Central venous pressure waveform analysis during sleep/rest: a novel approach to enhance intensive care unit post-extubation monitoring of extubation failure.

This pilot study aimed to investigate the relation between cardio-respiratory parameters derived from Central Venous Pressure (CVP) waveform and Extubation Failure (EF) in mechanically ventilated ICU patients during post-extubation period. This study also proposes a new methodology for analysing these parameters during rest/sleep periods to try to improve the identification of EF. We conducted a prospective observational study, computing CVP-derived parameters including breathing effort, spectral analyses, and entropy in twenty critically ill patients post-extubation. The Dynamic Warping Index (DWi) was calculated from the respiratory component extracted from the CVP signal to identify rest/sleep states. The obtained parameters from EF patients and patients without EF were compared both during arbitrary periods and during reduced DWi (rest/sleep). We have analysed data from twenty patients of which nine experienced EF. Our findings may suggest significantly increased respiratory effort in EF patients compared to those successfully extubated. Our study also suggests the occurrence of significant change in the frequency dispersion of the cardiac signal component. We also identified a possible improvement in the differentiation between the two groups of patients when assessed during rest/sleep states. Although with caveats regarding the sample size, the results of this pilot study may suggest that CVP-derived cardio-respiratory parameters are valuable for monitoring respiratory failure during post-extubation, which could aid in managing non-invasive interventions and possibly reduce the incidence of EF. Our findings also indicate the possible importance of considering sleep/rest state when assessing cardio-respiratory parameters, which could enhance respiratory failure detection/monitoring.

Lung Mechanics Over the Century: From Bench to Bedside and Back to Bench.

Lung physiology research advanced significantly over the last 100 years. Respiratory mechanics applied to animal models of lung disease extended the knowledge of the workings of respiratory system. In human research, a better understanding of respiratory mechanics has contributed to development of mechanical ventilators. In this review, we explore the use of respiratory mechanics in basic science to investigate asthma and chronic obstructive pulmonary disease (COPD). We also discuss the use of lung mechanics in clinical care and its role on the development of modern mechanical ventilators. Additionally, we analyse some bench-developed technologies that are not in widespread use in the present but can become part of the clinical arsenal in the future. Finally, we explore some of the difficult questions that intensive care doctors still face when managing respiratory failure. Bringing back these questions to bench can help to solve them. Interaction between basic and translational science and human subject investigation can be very rewarding, as in the conceptualization of "Lung Protective Ventilation" principles. We expect this interaction to expand further generating new treatments and managing strategies for patients with respiratory disease.

Nonlinear Flow Sensor Calibration with an Accurate Syringe.

Flow sensors are required for monitoring patients on mechanical ventilation and in respiratory research. Proper calibration is important for ensuring accuracy and can be done with a precision syringe. This procedure, however, becomes complex for nonlinear flow sensors, which are commonly used. The objective of the present work was to develop an algorithm to allow the calibration of nonlinear flow sensors using an accurate syringe. We first noticed that a power law equation could properly fit the pressure-flow relationship of nonlinear flow sensors. We then developed a software code to estimate the parameters for this equation using a 3 L syringe (calibration syringe). Finally, we tested the performance of a calibrated flow sensor using a different 3 L syringe (testing syringe) and a commercially available spirometer. After calibration, the sensor had a bias ranging from −1.7% to 3.0% and precision from 0.012 L to 0.039 L for volumes measured with the 3 L testing syringe. Calibrated sensor performance was at least as good as the commercial sensor. This calibration procedure can be done at the bedside for both clinical and research purposes, therefore improving the accuracy of nonlinear flow sensors.

Reductions in dead space ventilation with nasal high flow depend on physiological dead space volume: metabolic hood measurements during sleep in patients with COPD and controls.

Nasal high flow (NHF) reduces minute ventilation and ventilatory loads during sleep but the mechanisms are not clear. We hypothesised NHF reduces ventilation in proportion to physiological but not anatomical dead space.11 subjects (five controls and six chronic obstructive pulmonary disease (COPD) patients) underwent polysomnography with transcutaneous carbon dioxide (CO2) monitoring under a metabolic hood. During stable non-rapid eye movement stage 2 sleep, subjects received NHF (20 L·min-1) intermittently for periods of 5-10 min. We measured CO2 production and calculated dead space ventilation.Controls and COPD patients responded similarly to NHF. NHF reduced minute ventilation (from 5.6±0.4 to 4.8±0.4 L·min-1; p<0.05) and tidal volume (from 0.34±0.03 to 0.3±0.03 L; p<0.05) without a change in energy expenditure, transcutaneous CO2 or alveolar ventilation. There was a significant decrease in dead space ventilation (from 2.5±0.4 to 1.6±0.4 L·min-1; p<0.05), but not in respiratory rate. The reduction in dead space ventilation correlated with baseline physiological dead space fraction (r2=0.36; p<0.05), but not with respiratory rate or anatomical dead space volume.During sleep, NHF decreases minute ventilation due to an overall reduction in dead space ventilation in proportion to the extent of baseline physiological dead space fraction.

Nasal high-flow therapy reduces work of breathing compared with oxygen during sleep in COPD and smoking controls: a prospective observational study.

Patients with chronic obstructive pulmonary disease (COPD) endure excessive resistive and elastic loads leading to chronic respiratory failure. Oxygen supplementation corrects hypoxemia but is not expected to reduce mechanical loads. Nasal high-flow (NHF) therapy supports breathing by reducing dead space, but it is unclear how it affects mechanical loads of patients with COPD. The objective of this study was to compare the effects of low-flow oxygen and NHF therapy on ventilation and work of breathing (WOB) in patients with COPD and controls during sleep. Patients with COPD (n = 12) and controls (n = 6) were recruited and submitted to polysomnography to measure sleep parameters and ventilation in response to administration of oxygen and NHF. A subset of six patients also had an esophageal catheter inserted for the purpose of measuring WOB. Patients with COPD had similar minute ventilation (V̇e) but lower tidal volumes than matched controls. With oxygen, [Formula: see text]was increased and V̇e was reduced in both controls and patients with COPD, but there was an increase in transcutaneous CO2 levels. NHF produced a greater reduction in V̇e and was associated with a reduction in CO2 levels. Although NHF halved WOB, oxygen produced only a minor reduction in this parameter. We conclude that oxygen produced little change in WOB, which was associated with CO2 elevations. On the other hand, NHF produced a large reduction in V̇e and WOB with a concomitant decrease in CO2 levels. Our data indicate that NHF improves alveolar ventilation during sleep compared with oxygen and room air in patients with COPD and therefore can decrease their cost of breathing. NEW & NOTEWORTHY: Nasal high-flow (NHF) therapy can support ventilation in patients with chronic obstructive pulmonary disease during sleep by decreasing the work of breathing and improving CO2 levels. On the other hand, oxygen supplementation corrects hypoxemia, but it produces only a minimal reduction in work of breathing and is associated with increased CO2 levels. Therefore, NHF can be a useful method to assist ventilation in patients with increased respiratory mechanical loads.

Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury.

Acute lung injury (ALI) is a common complication associated with septic shock that directly influences the prognosis of sepsis patients. Currently, one of the main supportive treatment modalities for septic shock is fluid resuscitation. The use of hypertonic saline (HS: 7.5% NaCl) for fluid resuscitation has been described as a promising therapy in experimental models of sepsis-induced ALI, but it has failed to produce similar results in clinical practice. Thus, we compared experimental timing versus clinical timing effectiveness (i.e., early vs. late fluid resuscitation) after the inflammatory scenario was established in a rat model of bacterial lipopolysaccharide-induced ALI. We found that late fluid resuscitation with hypertonic saline (NaCl 7.5%) did not reduce the mortality rates of animals compared with the mortality late associated with early treatment. Late fluid resuscitation with both hypertonic and normal saline increased pulmonary inflammation, decreased pulmonary function, and induced pulmonary injury by elevating metalloproteinase-2 and metalloproteinase-9 activity and collagen deposition in the animals, unlike early treatment. The animals with lipopolysaccharide-induced ALI that received late resuscitation with any kind of fluids demonstrated aggravated pulmonary injury and respiratory function. Moreover, we showed that the therapeutic window for a beneficial effect of fluid resuscitation with hypertonic saline is very narrow.

The effect of increased lung volume in chronic obstructive pulmonary disease on upper airway obstruction during sleep.

Patients with chronic obstructive pulmonary disease (COPD) exhibit increases in lung volume due to expiratory airflow limitation. Increases in lung volumes may affect upper airway patency and compensatory responses to inspiratory flow limitation (IFL) during sleep. We hypothesized that COPD patients have less collapsible airways inversely proportional to their lung volumes, and that the presence of expiratory airflow limitation limits duty cycle responses to defend ventilation in the presence of IFL. We enrolled 18 COPD patients and 18 controls, matched by age, body mass index, sex, and obstructive sleep apnea disease severity. Sleep studies, including quantitative assessment of airflow at various nasal pressure levels, were conducted to determine upper airway mechanical properties [passive critical closing pressure (Pcrit)] and for quantifying respiratory timing responses to experimentally induced IFL. COPD patients had lower passive Pcrit than their matched controls (COPD: -2.8 ± 0.9 cmH2O; controls: -0.5 ± 0.5 cmH2O, P = 0.03), and there was an inverse relationship of subject's functional residual capacity and passive Pcrit (-1.7 cmH2O/l increase in functional residual capacity, r(2) = 0.27, P = 0.002). In response to IFL, inspiratory duty cycle increased more (P = 0.03) in COPD patients (0.40 to 0.54) than in controls (0.41 to 0.51) and led to a marked reduction in expiratory time from 2.5 to 1.5 s (P < 0.01). COPD patients have a less collapsible airway and a greater, not reduced, compensatory timing response during upper airway obstruction. While these timing responses may reduce hypoventilation, it may also increase the risk for developing dynamic hyperinflation due to a marked reduction in expiratory time.

Hypertonic Saline (NaCl 7.5%) Reduces LPS-Induced Acute Lung Injury in Rats.

Acute respiratory distress syndrome (ARDS) is the most severe lung inflammatory manifestation and has no effective therapy nowadays. Sepsis is one of the main illnesses among ARDS causes. The use of fluid resuscitation is an important treatment for sepsis, but positive fluid balance may induce pulmonary injury. As an alternative, fluid resuscitation with hypertonic saline ((HS) NaCl 7.5%) has been described as a promising therapeutical agent in sepsis-induced ARDS by the diminished amount of fluid necessary. Thus, we evaluated the effect of hypertonic saline in the treatment of LPS-induced ARDS. We found that hypertonic saline (NaCl 7.5%) treatment in rat model of LPS-induced ARDS avoided pulmonary function worsening and inhibited type I collagen deposition. In addition, hypertonic saline prevented pulmonary injury by decreasing metalloproteinase 9 (MMP-9) activity in tissue. Focal adhesion kinase (FAK) activation was reduced in HS group as well as neutrophil infiltration, NOS2 expression and NO content. Our study shows that fluid resuscitation with hypertonic saline decreases the progression of LPS-induced ARDS due to inhibition of pulmonary remodeling that is observed when regular saline is used.

Nasal insufflation treatment adherence in obstructive sleep apnea.

BACKGROUND: Nasal insufflation (NI) is a novel treatment method that has been introduced for improving respiration during sleep. NI's warmed and humidified nasal airflow provides ventilatory assistance delivered as a rapidly dispersed pressure head, with minimal side wall pressures, that may affect treatment tolerability. The aim of the current study was to investigate objective and subjective adherence rates for NI therapy in mild to moderate obstructive sleep apnea (OSA). METHODS: Ten patients (three men and seven women; age, 51.3 ± 9.6 years; BMI, 32.2 ± 7.7 kg/m2 [mean ± sd]) with recently diagnosed mild to moderate OSA (10.9 ± 5.8 events/h) were investigated. A crossover design was used to compare adherence to NI and continuous positive airway pressure (CPAP) therapy using a range of objective and subjective measurements. Objective (sleep efficiency (%) and arousal indices (arousal/h)) and subjective evaluations of sleep quality were carried out each night in the laboratory. During in-home treatment, adherence for both therapies was assessed objectively (time on therapy) and subjectively (self-reported sleep diary). RESULTS: Objectively derived adherence values were comparable for CPAP and NI, with both treatment devices sharing similar usage per night (3.5 ± 2.5 vs. 3.6 ± 1.6 h/night; respectively) and the number of nights with at least 4 h of treatment (5.5 ± 4.3 vs. 6.8 ± 3.3 nights/trial, respectively). Self-reported adherence was significantly higher than objectively assessed adherence (p < 0.03). CONCLUSIONS: This study showed similar adherence to NI and CPAP over a short period of usage. A randomized clinical trial is now essential for determining the comparative effectiveness of NI therapy in relation to treatment with CPAP.

Leptin and the control of pharyngeal patency during sleep in severe obesity.

RATIONALE: Obesity imposes mechanical loads on the upper airway, resulting in flow limitation and obstructive sleep apnea (OSA). In previous animal models, leptin has been considered to serve as a stimulant of ventilation and may prevent respiratory depression during sleep. We hypothesized that variations in leptin concentration among similarly obese individuals will predict differences in compensatory responses to upper airway obstruction during sleep. METHODS: An observational study was conducted in 23 obese women [body mass index (BMI): 46 ± 3 kg/m(2), age: 41 ± 12 yr] and 3 obese men (BMI: 46 ± 3 kg/m(2), age: 43 ± 4 yr). Subjects who were candidates for bariatric surgery were recruited to determine upper airway collapsibility under hypotonic conditions [pharyngeal critical pressure (passive PCRIT)], active neuromuscular responses to upper airway obstruction during sleep, and overnight fasting serum leptin levels. Compensatory responses were defined as the differences in peak inspiratory airflow (ΔVImax), inspired minute ventilation (ΔVI), and pharyngeal critical pressure (ΔPCRIT) between the active and passive conditions. RESULTS: Leptin concentration was not associated with sleep disordered breathing severity, passive PCRIT, or baseline ventilation. In the women, increases in serum leptin concentrations were significantly associated with increases in ΔVImax (r(2) = 0.44, P < 0.001), ΔVI (r(2) = 0.40, P < 0.001), and ΔPCRIT (r(2) = 0.19, P < 0.04). These responses were independent of BMI, waist-to-hip ratio, neck circumference, or sagittal girth. CONCLUSION: Leptin may augment neural compensatory mechanisms in response to upper airway obstruction, minimizing upper airway collapse, and/or mitigating potential OSA severity. Variability in leptin concentration among similarly obese individuals may contribute to differences in OSA susceptibility.

Role of focal adhesion kinase in lung remodeling of endotoxemic rats.

Despite significant advances in the care of critically ill patients, acute lung injury continues to be a complex problem with high mortality. The present study was designed to characterize early lipopolysaccharide (LPS)-induced pulmonary injury and small interfering RNA targeting focal adhesion kinase (FAK) as a possible therapeutic tool in the septic lung remodeling process. Male Wistar rats were assigned into endotoxemic group and control group. Total collagen deposition was performed 8, 16, and 24 h after LPS injection. Focal adhesion kinase expression, interstitial and vascular collagen deposition, and pulmonary mechanics were analyzed at 24 h. Intravenous injection of small interfering RNA targeting FAK was used to silence expression of the kinase in pulmonary tissue. Focal adhesion kinase, total collagen deposition, and pulmonary mechanics showed increased in LPS group. Types I, III, and V collagen showed increase in pulmonary parenchyma, but only type V increased in vessels 24 h after LPS injection. Focal adhesion kinase silencing prevented lung remodeling in pulmonary parenchyma at 24 h. In conclusion, LPS induced a precocious and important lung remodeling. There was fibrotic response in the lung characterized by increased amount in total and specific-type collagen. These data may explain the frequent clinical presentation during sepsis of reduced lung compliance, oxygen diffusion, and pulmonary hypertension. The fact that FAK silencing was protective against lung collagen deposition underscores the therapeutic potential of FAK targeting by small interfering RNA.

Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study.

OBJECTIVE: To describe the composition of metabolic acidosis in patients with severe sepsis and septic shock at intensive care unit admission and throughout the first 5 days of intensive care unit stay. DESIGN: Prospective, observational study. SETTING: Twelve-bed intensive care unit. PATIENTS: Sixty patients with either severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were collected until 5 days after intensive care unit admission. We studied the contribution of inorganic ion difference, lactate, albumin, phosphate, and strong ion gap to metabolic acidosis. At admission, standard base excess was -6.69 +/- 4.19 mEq/L in survivors vs. -11.63 +/- 4.87 mEq/L in nonsurvivors (p < .05); inorganic ion difference (mainly resulting from hyperchloremia) was responsible for a decrease in standard base excess by 5.64 +/- 4.96 mEq/L in survivors vs. 8.94 +/- 7.06 mEq/L in nonsurvivors (p < .05); strong ion gap was responsible for a decrease in standard base excess by 4.07 +/- 3.57 mEq/L in survivors vs. 4.92 +/- 5.55 mEq/L in nonsurvivors with a nonsignificant probability value; and lactate was responsible for a decrease in standard base excess to 1.34 +/- 2.07 mEq/L in survivors vs. 1.61 +/- 2.25 mEq/L in nonsurvivors with a nonsignificant probability value. Albumin had an important alkalinizing effect in both groups; phosphate had a minimal acid-base effect. Acidosis in survivors was corrected during the study period as a result of a decrease in lactate and strong ion gap levels, whereas nonsurvivors did not correct their metabolic acidosis. In addition to Acute Physiology and Chronic Health Evaluation II score and serum creatinine level,inorganic ion difference acidosis magnitude at intensive care unit admission was independently associated with a worse outcome. CONCLUSIONS: Patients with severe sepsis and septic shock exhibit a complex metabolic acidosis at intensive care unit admission, caused predominantly by hyperchloremic acidosis,which was more pronounced in nonsurvivors. Acidosis resolution in survivors was attributable to a decrease in strong ion gap and lactate levels.

Exposure to ambient levels of particles emitted by traffic worsens emphysema in mice.

OBJECTIVES: We investigated effects of chronic exposure (2 months) to ambient levels of particulate matter (PM) on development of protease-induced emphysema and pulmonary remodeling in mice. METHODS: Balb/c mice received nasal drop of either papain or normal saline and were kept in two exposure chambers situated in an area with high traffic density. One of them received ambient air and the other had filters for PM. RESULTS: mean concentration of PM10 was 2.68 +/- 0.38 and 33.86 +/- 2.09 microg/m3, respectively, in the filtered and ambient air chambers (p < 0.001). After 2 months of exposure, lungs from papain-treated mice kept in the chamber with ambient air presented greater values of mean linear intercept, an increase in density of collagen fibers in alveolar septa and in expression of 8-isoprostane (p = 0.002, p < 0.05 and p = 0.002, respectively, compared to papain-treated mice kept in the chamber with filtered air). We did not observe significant differences between these two groups in density of macrophages and in amount of cells expressing matrix metalloproteinase-12. There were no significant differences in saline-treated mice kept in the two chambers. CONCLUSIONS: We conclude that exposure to urban levels of PM worsens protease-induced emphysema and increases pulmonary remodeling. We suggest that an increase in oxidative stress induced by PM exposure influences this response. These pulmonary effects of PM were observed only in mice with emphysema.

Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability.

Free fatty acids (FFAs) have been shown to produce alteration of heart rate variability (HRV) in healthy and diabetic individuals. Changes in HRV have been described in septic patients and in those with hyperglycemia and elevated plasma FFA levels. We studied if sepsis-induced heart damage and HRV alteration are associated with plasma FFA levels in patients. Thirty-one patients with sepsis were included. The patients were divided into two groups: survivors(n = 12) and nonsurvivors (n = 19). The following associations were investigated: (a) troponin I elevation and HRV reduction and (b) clinical evolution and HRV index, plasma troponin, and plasma FFA levels. Initial measurements of C-reactive protein and gravity Acute Physiology and Chronic Health Evaluation scores were similar in both groups. Overall, an increase in plasma troponin level was related to increased mortality risk. From the first day of study, the nonsurvivor group presented a reduced left ventricular stroke work systolic index and a reduced low frequency (LF) that is one of HRV indexes. The correlation coefficient for LF values and troponin was r(2) = 0.75 (P < 0.05). All patients presented elevated plasma FFA levels on the first day of the study (5.11 +/- 0.53 mg/mL), and this elevation was even greater in the nonsurvivor group compared with the survivors (6.88 +/- 0.13 vs. 3.85 +/- 0.48 mg/mL, respectively; P < 0.05). Cardiac damage was confirmed by measurement of plasma troponin I and histological analysis. Heart dysfunction was determined by left ventricular stroke work systolic index and HRV index in nonsurvivor patients. A relationship was found between plasma FFA levels, LFnu index, troponin levels, and histological changes. Plasma FFA levels emerged as possible cause of heart damage in sepsis.

Efeito da exposição à fumaça de cigarro e ao resíduo de óleo diesel (ROFA) em pulmões de camundongos C57/BI6 / Effects of the exposure to cigarette smoke and residual oil fly ash (ROFA) in lungs of C57/Bl6 mice

Vários mecanismos que participam do desenvolvimento da DPOC (Doença Pulmonar Obstrutiva Crônica) não são ainda bem esclarecidos. Neste estudo, expusemos camundongos C57/Bl6, por 2 meses, à fumaça de cigarro e/ou à ROFA (resíduo de óleo diesel). Os animais expostos à fumaça de cigarro desenvolveram aumento da resistência de grandes vias aéreas, provavelmente por espessamento da sua parede, resultante de alterações nas células epiteliais. Estes animais também desenvolveram enfisema inicial, com distensão de espaços aéreos em algumas regiões pulmonares. Não houve recrutamento de células inflamatórias, alteração de fibras elásticas ou colágenas ou aumento do estresse oxidativo, medido pelo Isoprostano 8. Este trabalho sugere que há uma lesão pulmonar inicial que se caracteriza por alterações nas células epiteliais e algum grau de enfisema, que pode ser mediado pelas próprias células epiteliais.

Many of the mechanisms leading to CPOD (Chronic Pulmonary Obstructive Disease) are not completely understood. In the present study, we exposed C57/Bl6 mice, for two months, to cigarette smoke and/or ROFA (Residual Oil Fly Ash). Animals exposed to cigarette smoke had an increased in proximal airways resistance, probably due to the thickening of airways walls that followed changes in epithelial cells. These animals also had a small degree of emphysema, once air spaces enlargement could be noticed in circumscribed lung areas. We observed no inflammatory cells recruitment, elastic or collagen fibers deposition or increases in oxidative stress, measured by staining Isoprotane8. This study shows an early stage of the CPOD development, in which we can detect changes in epithelial cells and a small degree of emphysema, which could be mediated by these same epithelial cells.

Diagnóstico sindrômico / Syndromic diagnoses

O raciocínio clínico diagnóstico mudou muito ao longo dos anos, partindo de diagnóstico (e tratamento) de sinais para, nos dias de hoje, fazermos diagnósticos mais precisos, visando o melhor tratamento. A partir da anamnese e usando técnicas de raciocínio diagnóstico hipotético-dedutivo ou reconhecimento de padrão (as duas mais utilizadas) procura-se, a partir de diagnósticos sindrômicos, chegar a diagnósticos etiológicos / Clinical diagnosis changed a lot in history, starting with diagnosing (and treating) signs and symptoms to, in modern times, making more precise diagnosis, seeking the best treatment. Starting with clinical history and using hypothetic-deductive way of thinking or pattern recognition (the two most used techniques), we seek, through syndromic diagnosis, the etiologic diagnosis...