Marcos F. Vidal Melo

Self-organized patchiness in asthma as a prelude to catastrophic shifts

Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

Perioperative Echocardiographic Examination for Ventricular Assist Device Implantation

Ventricular assist devices (VADs) are systems for mechanical circulatory support of the patient with severe heart failure. Perioperative transesophageal echocardiography is a major component of patient management, and important for surgical and anesthetic decision making. In this review we present the rationale and available data for a comprehensive echocardiographic assessment of patients receiving a VAD. In addition to the standard examination, device-specific pre-, intra-, and postoperative considerations are essential to the echocardiographic evaluation. These include: (a) the pre-VAD insertion examination of the heart and large vessels to exclude significant aortic regurgitation, tricuspid regurgitation, mitral stenosis, patent foramen ovale, or other cardiac abnormality that could lead to right-to-left shunt after left VAD placement, intracardiac thrombi, ventricular scars, pulmonic regurgitation, pulmonary hypertension, pulmonary embolism, and atherosclerotic disease in the ascending aorta; and to assess right ventricular function; and (b) the post-VAD insertion examination of the device and reassessment of the heart and large vessels. The examination of the device aims to confirm completeness of device and heart deairing, cannulas alignment and patency, and competency of device valves using two-dimensional, and color, continuous and pulsed wave Doppler modalities. The goal for the heart examination after implantation should be to exclude aortic regurgitation, or an uncovered right-to-left shunt; and to assess right ventricular function, left ventricular unloading, and the effect of device settings on global heart function. The variety of VAD models with different basic and operation principles requires specific echocardiographic assessment targeted to the characteristics of the implanted device.

Intraoperative protective mechanical ventilation and risk of postoperative respiratory complications: hospital based registry study

Objective To evaluate the effects of intraoperative protective ventilation on major postoperative respiratory complications and to define safe intraoperative mechanical ventilator settings that do not translate into an increased risk of postoperative respiratory complications. Design Hospital based registry study. Setting Academic tertiary care hospital and two affiliated community hospitals in Massachusetts, United States. Participants 69 265 consecutively enrolled patients over the age of 18 who underwent a non-cardiac surgical procedure between January 2007 and August 2014 and required general anesthesia with endotracheal intubation. Interventions Protective ventilation, defined as a median positive end expiratory pressure (PEEP) of 5 cmH2O or more, a median tidal volume of less than 10 mL/kg of predicted body weight, and a median plateau pressure of less than 30 cmH2O. Main outcome measure Composite outcome of major respiratory complications, including pulmonary edema, respiratory failure, pneumonia, and re-intubation. Results Of the 69 265 enrolled patients 34 800 (50.2%) received protective ventilation and 34 465 (49.8%) received non-protective ventilation intraoperatively. Protective ventilation was associated with a decreased risk of postoperative respiratory complications in multivariable regression (adjusted odds ratio 0.90, 95% confidence interval 0.82 to 0.98, P=0.013). The results were similar in the propensity score matched cohort (odds ratio 0.89, 95% confidence interval 0.83 to 0.97, P=0.004). A PEEP of 5 cmH2O and median plateau pressures of 16 cmH2O or less were associated with the lowest risk of postoperative respiratory complications. Conclusions Intraoperative protective ventilation was associated with a decreased risk of postoperative respiratory complications. A PEEP of 5 cmH2O and a plateau pressure of 16 cmH2O or less were identified as protective mechanical ventilator settings. These findings suggest that protective thresholds differ for intraoperative ventilation in patients with normal lungs compared with those used for patients with acute lung injury.

The distribution of ventilation during bronchoconstriction is patchy and bimodal: a PET imaging study.

