A Nationwide, Prospective Study of Tracheal Intubation in Critically Ill Adults in Spain: Management, Associated Complications, and Outcomes.

OBJECTIVES: Our aims were to explore current intubation practices in Spanish ICUs to determine the incidence and risk factors of peri-intubation complications (primary outcome measure: major adverse events), the rate and factors associated with first-pass success, and their impact on mortality as well as the changes of the intubation procedure observed in the COVID-19 pandemic. DESIGN: Prospective, observational, and cohort study. SETTING: Forty-three Spanish ICU. PATIENTS: A total of 1837 critically ill adult patients undergoing tracheal intubation. The enrollment period was six months (selected by each center from April 16, 2019, to October 31, 2020). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: At least one major adverse peri-intubation event occurred in 40.4 % of the patients (973 major adverse events were registered) the most frequent being hemodynamic instability (26.5%) and severe hypoxemia (20.3%). The multivariate analysis identified seven variables independently associated with a major adverse event whereas the use of neuromuscular blocking agents (NMBAs) was associated with reduced odds of major adverse events. Intubation on the first attempt was achieved in 70.8% of the patients. The use of videolaryngoscopy at the first attempt was the only protective factor (odds ratio 0.43; 95% CI, 0.28-0.66; p < 0.001) for first-attempt intubation failure. During the COVID-19 pandemic, the use of videolaryngoscopy and NMBAs increased significantly. The occurrence of a major peri-intubation event was an independent risk factor for 28-day mortality. Cardiovascular collapse also posed a serious threat, constituting an independent predictor of death. CONCLUSIONS: A major adverse event occurred in up to 40% of the adults intubated in the ICU. Peri-intubation hemodynamic instability but not severe hypoxemia was identified as an independent predictor of death. The use of NMBAs was a protective factor for major adverse events, whereas the use of videolaringoscopy increases the first-pass success rate of intubation. Intubation practices changed during the COVID-19 pandemic.

COVID-19 Associated Pulmonary Aspergillosis (CAPA): Hospital or Home Environment as a Source of Life-Threatening Aspergillus fumigatus Infection?

Most cases of invasive aspergillosis are caused by Aspergillus fumigatus, whose conidia are ubiquitous in the environment. Additionally, in indoor environments, such as houses or hospitals, conidia are frequently detected too. Hospital-acquired aspergillosis is usually associated with airborne fungal contamination of the hospital air, especially after building construction events. A. fumigatus strain typing can fulfill many needs both in clinical settings and otherwise. The high incidence of aspergillosis in COVID patients from our hospital, made us wonder if they were hospital-acquired aspergillosis. The purpose of this study was to evaluate whether the hospital environment was the source of aspergillosis infection in CAPA patients, admitted to the Hospital Universitario Central de Asturias, during the first and second wave of the COVID-19 pandemic, or whether it was community-acquired aspergillosis before admission. During 2020, sixty-nine A. fumigatus strains were collected for this study: 59 were clinical isolates from 28 COVID-19 patients, and 10 strains were environmentally isolated from seven hospital rooms and intensive care units. A diagnosis of pulmonary aspergillosis was based on the ECCM/ISHAM criteria. Strains were genotyped by PCR amplification and sequencing of a panel of four hypervariable tandem repeats within exons of surface protein coding genes (TRESPERG). A total of seven genotypes among the 10 environmental strains and 28 genotypes among the 59 clinical strains were identified. Genotyping revealed that only one environmental A. fumigatus from UCI 5 (box 54) isolated in October (30 October 2020) and one A. fumigatus isolated from a COVID-19 patient admitted in Pneumology (Room 532-B) in November (24 November 2020) had the same genotype, but there was a significant difference in time and location. There was also no relationship in time and location between similar A. fumigatus genotypes of patients. The global A. fumigatus, environmental and clinical isolates, showed a wide diversity of genotypes. To our knowledge, this is the first study monitoring and genotyping A. fumigatus isolates obtained from hospital air and COVID-19 patients, admitted with aspergillosis, during one year. Our work shows that patients do not acquire A. fumigatus in the hospital. This proves that COVID-associated aspergillosis in our hospital is not a nosocomial infection, but supports the hypothesis of "community aspergillosis" acquisition outside the hospital, having the home environment (pandemic period at home) as the main suspected focus of infection.

