Alessandro Beda

Size at Birth and Autonomic Function During Psychological Stress

Small size at birth is associated with exaggerated blood pressure responses to psychological stressors, which increase the risk of developing sustained hypertension in adult life. Explanatory mechanisms for this association are not well characterized. We investigated the hypothesis that an adverse fetal environment, reflected by small size at birth, persistently alters autonomic nervous system and baroreflex control of cardiovascular function, resulting in exaggerated blood pressure and heart rate responses to stressors. Men and women from an Australian prospective cohort study underwent a series of 3 psychological stressors (Stroop, mirror-tracing, and speech) while their blood pressure was recorded continuously using a Portapres. Indices of autonomic function were derived using spectrum analysis (wavelet packet transform), and baroreflex function was estimated using an adaptive autoregressive model. We found that women who were small at birth demonstrated increased levels of low-frequency blood pressure variability at rest (r=−0.28; P<0.05) and during stress (r=−0.42; P<0.001), reduced levels of high-frequency heart period variability (r=0.22; P<0.05), and reduced baroreflex sensitivity (r=0.34; P<0.01). These findings were not present in the men. This study provides evidence that markers of impaired fetal growth are related to autonomic cardiovascular control involving modulation of both sympathetic and parasympathetic function but in a sex-specific manner. We also provide the first human evidence of a relationship between size at birth and baroreflex function.

Pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support.

Objectives:To explore whether 1) conventional pressure support ventilation improves lung function and attenuates the pulmonary inflammatory response compared to pressure-controlled ventilation and 2) random variation of pressure support levels (noisy pressure support ventilation) adds further beneficial effects to pressure support ventilation. Design:Three-arm, randomized, experimental study. Setting:University hospital research facility. Subjects:Twenty-four juvenile pigs. Interventions:Acute lung injury was induced by surfactant depletion. Animals were randomly assigned to 6 hrs of mechanical ventilation (n = 8 per group) with either 1) pressure-controlled ventilation, 2) pressure support ventilation, or 3) noisy pressure support ventilation. During noisy pressure support ventilation, the pressure support varied randomly, with values following a normal distribution. In all groups, the driving pressures were set to achieve a mean tidal volume of 6 mL/kg. At the end of experiments, animals were killed and lungs extracted for histologic and biochemical analysis. Measurements and Main Results:Respiratory, gas-exchange, and hemodynamics variables were assessed hourly. The diffuse alveolar damage and the inflammatory response of lungs were quantified. Pressure support ventilation and noisy pressure support ventilation improved gas exchange and were associated with reduced histologic damage and interleukin-6 concentrations in lung tissue compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange and decreased the inspiratory effort while reducing alveolar edema and inflammatory infiltration compared to pressure support ventilation. Conclusions:In this model of acute lung injury, pressure support ventilation and noisy pressure support ventilation attenuated pulmonary inflammatory response and improved gas exchange as compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange, reduced the inspiratory effort, and attenuated alveolar edema and inflammatory infiltration as compared to conventional pressure support ventilation.

Sex-specific programming of cardiovascular physiology in children

AIMS Increasing evidence suggests that adverse prenatal environments, as indicated by low birth weight, cause long-term changes in cardiovascular physiology that predispose to circulatory disease. The mechanisms are poorly understood, most human studies have been carried out in adults and little is known about early pathophysiological changes. Therefore, we have assessed the relationship between birth weight and cardiovascular physiology in children. METHODS AND RESULTS In 140 healthy boys and girls (aged 7-9 years), born at term and followed prospectively, we continuously recorded blood pressure, electrocardiograms and cardiac impedance before, during, and after 10 min of psychosocial stress (Trier Social Stress Test for Children). In boys, an association of lower birth weight with higher resting systemic arterial pressure (β = -6.8 mmHg/kg, P= 0.03) and a trend towards higher vascular resistance (β = -87 dyne s/cm(5)/kg, ns) were substantially strengthened following stress (β = -9.5 mmHg/kg, P= 0.003 and β = -139 dyne s/cm(5)/kg, P = 0.02, respectively). In girls, lower birth weight was associated with a shorter pre-ejection period (β = 8.0 ms/kg, P = 0.005) and corrected QT interval (β = 11.9 ms/kg, P = 0.003) at rest and little changed by stress. CONCLUSION Smaller size at birth is associated with sex-specific alterations in cardiac physiology; boys had higher systemic vascular resistance and girls had increased cardiac sympathetic activation.

Pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow.

BACKGROUND:Spontaneous breathing (SB) activity may improve gas exchange during mechanical ventilation mainly by the recruitment of previously collapsed regions. Pressure support ventilation (PSV) and biphasic positive airway pressure (BIPAP) are frequently used modes of SB, but little is known about the mechanisms of improvement of lung function during these modes of assisted mechanical ventilation. We evaluated the mechanisms behind the improvement of gas exchange with PSV and BIPAP. METHODS:Five pigs (25–29.3 kg) were mechanically ventilated in supine position, and acute lung injury (ALI) was induced by surfactant depletion. After stabilization, BIPAP was initiated with lower continuous positive airway pressure equal to 5 cm H2O and the higher continuous positive airway pressure titrated to achieve a tidal volume between 6 and 8 mL/kg. The depth of anesthesia was reduced, and when SB represented ≥20% of total minute ventilation, PSV and BIPAP + SB were each performed for 1 h (random sequence). Whole chest helical computed tomography was performed during end-expiratory pauses and functional variables were obtained. Pulmonary blood flow (PBF) was marked with IV administered fluorescent microspheres, and spatial cluster analysis was used to determine the effects of each ventilatory mode on the distribution of PBF. RESULTS:ALI led to impairment of lung function and increase of poorly and nonaerated areas in dependent lung regions (P < 0.05). PSV and BIPAP + SB similarly improved oxygenation and reduced venous admixture compared with controlled mechanical ventilation (P < 0.05). Despite that, a significant increase of nonaerated areas in dependent regions with a concomitant decrease of normally aerated areas was observed during SB. In five of six lung clusters, redistribution of PBF from dependent to nondependent, better aerated lung regions were observed during PSV and BIPAP + SB. CONCLUSIONS:In this model of ALI, the improvements of oxygenation and venous admixture obtained during assisted mechanical ventilation with PSV and BIPAP + SB were explained by the redistribution of PBF toward nondependent lung regions rather than recruitment of dependent zones.

Distribution of regional lung aeration and perfusion during conventional and noisy pressure support ventilation in experimental lung injury

In acute lung injury (ALI), pressure support ventilation (PSV) may improve oxygenation compared with pressure-controlled ventilation (PCV), and benefit from random variation of pressure support (noisy PSV). We investigated the effects of PCV, PSV, and noisy PSV on gas exchange as well as the distribution of lung aeration and perfusion in 12 pigs with ALI induced by saline lung lavage in supine position. After injury, animals were mechanically ventilated with PCV, PSV, and noisy PSV for 1 h/mode in random sequence. The driving pressure was set to a mean tidal volume of 6 ml/kg and positive end-expiratory pressure to 8 cmH₂O in all modes. Functional variables were measured, and the distribution of lung aeration was determined by static and dynamic computed tomography (CT), whereas the distribution of pulmonary blood flow (PBF) was determined by intravenously administered fluorescent microspheres. PSV and noisy PSV improved oxygenation and reduced venous admixture compared with PCV. Mechanical ventilation with PSV and noisy PSV did not decrease nonaerated areas but led to a redistribution of PBF from dorsal to ventral lung regions and reduced tidal reaeration and hyperinflation compared with PCV. Noisy PSV further improved oxygenation and redistributed PBF from caudal to cranial lung regions compared with conventional PSV. We conclude that assisted ventilation with PSV and noisy PSV improves oxygenation compared with PCV through redistribution of PBF from dependent to nondependent zones without lung recruitment. Random variation of pressure support further redistributes PBF and improves oxygenation compared with conventional PSV.

Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury.

Background:Spontaneous breathing (SB) in the early phase of the acute respiratory distress syndrome is controversial. Biphasic positive airway pressure/airway pressure release ventilation (BIPAP/APRV) is commonly used, but the level of SB necessary to maximize potential beneficial effects is unknown. Methods:Experimental acute respiratory distress syndrome was induced by saline lung lavage in anesthetized and mechanically ventilated pigs (n = 12). By using a Latin square and crossover design, animals were ventilated with BIPAP/APRV at four different levels of SB in total minute ventilation (60 min each): (1) 0% (BIPAP/APRV0%); (2) greater than 0 to 30% (BIPAP/APRV>0–30%); (3) greater than 30 to 60% (BIPAP/APRV>30–60%); and (4) greater than 60% (BIPAP/APRV>60%). Gas exchange, hemodynamics, and respiratory variables were measured. Lung aeration was assessed by high-resolution computed tomography. The distribution of perfusion was marked with 68Ga-labeled microspheres and evaluated by positron emission tomography. Results:The authors found that higher levels of SB during BIPAP/APRV (1) improved oxygenation; (2) decreased mean transpulmonary pressure (stress) despite increased inspiratory effort; (3) reduced nonaerated lung tissue, with minimal changes in the distribution of perfusion, resulting in decreased low aeration/perfusion zones; and (4) decreased global strain (mean ± SD) (BIPAP/APRV0%: 1.39 ± 0.08; BIPAP/APRV0–30%: 1.33 ± 0.03; BIPAP/APRV30–60%: 1.27 ± 0.06; BIPAP/APRV>60%: 1.25 ± 0.04, P < 0.05 all vs. BIPAP/APRV0%, and BIPAP/APRV>60% vs. BIPAP/APRV0–30%). Conclusions:In a saline lung lavage model of experimental acute respiratory distress syndrome in pigs, levels of SB during BIPAP/APRV higher than currently recommended for clinical practice, that is, 10 to 30%, improve oxygenation by increasing aeration in dependent lung zones without relevant redistribution of perfusion. In presence of lung recruitment, higher levels of SB reduce global stress and strain despite an increase in inspiratory effort.

Comparative effects of proportional assist and variable pressure support ventilation on lung function and damage in experimental lung injury.

Objective:To investigate the effects of proportional assist ventilation, variable pressure support, and conventional pressure support ventilation on lung function and damage in experimental acute lung injury. Design:Randomized experimental study. Setting:University hospital research facility. Subjects:Twenty-four juvenile pigs. Interventions:Pigs were anesthetized, intubated, and mechanically ventilated. Acute lung injury was induced by saline lung lavage. After resuming of spontaneous breathing, animals were randomly assigned to 6 hrs of assisted ventilation with pressure support ventilation, proportional assist ventilation, or variable pressure support (n = 8 per group). Mean tidal volume was kept at ≈6 mL/kg in all modes. Measurements and Main Results:Lung functional parameters, distribution of ventilation by electrical impedance tomography, and breathing patterns were analyzed. Histological lung damage and pulmonary inflammatory response were determined postmortem. Variable pressure support and proportional assist ventilation improved oxygenation and venous admixture compared with pressure support ventilation. Proportional assist ventilation led to higher esophageal pressure time product than variable pressure support and pressure support ventilation, and redistributed ventilation from central to dorsal lung regions compared to pressure support ventilation. Variable pressure support and proportional assist ventilation yielded higher tidal volume variability than pressure support ventilation. Such pattern was deterministic (self-organized) during proportional assist ventilation and stochastic (random) during variable pressure support. Subject-ventilator synchrony as well as pulmonary inflammatory response and damage did not differ among groups. Conclusions:In a lung lavage model of acute lung injury, both variable pressure support and proportional assist ventilation increased the variability of tidal volume and improved oxygenation and venous admixture, without influencing subject-ventilator synchrony or affecting lung injury compared with pressure support ventilation. However, variable pressure support yielded less inspiratory effort than proportional assist ventilation at comparable mean tidal volumes of 6 mL/kg.

Effects of intravascular volume replacement on lung and kidney function and damage in nonseptic experimental lung injury.

Background:Intravascular volume replacement is often required in the presence of increased pulmonary capillary leakage, for example in patients with volutrauma with major hemorrhage. In the present study, the effects of Ringer’s acetate (RA), gelatin-polysuccinate (GEL), and a modern hydroxyethyl starch (HES, 6% 130/0.42) on lung and kidney function and damage were compared in a two-hit model of acute lung injury. The authors hypothesized that GEL and HES, compared to RA: (1) reduced lung histological damage, (2) impaired kidney morphology and function. Methods:Acute lung injury was induced in 30 anesthetized pigs by tidal volumes approximately 40 ml/kg, after saline lung lavage. Protective ventilation was initiated and approximately≈25% of estimated blood volume was drawn. Animals were randomly assigned to receive RA, GEL, or HES (n = 10/group) aimed at approximately 90% of intrathoracic blood volume before blood drainage. Results:Fluid volumes were higher with RA (2,250 ± 764 ml) than GEL (704 ± 159 ml) and HES (837 ± 82 ml) (P < 0.05). Compared to RA, HES reduced diffuse alveolar damage overall, and GEL in nondependent zones only. GEL and HES yielded lower wet-to-dry ratios compared to RA (6.5 ± 0.5 and 6.5 ± 0.6 vs. 7.9 ± 0.9, respectively, P < 0.05). HES and RA resulted in less kidney damage than GEL, but kidney function did not differ significantly among groups. Compared to GEL, HES yielded lower lung elastance (55 ± 12 vs. 45 ± 13 cm H2O/l, P < 0.05) and intra-abdominal pressure (15 ± 5 vs. 11 ± 4 cm 14;H2O, P < 0.05). Conclusions:In this model of acute lung injury, intravascular volume expansion after major hemorrhage with HES yielded less lung damage than RA and less kidney damage than GEL.

Extrapolation in the analysis of lung aeration by computed tomography: a validation study

IntroductionComputed tomography (CT) is considered the gold standard for quantification of global or regional lung aeration and lung mass. Quantitative CT, however, involves the exposure to ionizing radiation and requires manual image processing. We recently evaluated an extrapolation method which calculates quantitative CT parameters characterizing the entire lung from only 10 reference CT-slices thereby reducing radiation exposure and analysis time. We hypothesized that this extrapolation method could be further validated using CT-data from pigs and sheep, which have a different thoracic anatomy.MethodsWe quantified volume and mass of the total lung and differently aerated lung compartments in 168 ovine and 55 porcine whole-lung CTs covering lung conditions from normal to gross deaeration. Extrapolated volume and mass parameters were compared to the respective values obtained by whole-lung analysis. We also tested the accuracy of extrapolation for all possible numbers of CT slices between 15 and 5. Bias and limits of agreement (LOA) were analyzed by the Bland-Altman method.ResultsFor extrapolation from 10 reference slices, bias (LOA) for the total lung volume and mass of sheep were 18.4 (-57.2 to 94.0) ml and 4.2 (-21.8 to 30.2) grams, respectively. The corresponding bias (LOA) values for pigs were 5.1 (-55.2 to 65.3) ml and 1.6 (-32.9 to 36.2) grams, respectively. All bias values for differently aerated lung compartments were below 1% of the total lung volume or mass and the LOA never exceeded ± 2.5%. Bias values diverged from zero and the LOA became considerably wider when less than 10 reference slices were used.ConclusionsThe extrapolation method appears robust against variations in thoracic anatomy, which further supports its accuracy and potential usefulness for clinical and experimental application of quantitative CT.

A novel adaptive control system for noisy pressure-controlled ventilation: a numerical simulation and bench test study

PurposeThere is growing interest in the use of both variable and pressure-controlled ventilation (PCV). The combination of these approaches as “noisy PCV” requires adaptation of the mechanical ventilator to the respiratory system mechanics. Thus, we developed and evaluated a new control system based on the least-mean-squares adaptive approach, which automatically and continuously adjusts the driving pressure during PCV to achieve the desired variability pattern of tidal volume (VT).MethodsThe controller was tested during numerical simulations and with a physical model reproducing the mechanical properties of the respiratory system. We applied step changes in respiratory system mechanics and mechanical ventilation settings. The time needed to converge to the desired VT variability pattern after each change (tc) and the difference in minute ventilation between the measured and target pattern of VT (ΔMV) were determined.ResultsDuring numerical simulations, the control system for noisy PCV achieved the desired variable VT pattern in less than 30 respiratory cycles, with limited influence of the dynamic elastance (E*) on tc, except when E* was underestimated by >25%. We also found that, during tests in the physical model, the control system converged in <60 respiratory cycles and was not influenced by airways resistance. In all measurements, the absolute value of ΔMV was <25%.ConclusionThe new control system for noisy PCV can prove useful for controlled mechanical ventilation in the intensive care unit.