Recent PET imaging data from bronchoconstricted sheep (Vidal Melo et al., 2005) showed that V /Q distributions were bimodal and topographically patchy, but including a substantial heterogeneity at scales <2.2 ml. In this paper, we reanalyze the experimental data to establish the contribution of ventilation (V (r)) heterogeneity to the bimodality in V /Q . This analysis demonstrates that the distribution of V (r) during bronchoconstriction was bimodal with large patches of severe hypoventilation occupying an average of 41% of the imaged lung. The degree of hypoventilation to these regions was highly correlated with the degree of oxygenation impairment, but was quite variable amongst animals in spite of consistent degrees of mechanical obstruction. Remarkably, those regions were found to be hyperventilated before methacholine and their degree of hyperventilation was correlated with their degree of hypoventilation during bronchoconstriction. These data suggest that improving the uniformity of ventilation at baseline may be a desirable therapeutic target if the risk of severe hypoxemia during asthma attacks is to be minimized and/or the distribution of inhaled pharmaceuticals is to be optimized.

Mechanism by Which a Sustained Inflation Can Worsen Oxygenation in Acute Lung Injury

BackgroundSustained lung inflations (recruitment maneuvers [RMs]) are occasionally used during mechanical ventilation of patients with acute lung injury to restore aeration to atelectatic alveoli. However, RMs do not improve, and may even worsen, gas exchange in a fraction of these patients. In this study, the authors sought to determine the mechanism by which an RM can impair gas exchange in acute lung injury. MethodsThe authors selected a model of acute lung injury that was unlikely to exhibit sustained recruitment in response to a lung inflation. In five sheep, lung injury was induced by lavage with 0.2% polysorbate 80 in saline. Positron emission tomography and [13N]nitrogen were used to assess regional lung function in dependent, middle, and nondependent lung regions. Physiologic data and positron emission scans were collected before and 5 min after a sustained inflation (continuous positive airway pressure of 50 cm H2O for 30 s). ResultsAll animals showed greater loss of aeration and higher perfusion and shunting blood flow in the dependent region. After the RM, Pao2 decreased in all animals by 35 ± 22 mmHg (P < 0.05). This decrease in Pao2 was associated with redistribution of pulmonary blood flow from the middle, more aerated region to the dependent, less aerated region (P < 0.05) and with an increase in the fraction of pulmonary blood flow that was shunted in the dependent region (P < 0.05). Neither respiratory compliance nor aeration of the dependent region improved after the RM. ConclusionsWhen a sustained inflation does not restore aeration to atelectatic regions, it can worsen oxygenation by increasing the fraction of pulmonary blood flow that is shunted in nonaerated regions.

Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury

Background:Alveolar overdistension and repetitive derecruitment–recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident. Methods:The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left (“test”) lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of −10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right (“control”) lung was protected from VILI. Results:Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone. Conclusion:The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.

Changes in Regional Ventilation after Autologous Blood Clot Pulmonary Embolism

BACKGROUND Previous studies have suggested that pulmonary embolism (PE) and pulmonary artery occlusion result in a shift in alveolar ventilation away from unperfused regions. This study aimed to directly assess changes in regional specific ventilation (sV(A)) due to autologous blood clot PE using positron emission tomography. METHODS Pulmonary embolism was created in six anesthetized, paralyzed, and mechanically ventilated sheep by injecting cylindrical clots of autologous blood (7 mm in diameter and height). Clots were progressively infused into a central vein until a stable mean pulmonary artery pressure between 30 and 40 mmHg was achieved. A multislice positron emission tomography camera was used to image 15 contiguous, 6.5-mm-thick transverse cross-sections of the chest beginning just above the diaphragm. sV(A) from perfused regions (sV(A),(p)) was assessed as the ventilatory turnover rate of the tracer NN after central venous injection of NN-labeled saline. RESULTS Pulmonary embolism obstructed flow to 64% of imaged areas. Before PE, (sV(A),(p))was equivalent in areas that would remain perfused and those that would become embolized after PE (0.021 +/- 0.007 0.021 +/- 0.006 s(-1); P = nonsignificant). After PE, sV(A),(p) of areas remaining perfused increased to 0.033 +/- 0.011 s (-1) (P < 0.005). This effect on regional sV(A),(p) could have been caused by active redistribution of sV(A),(p) or by a reduction in tracer concentration of perfused areas due to the dead space common to perfused and embolized regions. Model simulations indicated that the common dead-space effect could only explain a small part of the sV(A),(p) increase. CONCLUSIONS An increase in sV(A),(p) of perfused regions occurs following PE with 7-mm autologous blood clots. This increase is most likely caused by a shift in ventilation away from embolized areas mediated by hypocapnic pneumoconstriction.