Spread of OXA-48-producing Klebsiella pneumoniae among COVID-19-infected patients: The storm after the storm.

The impact of secondary infections by multidrug-resistant bacteria in COVID-19- infected patients has yet to be evaluated. Here, we report the clinical and molecular features of an outbreak of seven patients carrying CTX-M-15- and OXA-48-producing Klebsiella pneumoniae belonging to ST326 during COVID-19 pandemic in an ICU in northern Spain. Those patients were admitted to beds close to each other, two of them developed ventilator-associated pneumonia (VAP), one exhibited primary bacteremia and the remaining four were considered to be colonized. None of them was colonized prior to admission to the ICU an all, except one of those who developed VAP, were discharged. Hydroxychloroquine and lopinavir/ritonavir were administered to all of them as COVID-19 therapy and additionally, three of them received tocilizumab and corticosteroids, respectively. Reusing of personal protective equipment due to its initial shortage, relaxation in infection control measures and negative-pressure air in ICU rooms recommended for the protection of health care workers (HCWs), could have contributed to this outbreak. Maximization of infection control measures is essential to avoid secondary infections by MDR bacteria in COVID-infected patients.

Standardization and Chemical Characterization of Intravenous Therapy in Adult Patients: A Step Further in Medication Safety.

BACKGROUND: Intravenous drug administration is associated with potential complications, such as phlebitis. The physiochemical characteristics of the infusate play a very important role in some of these problems. AIM: The aim of this study was to standardize the dilutions of intravenous drugs most commonly used in hospitalized adult patients and to characterize their pH, osmolarity and cytotoxic nature to better guide the selection of the most appropriate vascular access. METHODS: The project was conducted in three phases: (i) standardization of intravenous therapy, which was conducted using a modified double-round Delphi method; (ii) characterization of the dilutions agreed on in the previous phase by means of determining the osmolarity and pH of each of the agreed concentrations, and recording the vesicant nature based on the information in literature; and (iii) algorithm proposal for selecting the most appropriate vascular access, taking into account the information gathered in the previous phases. RESULTS: In total, 112 drugs were standardized and 307 different admixtures were assessed for pH, osmolarity and vesicant nature. Of these, 123 admixtures (40%), had osmolarity values >600 mOsm/L, pH < 4 or > 9, or were classified as vesicants. In these cases, selection of the most suitable route of infusion and vascular access device is crucial to minimize the risk of phlebitis-type complications. CONCLUSIONS: Increasing safety of intravenous therapy should be a priority in the healthcare settings. Knowing the characteristics of drugs to assess the risk involved in their administration related to their physicochemical nature may be useful to guide decision making regarding the most appropriate vascular access and devices.

SARS-CoV-2 analysis on environmental surfaces collected in an intensive care unit: keeping Ernest Shackleton's spirit.

BACKGROUND: Intensive care unit workers are at high risk of acquiring COVID-19 infection, especially when performing invasive techniques and certain procedures that generate aerosols (< 5 µm). Therefore, one of the objectives of the health systems should implement safety practices to minimize the risk of contagion among these health professionals. Monitoring environmental contamination of SARS-CoV-2 may help to determine the potential of the environment as a transmission medium in an area highly exposed to SARS-CoV-2, such as an intensive care unit. The objective of the study was to analyze the environmental contamination by SARS-CoV-2 on surfaces collected in an intensive care unit, which is dedicated exclusively to the care of patients with COVID-19 and equipped with negative pressure of - 10 Pa and an air change rate of 20 cycles per hour. Furthermore, all ICU workers were tested for COVID-19 by quantitative RT-PCR and ELISA methods. RESULTS: A total of 102 samples (72 collected with pre-moistened swabs used for collection of nasopharyngeal exudates and 30 with moistened wipes used in the environmental microbiological control of the food industry) were obtained from ventilators, monitors, perfusion pumps, bed rails, lab benches, containers of personal protective equipment, computer keyboards and mice, telephones, workers' shoes, floor, and other areas of close contact with COVID-19 patients and healthcare professionals who cared for them. The analysis by quantitative RT-PCR showed no detection of SARS-CoV-2 genome in environmental samples collected by any of the two methods described. Furthermore, none of the 237 ICU workers was infected by the virus. CONCLUSIONS: Presence of SARS-CoV-2 on the ICU surfaces could not be determined supporting that a strict cleaning protocol with sodium hypochlorite, a high air change rate, and a negative pressure in the ICU are effective in preventing environmental contamination. These facts together with the protection measures used could also explain the absence of contagion among staff inside ICUs.

Evaluation of a commercial multiplex PCR for diagnosis of central nervous system (CNS) nosocomial infections.

Nosocomial Central Nervous System (CNS) infections are often serious complications of neurosurgical procedures. Their diagnosis is complex and frequently based on microbiological culture. The aim of this work was to evaluate the effectiveness of the FilmArray® Blood Culture Identification (BCID) panel, a multiplex PCR designed to identify the most common etiologic agents of sepsis involved with nosocomial CNS infections. A total of ninety samples were analyzed with the BCID panel. The sensitivity and specificity achieved were 77.4% and 100% respectively, when compared with the reference method (culture). Based on the analysis of the melting curves, another cut-off was established improving sensitivity to 83.9% whilst maintaining 98.3% specificity. The BCID panel seems to be a helpful tool for the prompt diagnosis of CNS nosocomial infections. The cut-off proposed here can increase sensitivity, but further studies are required to confirm its effectiveness and its applicability in clinical microbiology laboratories.

Pseudomonas aeruginosa nosocomial meningitis in neurosurgical patients with intraventricular catheters: Therapeutic approach and review of the literature / Meningitis nosocomial por Pseudomonas aeruginosa en pacientes portadores de catéteres intraventriculares: aproximación terapéutica y revisión de la literatura

BACKGROUND: Pseudomonas aeruginosa neurosurgical meningitis is a rare entity, usually related with intraventricular catheters and associated with high mortality rates. We describe the clinical characteristics, treatment and outcomes of a series of neurosurgical meningitis caused by P. aeruginosa along 1990-2016. METHODS: Descriptive, retrospective study of all postsurgical meningitis due to P. aeruginosa related to intraventricular catheters in Hospital Universitario Central de Asturias, between 1990 and 2016. Clinical features, therapeutic approaches and prognostic factors were analyzed statistically. A binary logistic regression analysis was performed to determine the factors influencing the infection mortality. RESULT: 51 episodes from 51 different patients with CSF culture positive for P. aeruginosa were reviewed. Seventeen patients (33.3%) died as a direct consequence of the infection. Univariate analysis showed that mortality was higher in the group of patients treated with ceftazidime (12 vs. 15, p = 0.068, OR 3.040 [0.877-10.544]) and lower in patients whom had received intrathecal therapy (2 vs. 13, p = 0.050, OR 4.64 [0.80-34.93]), without differences observed between those patients treated with aminoglycosides or with colistin. Any patient treated with colistin died (0 vs. 6, p = 0.067, OR: not defined). In the multivariate analysis mortality was only significant higher for patients without catheter withdrawal (p = 0.014) and lower for those patients who received intrathecal therapy (p = 0.05) or adequate empirical treatment (p = 0.006). CONCLUSIONS: The mortality of P. aeruginosa meningitis is high especially in infections without catheter withdrawal and in patients for whom the intrathecal route of administration was not used. Catheter withdrawal was an independent factor of good outcome in our series

ANTECEDENTES: La meningitis nosocomial por Pseudomonas aeruginosa es una entidad poco frecuente, generalmente relacionada con catéteres intraventriculares y asociada con altas tasas de mortalidad. Se describen las características clínicas, con especial hincapié en su tratamiento, de una serie de meningitis neuroquirúrgicas por P. aeruginosa entre 1990 y 2016. MÉTODOS: Estudio descriptivo, retrospectivo, de todas las meningitis posquirúrgicas por P. aeruginosa relacionadas con catéteres intraventriculares en el Hospital Universitario Central de Asturias entre 1990 y 2016, con especial hincapié en los enfoques terapéuticos y factores pronósticos. Los factores asociados con mortalidad se analizaron mediante regresión logística binaria. RESULTADOS: Se revisaron 51 episodios de 51 pacientes diferentes con cultivos de LCR positivos para P. aeruginosa. Diecisiete pacientes (33,3%) murieron como consecuencia directa de la infección. La mortalidad fue mayor en el grupo de pacientes tratados con ceftazidima (12 vs. 15, p = 0,068, OR 3,040 [0,877-10,544]) y menor en los pacientes que habían recibido terapia intratecal (2 vs. 13, p = 0,050, OR 4,64 [0,80-34,93]), sin diferencias en estos últimos entre los tratados con aminoglucósidos o con colistina. Ningún paciente tratado con colistina falleció (0 vs. 6, p = 0,067, OR no definida). El análisis multivariable únicamente confirmó la asociación con la ausencia de terapia intratecal (p = 0,05) o tratamiento empírico adecuado (p = 0,006). CONCLUSIONES: La mortalidad de la meningitis por P. aeruginosa es elevada, especialmente en pacientes en quienes no se utilizó la vía de administración intratecal. La retirada del catéter fue un factor independiente de buena evolución en nuestra serie

Pseudomonas aeruginosa nosocomial meningitis in neurosurgical patients with intraventricular catheters: Therapeutic approach and review of the literature.

BACKGROUND: Pseudomonas aeruginosa neurosurgical meningitis is a rare entity, usually related with intraventricular catheters and associated with high mortality rates. We describe the clinical characteristics, treatment and outcomes of a series of neurosurgical meningitis caused by P. aeruginosa along 1990-2016. METHODS: Descriptive, retrospective study of all postsurgical meningitis due to P. aeruginosa related to intraventricular catheters in Hospital Universitario Central de Asturias, between 1990 and 2016. Clinical features, therapeutic approaches and prognostic factors were analyzed statistically. A binary logistic regression analysis was performed to determine the factors influencing the infection mortality. RESULT: 51 episodes from 51 different patients with CSF culture positive for P. aeruginosa were reviewed. Seventeen patients (33.3%) died as a direct consequence of the infection. Univariate analysis showed that mortality was higher in the group of patients treated with ceftazidime (12 vs. 15, p=0.068, OR 3.040 [0.877-10.544]) and lower in patients whom had received intrathecal therapy (2 vs. 13, p=0.050, OR 4.64 [0.80-34.93]), without differences observed between those patients treated with aminoglycosides or with colistin. Any patient treated with colistin died (0 vs. 6, p=0.067, OR: not defined). In the multivariate analysis mortality was only significant higher for patients without catheter withdrawal (p=0.014) and lower for those patients who received intrathecal therapy (p=0.05) or adequate empirical treatment (p=0.006). CONCLUSIONS: The mortality of P. aeruginosa meningitis is high especially in infections without catheter withdrawal and in patients for whom the intrathecal route of administration was not used. Catheter withdrawal was an independent factor of good outcome in our series.

Intoxicación por magnesio, fallo multiorgánico y colitis isquémica secundaria a ingesta crónica de un producto de parafarmacia / Magnesium poisoning, multi-organ failure and ischemic colitis secondary to chronic ingestion of a parapharmacy product

En el artículo se describe el caso clínico de una paciente con fallo multiorgánico y colitis isquémica secundario a intoxicación por magnesio, debido a la ingesta crónica de un producto de parafarmacia, utilizado para el tratamiento del estreñimiento crónico. Se describe el caso clínico y se realiza una revisión de la literatura

The article describes the clinical case of a patient with multi-organ failure and ischemic colitis secondary to magnesium poisoning, due to the chronic intake of a parapharmacy product, used for the treatment of chronic constipation. The clinical case is described and a review of the literature is made

Magnesium poisoning, multi-organ failure and ischemic colitis secondary to chronic ingestion of a parapharmacy product.

The article describes the clinical case of a patient with multi-organ failure and ischemic colitis secondary to magnesium poisoning, due to the chronic intake of a parapharmacy product, used for the treatment of chronic constipation. The clinical case is described and a review of the literature is made.

Vigilancia epidemiológica para microorganismos multirresistentes en una UCI polivalente / Epidemiological surveillance for multidrug-resistant microorganisms in a general ICU

Introducción. Los microorganismos multirresistentes (MMR) suponen una amenaza para los pacientes ingresados en las Unidades de Cuidados Intensivos (UCIs). El objetivo de este estudio es analizar los resultados de los cultivos de vigilancia epidemiológica de dichos microorganismos en una de estas unidades. Material y métodos. UCI polivalente. Análisis retrospectivo, estadística descriptiva. Análisis de cultivos de vigilancia epidemiológica para MMR. Microorganismos estudiados: Staphylococcus aureus resistente a meticilina (SARM), Klebsiella pneumoniae productora de BLEE y/o carbapenemasa (KPBLEE-C) y Acinetobacter baumannii multirresistente (ABMR). Resultados. 1.259 pacientes ingresados. Se analizaron 2.234 muestras (exudado rectal 690, faríngeo 634, nasal 624, cutáneo 286) procedentes de 384 pacientes. La mayor rentabilidad alcanzada con las diferentes muestras para los distintos microorganismos fue: SARM, exudado nasal 79%, nasal + faríngeo 90%. ABMR: faríngeo 80%, faríngeo + rectal 95%. KPBLEE-C: rectal 95%, faríngeo + rectal 98%. De los 384 pacientes 94 (24,4%) estaban colonizados/infectados al ingreso con alguno de estos microorganismos. Durante su estancia, 134 pacientes (10,6% del total de pacientes ingresados) se colonizaron/infectaron por un total de 169 microorganismos. La colonización/infección más precoz fue para SARM (9,2 ± 6,4 días) y la más tardía para enterobacterias productoras de BLEE (18,7±16,4 días). Conclusiones. El 24,4% de los pacientes estaban colonizados/infectados por MMR al ingreso. Las muestras más rentables fueron exudado nasal para SARM, faríngeo para ABMR y rectal para KPBLEE-C. La asociación de dos muestras mejora la detección, excepto en KPBLEE-C. Los exudados cutáneos son poco rentables. El MMR más frecuente al ingreso son las enterobacterias productoras de BLEE y el adquirido intra UCI el ABMR (AU)

Introduction. Multidrug resistant (MDR) microorganisms represent a threat for patients admitted in Intensive Care Units (ICUs). The objective of the present study is to analyse the results of epidemiological surveillance cultures for these microorganisms in one of these units. Material and methods. General ICU. Retrospective analysis, descriptive statistics. Analysis of epidemiological surveillance cultures for MDR microorganisms in 2015. Studied microorganisms: Methicillin-resistant Staphylococcus aureus (MRSA), ESBL-and/or carbapenemase-producing Klebsiella pneumoniae (CESBL-KP) and MDR Acinetobacter baumannii (MDRAB). Results. One thousand, two hundred and fifty nine patients admitted. A total of 2,234 specimens from 384 patients were analysed (690, 634, 62 and 286 were rectal, throat, nasal and skin swabs respectively). Global APACHE II was 18.3 ± 8 versus 21.7 ± 7.8 in patients colonized/infected on admission. Global mortality was 19.7% versus 22.3% in patients colonized/infected on admission. The higher sensitivities achieved with the different samples for the different microorganism detection were as follows. MRSA: 79% and 90% for nasal and nasal + throat swabs, respectively. MDRAB: 80% and 95% for throat and throat + rectal swabs, respectively. CESBL-KP: 95% and 98% for rectal and rectal + throat swabs, respectively. 94 out of the 384 patients (24.4%) were colonized/infected with MDR at admission. 134 patients (10.6% of the total patients admitted) were colonized/infected with a total of 169 MMR during the hospital stay. MRSA has the earliest colonization/ infection (9.2 ± 6.4days) and ESBL-producing Enterobacteriaceae, the latest (18.7± 16.4 days). Conclusions. 24.4% of patients were colonized/infected by MDR at admission. Nasal, throat and rectal swabs were the most effective specimens for recovering MRSA, MDRAB and CESBL-KP, respectively. The combination of two specimens improves MDR detection except for CESBL-KP. Skin swabs are worthless. The most prevalent MDR at admission were ESBL-producing Enterobacteriaceae while the most frequent hospital acquired MDR was MDRAB (AU)

Impact of Initial Ventilatory Strategy in Hematological Patients With Acute Respiratory Failure: A Systematic Review and Meta-Analysis.

OBJECTIVE: Acute respiratory failure in hematological patients is related to a high mortality. Noninvasive mechanical ventilation may benefit a subset of these patients, but the overall effect on mortality and the risks derived from its failure are unclear. Our objective was to review the impact of initial ventilatory strategy on mortality and the risks related to noninvasive mechanical ventilation failure in this group of patients. DATA SOURCES: Data sources, including PubMed and conference proceedings, were searched from the year 2000 to January 2015. STUDY SELECTION: We selected studies reporting mortality and the need for mechanical ventilation in hematological patients with acute respiratory failure. DATA EXTRACTION: Two trained reviewers independently conducted study selection, abstracted data, and assessed the risk of bias. Discrepancies between reviewers were resolved through discussion and consensus. The outcomes explored were all-cause mortality after mechanical ventilation and incidence of noninvasive mechanical ventilation failure. DATA SYNTHESIS: A random-effects model was used in all the analysis. Thirteen studies, involving 2,380 patients, were included. Use of noninvasive mechanical ventilation was related to a better outcome than initial intubation (risk ratio, 0.74; 95% CI, 0.65-0.84). Failure of noninvasive mechanical ventilation did not increase the overall risk of death (risk ratio, 1.02; 95% CI, 0.93-1.13). There were signs of publication bias and substantial heterogeneity among the studies. Compensation of this bias by using the trim-and-fill method showed a significant risk of death after noninvasive mechanical ventilation failure (risk ratio, 1.07; 95% CI, 1.00-1.14). Meta-regression analysis showed that the predicted risk of death for the noninvasive mechanical ventilation group acted as a significant moderator, with a higher risk of death after noninvasive mechanical ventilation failure in those studies reporting lower predicted mortality. CONCLUSIONS: Noninvasive mechanical ventilation is associated with a lower risk of death in hematological patients with respiratory failure. Noninvasive mechanical ventilation failure may worsen the prognosis, mainly in less severe patients.

Impact of Recruitment on Static and Dynamic Lung Strain in Acute Respiratory Distress Syndrome.

BACKGROUND: Lung strain, defined as the ratio between end-inspiratory volume and functional residual capacity, is a marker of the mechanical load during ventilation. However, changes in lung volumes in response to pressures may occur in injured lungs and modify strain values. The objective of this study was to clarify the role of recruitment in strain measurements. METHODS: Six oleic acid-injured pigs were ventilated at positive end-expiratory pressure (PEEP) 0 and 10 cm H2O before and after a recruitment maneuver (PEEP = 20 cm H2O). Lung volumes were measured by helium dilution and inductance plethysmography. In addition, six patients with moderate-to-severe acute respiratory distress syndrome were ventilated with three strategies (peak inspiratory pressure/PEEP: 20/8, 32/8, and 32/20 cm H2O). Lung volumes were measured in computed tomography slices acquired at end-expiration and end-inspiration. From both series, recruited volume and lung strain (total, dynamic, and static) were computed. RESULTS: In the animal model, recruitment caused a significant decrease in dynamic strain (from [mean ± SD] 0.4 ± 0.12 to 0.25 ± 0.07, P < 0.01), while increasing the static component. In patients, total strain remained constant for the three ventilatory settings (0.35 ± 0.1, 0.37 ± 0.11, and 0.32 ± 0.1, respectively). Increases in tidal volume had no significant effects. Increasing PEEP constantly decreased dynamic strain (0.35 ± 0.1, 0.32 ± 0.1, and 0.04+0.03, P < 0.05) and increased static strain (0, 0.06 ± 0.06, and 0.28 ± 0.11, P < 0.05). The changes in dynamic and total strain among patients were correlated to the amount of recruited volume. An analysis restricted to the changes in normally aerated lung yielded similar results. CONCLUSION: Recruitment causes a shift from dynamic to static strain in early acute respiratory distress syndrome.

Anti-inflammatory effects of clarithromycin in ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury. METHODS: Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH2O, PEEP 2 cmH2O) or high (20 cmH2O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed. RESULTS: There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin. CONCLUSIONS: Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.

Lung strain and biological response in mechanically ventilated patients.

PURPOSE: Lung tissue may exhibit a biochemical response to excessive deformation. Since strain has been proposed as a marker of such deformation, we studied the relationships between strain and matrix remodeling and inflammation markers in mechanically ventilated patients with and without acute lung injury (ALI). METHODS: Twenty-two ventilated patients were studied (16 with ALI, 6 controls). Clinical data, gas exchange and respiratory mechanics were recorded, and end-expiratory lung volume (EELV) was measured by oxygen washin/washout. Extracellular matrix remodeling markers (procollagen, matrix metalloproteinases -2 and -9, TIMP-1) and inflammation markers (IL-6, IL-8, IL-10, IFNγ, IL-17A, and VEGF) were measured in bronchoalveolar lavage fluid (BALF). Strain was computed as the ratio between tidal volume and EELV. Patients with ALI were divided into two subgroups according to the median strain value (0.27). RESULTS: Patients in the ALI group exhibited higher airway pressures, lower EELV and higher strain than the control group. There were no significant differences in gas exchange, respiratory mechanics, or the matrix remodeling markers between ALI patients with normal and high strain. The subgroup of patients with high strain showed a fourfold increase of IL-6 and IL-8 concentrations in BALF, compared with patients with ALI and normal strain or patients without ALI. In the whole sample, IL-6 and IL-8 concentrations in BALF were correlated with strain (Spearman's ρ = 0.67 and 0.77, respectively). CONCLUSIONS: Increased strain is associated with a proinflammatory lung response in patients with ALI.

Inflammation and matrix remodeling during repair of ventilator-induced lung injury.

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10.

BACKGROUND: Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. METHODOLOGY AND PRINCIPAL FINDINGS: To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFß and IL-10 were measured in lung tissue. Mmp8(-/-) mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. CONCLUSIONS: According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo.

Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury.

Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.

Effects of melatonin in an experimental model of ventilator-induced lung injury.

Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice (n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH(2)O, positive end-expiratory pressure (PEEP) 2 cmH(2)O], and high-pressure ventilation (peak inspiratory pressure 25 cmH(2)O, PEEP 0 cmH(2)O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1beta, IL-6, TNF-alpha, and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF-alpha, IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-alpha, IL-1beta, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.