Jose G. Venegas

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.

Use of recruitment maneuvers and high-positive end-expiratory pressure in a patient with acute respiratory distress syndrome.

Objective: To present the use of a novel high‐pressure recruitment maneuver followed by high levels of positive end‐expiratory pressure in a patient with the acute respiratory distress syndrome (ARDS). Design: Observations in one patient. Setting: The medical intensive care unit at a tertiary care university teaching hospital. Patient: A 32‐yr‐old woman with severe ARDS secondary to streptococcal sepsis. Interventions: The patient had severe gas exchange abnormalities because of acute lung injury and marked lung collapse. Attempts to optimize recruitment based on the inflation pressure‐volume (PV) curve were not sufficient to avoid dependent lung collapse. We used a recruitment maneuver using 40 cm H2O of positive end‐expiratory pressure (PEEP) and 20 cm H2O of pressure controlled ventilation above PEEP for 2 mins to successfully recruit the lung. The recruitment was maintained with 25 cm H2O of PEEP, which was much higher than the PEEP predicted by the lower inflection point (PFlex) of the PV curve. Measurements and Main Results: Recruitment was assessed by improvements in oxygenation and by computed tomography of the chest. With the recruitment maneuvers, the patient had a dramatic improvement in gas exchange and we were able to demonstrate nearly complete recruitment of the lung by computed tomography. A PV curve was measured that demonstrated a PFlex of 16‐18 cm H2O. Conclusion: Accumulating data suggest that the maximization and maintenance of lung recruitment may reduce lung parenchymal injury from positive pressure ventilation in ARDS. We demonstrate that in this case PEEP alone was not adequate to recruit the injured lung and that a high‐pressure recruitment maneuver was required. After recruitment, high‐level PEEP was needed to prevent derecruitment and this level of PEEP was not adequately predicted by the PFlex of the PV curve.

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.

Understanding the pressure cost of ventilation: why does high-frequency ventilation work?

Objectives: To understand when the use of high‐frequency ventilation would be advantageous, we formulated the problem of achieving adequate alveolar ventilation at minimal pressure cost by dividing it into two simpler problems: a) the pressure cost per unit of convective oscillatory flow; and b) the convective flow cost necessary to achieve a unit of alveolar ventilation. Methods: Simple solutions for each of these cost functions were formulated using established models of gas exchange and lung mechanics, including the effects of lung inflation tidal volume and respiratory frequency in alveolar ventilation, nonlinear lung tissue compliance, and alveolar recruitment and derecruitment. Solutions to these models were combined to assess the total pressure cost of high‐frequency ventilation as a function of the ventilatory settings and the pathophysiologic variables of the patient. Main Results: The model predicted that for variables applicable to an infant with respiratory distress syndrome, the selection of positive end‐expiratory pressure (PEEP) becomes critical because the penalties in pressure cost are amplified for both high and low values of PEEP. The selection of frequency is not as critical for frequencies >10 Hz, although it is more important than in the normal neonatal lung. Conclusions: This analysis illustrates the importance of using high‐frequency ventilation in infant respiratory distress syndrome and of optimizing the amount of PEEP. It also points out the danger of barotrauma in the derecruited lung. When the lungs are in a derecruited state, the combinations of frequency, PEEP, and tidal volume that yield adequate ventilation with safe distention of recruited alveoli are severely limited. (Crit Care Med 1994; 22:S49‐S57)

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.

Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

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.

Mouth occlusion pressure (P0.1) in acute respiratory failure

We studied 20 unselected patients admitted to our Intensive Care Unit (ICU) suffering from acute respiratory failure (ARF), who needed mechanical ventilatory support. In all of them we followed a prospective protocol to investigate the value of mouth occlusion pressure (P0.1) as an indicator for weaning. Fifty-two tests were classified into three groups: a need to be reconnected to mechanical ventilation (MV), stable on intermittent mandatory ventilation (IMV), or spontaneous breathing on a T-tube (TT). The results showed that at increased values of P0.1 there were more difficulties in weaning patients from MV. Seventy-eight percent (78%) of the occasions where weaning was successful, values of P0.1 were ≤4.2 cm H2O, in chronic or non-chronic patients. Eighty-nine percent (89%) of the times when P0.1 values were higher than 4.2 cm H2O the same patients required ventilatory support, total (MV) or partial (IMV). These differences were statistically significant (p<0.01). We conclude that the P0.1 is an easily obtained non-invasive parameter, that can contribute along with other more conventional measurements to a superior indication for weaning.

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.

Effects of nebulized salbutamol on respiratory mechanics in adult respiratory distress syndrome

Objective:To determine whether nebulized salbutamol improves the respiratory mechanics of patients with adult respiratory distress syndrome (ARDS). We also assessed the mechanisms that contribute to high respiratory system resistances during this disease.Patients and setting:Eleven consecutive patients with ARDS without clinical evidence of chronic obstructive pulmonary disease, admitted to a polivalent intensive care unit, and mechanically ventilated with Siemens Elema Servo C ventilator at constant inspiratory flow.Method:Peak airway pressure (Ppeak), airway pressure immediately after end inspiratory occlusion (P1), plateau pressure (P2) and intrinsic positive end-expiratory pressure (PEEPi) were measured at baseline condition and then 5, 15, and 30 min after 1 mg of salbutamol had been administered via a nebulizer through the endotracheal tube. Partial pressure of arterial oxygen (PaO2), heart rate (HR) and mean blood pressure (BP) were monitored and minimal respiratory system resistances (Rrs, m), additional resistances (DRrs) and static compliance (Cst) were computedResults:Between baseline and post-salbutamol, we observed changes in Ppeak, P1, P2, PEEPi and Rrs, m. As there were no significant differences between values at the different intervals during post administration, the results are described comparing baseline and 15 min post-salbutamol administration values. We found a significant decrease in Ppeak (4.9±0.8 cmH2O), P1 (3±0.6 cmH2O), P2 (2.1±0.6 cmH2O), PEEPi (1.9±0.5 cmH2O) and Rrs, m (1.9±0.3 cmH2O/1 s-1); DR, rs decreased in five patients, did not change in four and increased in two. HR, PaO2 and BP did not change.Conclusions:a) Salbutamol administered through the endotracheal tube by a nebulizer device lessens respiratory system resistances and airway and alveolar pressures, and therefore could decrease the risk of barotrauma and alveolar damage; b) high respiratory system resistances in ARDS have an increased smooth muscle tone component that can be reversible with salbutamol.