Assessment of Lung Inflammation With 18F-FDG PET During Acute Lung Injury

OBJECTIVE The purpose of this review is to describe the current experimental and clinical data regarding the fundamentals and applications of (18)F-FDG PET during acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). CONCLUSION Lung inflammation is a key feature of ALI. During ALI, FDG PET can be used to monitor lung neutrophils, which are essential cells in the pathophysiologic mechanisms of ALI. Pulmonary FDG kinetics are altered during experimental and human ALI and are associated with regional lung dysfunction, histologic abnormalities, and prognosis. FDG PET may be a valuable noninvasive method for gaining comprehensive understanding of the mechanisms of ALI/ARDS and for evaluating therapeutic interventions.

Spatial Heterogeneity of Lung Perfusion Assessed with 13N PET as a Vascular Biomarker in Chronic Obstructive Pulmonary Disease

Although it is known that structural and functional changes in the pulmonary vasculature and parenchyma occur in the progress of chronic obstructive pulmonary disease (COPD), information is limited on early regional perfusion (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r) alterations. Methods: We studied 6 patients with mild or moderate COPD and 9 healthy subjects (6 young and 3 age-matched). The PET 13NN-labeled saline injection method was used to compute images of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r and regional ventilation (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r). Transmission scans were used to assess regional density. We used the squared coefficient of variation to quantify \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity and length-scale analysis to quantify the contribution to total perfusion heterogeneity of regions ranging from less than 12 to more than 108 mm. Results: Perfusion distribution in COPD subjects showed larger \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity, higher contribution from large length scales and lower contribution from small length scales, and larger heterogeneity of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r normalized by tissue density than did healthy subjects. Dorsoventral gradients of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r were present in healthy subjects, with larger ventilation in dependent regions, whereas no gradient was present in COPD. Heterogeneity of ventilation–perfusion ratios was larger in COPD. Conclusion: \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r is significantly redistributed in COPD. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity in COPD patients is greater than in healthy subjects, mainly because of the contribution of large lung regions and not because of changes in tissue density or \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r. The assessment of spatial heterogeneity of lung perfusion with 13NN-saline PET may serve as a vascular biomarker in COPD.

Mild endotoxemia during mechanical ventilation produces spatially heterogeneous pulmonary neutrophilic inflammation in sheep.

Background:There is limited information on the regional inflammatory effects of mechanical ventilation and endotoxemia on the production of acute lung injury. Measurement of 18F-fluorodeoxyglucose (18F-FDG) uptake with positron emission tomography allows for the regional, in vivo and noninvasive, assessment of neutrophilic inflammation. The authors tested whether mild endotoxemia combined with large tidal volume mechanical ventilation bounded by pressures within clinically acceptable limits could yield measurable and anatomically localized neutrophilic inflammation. Methods:Sheep were mechanically ventilated with plateau pressures = 30-32 cm H2O and positive end-expiratory pressure = 0 for 2 h. Six sheep received intravenous endotoxin (10 ng · kg−1 · min−1), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused 13N-nitrogen and 18F-FDG to compute regional perfusion and 18F-FDG uptake. Transmission scans were used to assess aeration. Results:Mean gas fraction and perfusion distribution were similar between groups. In contrast, a significant increase in 18F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, 18F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the 18F-FDG uptake was associated with regional aeration (P < 0.01) and perfusion (P < 0.01). Conclusions:Mild short-term endotoxemia in the presence of heterogeneous lung aeration and mechanical ventilation with pressures within clinically acceptable limits produces marked spatially heterogeneous increases in pulmonary neutrophilic inflammation. The dependence of inflammation on aeration and perfusion suggests a multifactorial basis for that finding. 18F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions.