compared with 0.7 +/- 0.4 at the low lung volume. The corresponding values for epithelium were 8.5 +/- 1.6 and 0.9 +/- 0.6. Both differences were significant (P less than 0.05). At 52.5 cmH2O Ptm, the results for endothelium were 20.7 +/- 7.6 (high volume) and 7.1 +/- 2.1 (low volume), and the corresponding results for epithelium were 32.8 +/- 11.9 and 11.4 +/- 3.7. At 32.5 cmH2O Ptm, the thickness of the blood-gas barrier was greater at the higher lung volume, consistent with the development of more interstitial edema. Ballooning of the epithelium caused by accumulation of edema fluid between the epithelial cell and its basement membrane was seen at 32.5 and 52.5 cmH2O Ptm. At high lung volume, the breaks tended to be narrower and fewer were oriented perpendicular to the axis of the pulmonary capillaries than at low lung volumes. Transmission and scanning electron microscopy measurements agreed well. Our findings provide a physiological mechanism for other studies showing increased capillary permeability at high states of lung inflation.
Electronmicroscopic appearances of pulmonary capillaries were studied in rabbit lungs perfused in situ when the capillary transmural pressure (Ptm) was systematically raised from 12.5 to 72.5 +/- 2.5 cmH2O. The animals were anesthetized and exsanguinated, and after the chest was opened, the pulmonary artery and left atrium were cannulated and attached to reservoirs. The lungs were perfused with autologous blood for 1 min, and this was followed by saline-dextran and then buffered glutaraldehyde to fix the lungs for electron microscopy. Normal appearances were seen at 12.5 cmH2O Ptm. At 52.5 and 72.5 cmH2O Ptm, striking discontinuities of the capillary endothelium and alveolar epithelium were seen. A few disruptions were seen at 32.5 cmH2O Ptm (mostly in one animal), but the number of breaks per millimeter cell lining increased markedly up to 72.5 cmH20 Ptm, where the mean frequency was 27.8 +/- 8.6 and 13.6 +/- 1.4 (SE) breaks/mm for endothelium and epithelium, respectively. In some instances, all layers of the blood-gas barrier were disrupted and erythrocytes could be seen moving into the alveolar spaces. In about half the endothelial and epithelial breaks, the basement membranes remained intact. The average break lengths for both endothelium and epithelium did not change significantly with pressure. The width of the blood-gas barrier increased at 52.5 and 72.5 cmH2O Ptm as a result of widening of the interstitium caused by edema. The cause of the disruptions is believed to be stress failure of the capillary wall. The results show that high capillary hydrostatic pressures cause major changes in the ultrastructure of the walls of the capillaries, leading to a high-permeability form of edema.
Intercellular communication between epithelial cells and fibroblasts of the alveolar wall has been postulated from studies of lung development and repair. We examined the epithelial cell-fibroblast interactions with respect to growth control and epithelial cell function using cultured fetal and adult lung cells. The role of diffusing factor(s) as compared to direct cell-to-cell contact was studied by culturing epithelial cells either on a permeable culture well insert over fibroblasts or in co-culture with fibroblasts. The results show that the normal low proliferative rate of epithelial cells in culture is increased when exposed to fibroblast supernatants. In contrast, epithelial cells (particularly from adult lung) secrete a factor that suppresses fibroblast growth when cultured with a filter between the cell types. However, when cell-cell contact occurs in co-culture, the growth rate of fibroblasts is greatly increased. Synthesis of disaturated phosphatidylcholine by epithelial cells is increased under serum-free conditions and further rises when fetal epithelial cells are exposed to steroid-treated fibroblasts, when the cell types are separated, and when cells are in contact. This indicates that a fibroblast-derived factor stimulates epithelial differentiation, and morphologic evidence relating the appearance of lamellar bodies to the areas of direct epithelial cell-fibroblast contact was found. The results indicate the complex interdependence of these two types of cell where a secretory product of one cell or direct cell-cell contact may alter when regulatory control of the other cell type. These interactions are likely to be important in orderly development and in the reparative response of the lung to injury.
We investigated the histopathologic pulmonary changes induced by mechanical pulmonary ventilation (MV) with a high peak airway pressure and a large tidal volume in healthy baby pigs. Eleven animals were mechanically ventilated at a peak inspiratory pressure (PIP) of 40 cm H2O, a respiratory rate (RR) of 20 min-1, a positive end-expiratory pressure (PEEP) of 3 to 5 cm H2O, and an FIO2 of 0.4. High airway pressure MV was terminated in 22 +/- 11 h because of severe hypoxemia in the animals. Five of the baby pigs were killed for gross and light microscope studies. The pulmonary changes consisted of alveolar hemorrhage, alveolar neutrophil infiltration, alveolar macrophage and type II pneumocyte proliferation, interstitial congestion and thickening, interstitial lymphocyte infiltration, emphysematous change, and hyaline membrane formation. Those lesions were similar to that seen in the early stage of the adult respiratory distress syndrome (ARDS). The remaining six animals were treated for 3 to 6 days with conventional respiratory care with appropriate ventilator settings. Prominent organized alveolar exudate in addition to lesions was also found in the five animals. These findings were indistinguishable from the clinical late stage of ARDS. Six control animals were mechanically ventilated at a PIP of less than 18 cm H2O, a RR of 20 min-1, a PEEP of 3 to 5 cm H2O, and an FIO2 of 0.4 for 48 h. They showed no notable changes in lung functions and histopathologic findings. Aggressive MV with a high PIP is often applied to patients with respiratory distress to attain adequate pulmonary gas exchange.(ABSTRACT TRUNCATED AT 250 WORDS)
Deep inflation of the lung stimulates surfactant secretion by unknown mechanisms. The hypothesis that mechanical distension
directly stimulates type II cells to secrete surfactant was tested by stretching type II cells cultured on silastic membranes.
The intracellular Ca2+ concentration was measured in single cells, before and after stretching. A single stretch of alveolar
type II cells caused a transient (less than 60 seconds) increase in cytosolic Ca2+ followed by a sustained (15 to 30 minutes)
stimulation of surfactant secretion. Both Ca2+ mobilization and exocytosis exhibited dose-dependence to the magnitude of the
stretch-stimulus. Thus, mechanical factors can trigger complex cellular events in nonneuron, nonmuscle cells and may be involved
in regulating normal lung functions.
When normal lungs are ventilated with large tidal volumes (VT) and end-inspired pressures (Pei), surfactant is depleted and pulmonary edema develops. Both effects are diminished by positive end-expiratory pressure (PEEP). We reasoned that ventilatory with large VT-low PEEP would similarly increase edema following acute lung injury. To test this hypothesis, we ventilated dogs 1 h after hydrochloric acid (HCl) induced pulmonary edema with a large VT (30 ml/kg) and low PEEP (3 cm H2O) (large VT-low PEEP) and compared their results with dogs ventilated with a smaller VT (15 ml/kg) and 12 cm H2O PEEP (small VT-high PEEP). The small VT was the smallest that maintained eucapnia in our preparation; the large VT was chosen to match Pei and end-inspired lung volume. Pulmonary capillary wedge transmural pressure (Ppwtm) was kept at 8 mm Hg in both groups. Five hours after injury, the median lung wet weight to body weight ratio (WW/BW) was 25 g/kg higher in the large VT-low PEEP group than in the small VT-high PEEP group (p less than 0.05). Venous admixture (Qva/Qt) was similarly greater in the large VT-low PEEP group (49.8 versus 23.5%) (p less than 0.05). We conclude that small VT-high PEEP is a better mode of ventilating acute lung injury than large VT-low PEEP because edema accumulation is less and venous admixture is less. These advantages did not result from differences in Pei, end-inspiratory lung volume, or preload (Ppwtm).(ABSTRACT TRUNCATED AT 250 WORDS)
Many animal studies have shown that high peak inspiratory pressures (PIP) during mechanical ventilation can induce acute lung injury with hyaline membranes. Since 1984 we have limited PIP in patients with ARDS by reducing tidal volume, allowing spontaneous breathing with SIMV and disregarding hypercapnia. Since 1987 50 patients with severe ARDS with a “lung injury score” ≥2.5 and a mean PaO2/FiO2 ratio of 94 were managed in this manner. The mean maximum PaCO2 was 62 mmHg, the highest being 129 mmHg. The hospital mortality was significantly lower than that predicted by Apache II (16% vs. 39.6%,x
2=11.64,p<0.001). Only one death was due to respiratory failure, caused by pneumocystis pneumonia. 10 patients had a “ventilator score” >80, which has previously predicted 100% mortality from respiratory failure. Only 2 died, neither from respiratory failure. There was no significant difference in lung injury score, ventilator score, PaO2/FiO2 or maximum PaCO2 between survivors and non-survivors. We suggest that this ventilatory management may substantially reduce mortality in ARDS, particularly from respiratory failure.
High peak inspiratory pressures (PIP) during mechanical ventilation can induce lung injury. In the present study we compare the respective roles of high tidal volume with high PIP in intact immature rabbits to determine whether the increase in capillary permeability is the result of overdistension of the lung or direct pressure effects. New Zealand White rabbits were assigned to one of three protocols, which produced different degrees of inspiratory volume limitation: intact closed-chest animals (CC), closed-chest animals with a full-body plaster cast (C), and isolated excised lungs (IL). The intact animals were ventilated at 15, 30, or 45 cmH2O PIP for 1 h, and the lungs of the CC and C groups were placed in an isolated lung perfusion system. Microvascular permeability was evaluated using the capillary filtration coefficient (Kfc). Base-line Kfc for isolated lungs before ventilation was 0.33 +/- 0.31 ml.min-1.cmH2O-1.100g-1 and was not different from the Kfc in the CC group ventilated with 15 cmH2O PIP. Kfc increased by 850% after ventilation with only 15 cmH2O PIP in the unrestricted IL group, and in the CC group Kfc increased by 31% after 30 cmH2O PIP and 430% after 45 cmH2O PIP. Inspiratory volume limitation by the plaster cast in the C group prevented any significant increase in Kfc at the PIP values used. These data indicate that volume distension of the lung rather than high PIP per se produces microvascular damage in the immature rabbit lung.
Sixteen rabbits were anaesthetized and subjected to saline lavage of the lungs to produce surfactant deficiency. This resulted in an arterial oxygen tension of less than 12 kPa on 100% inspired oxygen and an inflection point on the pressure-volume curve at a pressure of 8-12 mmHg. After lavage the animals were randomly assigned to receive either conventional mechanical ventilation (CMV) with a positive end-expiratory pressure (PEEP) of 1-2 mmHg (group I - low PEEP) or CMV with PEEP equal to the inflection point pressure (group II - high PEEP). Mean airway pressures were kept at 14-16 mmHg in both groups by increasing the inspiratory:expiratory time ratios in the low PEEP group. The 5-h protocol was completed by 4 animals in group I and 6 animals in group II, early death usually being associated with a metabolic acidosis. On 100% oxygen, the mean PaO2 at 2-h post-lavage was 15.2 +/- 8.3 kPa in group I and 39.6 +/- 21.8 kPa in group II. Group I had much lower end-expiratory lung volumes (3.0 +/- 1.5 ml above FRC) than group II (34.9 +/- 12.2 ml above FRC). Histological examination of the lungs revealed significantly less hyaline membrane formation in group II (p = 0.001). Thus, the prevention of alveolar collapse by the use of high PEEP levels appears to reduce lung damage in this preparation.
In a previous paper Cutz, Bryan et al. showed that in rabbits after repetitive lung lavage high-frequency oscillatory ventilation maintained excellent gas exchange and did not cause hyaline membrane formation (J. Appl. Physiol. 55: 131-138, 1983). In contrast, conventional mechanical ventilation had poor gas exchange and extensive hyaline membrane formation and we attributed these differences to mechanical barotrauma. However, we completely overlooked the large number of granulocytes in the damaged lung. To investigate this using the same model we have used mechanical ventilation on two groups of rabbits, one with normal granulocytes, the other depleted of granulocytes by pretreatment with nitrogen mustard. The nondepleted rabbits had poor gas exchange, a substantial protein leak into the lung and extensive hyaline membranes. The depleted animals had good gas exchange, a very small protein leak and no hyaline membranes. Repletion of granulocytes from donor rabbits lead to poor gas exchange and hyaline membrane formation. It is concluded that lung lavage causes prompt margination of granulocytes which become activated by the ongoing epithelial barotrauma of conventional ventilation.
Polyclonal affinity-purified antibodies to human collagen types I, III, and IV, and laminin were used to compare the extracellular matrix (ECM) in 10 normal and 32 abnormal lungs by indirect immunofluorescence. In normal lungs, type IV collagen and laminin codistributed in a uniform linear pattern along the epithelial and endothelial basement membranes. Type III collagen was found within the alveolar septa and interstitium in an interrupted ribbonlike pattern and was aggregated at the entrance rings of the alveoli. Type I collagen was distributed irregularly within the alveolar wall and was less prominent than type III collagen. In patients with pulmonary disease not characterized by interstitial fibrosis (n = 15), the distribution of ECM components studied was essentially normal. In pulmonary disease in which interstitial fibrosis was the characteristic feature, such as idiopathic pulmonary fibrosis (IPF) and adult respiratory distress syndrome (ARDS) (n = 17), collagen types I and III accumulated in the expanded interstitium. Type III collagen was initially predominant in the thickened alveolar septa and interstitium, whereas type I collagen appeared to be the principal collagen at later stages in the disease course. The basement membrane was disrupted early in the disease course with invasion of the alveolar spaces by interstitial collagens similar in type to those present in the adjacent interstitium.
The mechanisms by which intermittent positive-pressure ventilation with high inflation pressure (HIPPV) induces pulmonary edema remain uncertain. In this study we investigated the physiologic and anatomic changes related to HIPPV at 45 cmH2O peak inspiratory pressure in rats. Edema was quantified by the extravascular lung water obtained from postmortem weighing and by 22Na distribution space. Pulmonary microvascular permeability was assessed by dry lung weight and fractional albumin uptake. After only 5 min of HIPPV, there was a significant increase in Na space, dry lung weight, and fractional albumin uptake when compared with that in control rats mechanically ventilated at 7 cmH2O peak inspiratory pressure. These changes suggest that edema may be due at least in part to alterations in microvascular permeability. Moderate peribronchovascular edema was present. At the ultrastructural level, some endothelial cells were found detached from their basement membrane. This lesion has been previously described in other types of pulmonary microvascular injury. The above findings remained almost unchanged after 10 min of HIPPV. After 20 min of HIPPV, we observed the outpouring of a high protein content alveolar flooding accompanied by a further significant increase in fractional albumin uptake and dry lung weight. Additional anatomic damage appeared including epithelial lesions and hyaline membranes. Thus, HIPPV edema presents all the features of high permeability edema. These results may be of concern in the ventilatory management of patients with acute respiratory failure in order to avoid additional damages induced by local overinflation.