Franco Valenza

Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.

We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.

Lung Stress and Strain during Mechanical Ventilation for Acute Respiratory Distress Syndrome

RATIONALE Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio). OBJECTIVES To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects. METHODS Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume. MEASUREMENTS AND MAIN RESULTS Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume. CONCLUSIONS Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

Physical and biological triggers of ventilator-induced lung injury and its prevention.

Ventilator-induced lung injury is a side-effect of mechanical ventilation. Its prevention or attenuation implies knowledge of the sequence of events that lead from mechanical stress to lung inflammation and stress at rupture. A literature review was undertaken which focused on the link between the mechanical forces in the diseased lung and the resulting inflammation/rupture. The distending force of the lung is the transpulmonary pressure. This applied force, in a homogeneous lung, is shared equally by each fibre of the lungs fibrous skeleton. In a nonhomogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain. Indeed, if the global applied force is excessive, or the fibres near the diseased regions experience excessive stress/strain, biological activation and/or mechanical rupture are observed. Excessive strain activates macrophages and epithelial cells to produce interleukin‐8. This cytokine recruits neutrophils, with consequent full-blown inflammation. In order to prevent initiation of ventilator-induced lung injury, transpulmonary pressure must be kept within the physiological range. The prone position may attenuate ventilator-induced lung injury by increasing the homogeneity of transpulmonary pressure distribution. Positive end-expiratory pressure may prevent ventilator-induced lung injury by keeping open the lung, thus reducing the regional stress/strain maldistribution. If the transpulmonary pressure rather than the tidal volume per kilogram of body weight is taken into account, the contradictory results of the randomised trials dealing with different strategies of mechanical ventilation may be better understood.

The application of esophageal pressure measurement in patients with respiratory failure.

This report summarizes current physiological and technical knowledge on esophageal pressure (Pes) measurements in patients receiving mechanical ventilation. The respiratory changes in Pes are representative of changes in pleural pressure. The difference between airway pressure (Paw) and Pes is a valid estimate of transpulmonary pressure. Pes helps determine what fraction of Paw is applied to overcome lung and chest wall elastance. Pes is usually measured via a catheter with an air-filled thin-walled latex balloon inserted nasally or orally. To validate Pes measurement, a dynamic occlusion test measures the ratio of change in Pes to change in Paw during inspiratory efforts against a closed airway. A ratio close to unity indicates that the system provides a valid measurement. Provided transpulmonary pressure is the lung-distending pressure, and that chest wall elastance may vary among individuals, a physiologically based ventilator strategy should take the transpulmonary pressure into account. For monitoring purposes, clinicians rely mostly on Paw and flow waveforms. However, these measurements may mask profound patient-ventilator asynchrony and do not allow respiratory muscle effort assessment. Pes also permits the measurement of transmural vascular pressures during both passive and active breathing. Pes measurements have enhanced our understanding of the pathophysiology of acute lung injury, patient-ventilator interaction, and weaning failure. The use of Pes for positive end-expiratory pressure titration may help improve oxygenation and compliance. Pes measurements make it feasible to individualize the level of muscle effort during mechanical ventilation and weaning. The time is now right to apply the knowledge obtained with Pes to improve the management of critically ill and ventilator-dependent patients.

Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome.

ObjectiveTo determine whether gas exchange improvement in response to the prone position is associated with an improved outcome in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). DesignRetrospective analysis of patients in the pronation arm of a controlled randomized trial on prone positioning and patients enrolled in a previous pilot study of the prone position. SettingTwenty-eight Italian and two Swiss intensive care units. PatientsWe studied 225 patients meeting the criteria for ALI or ARDS. InterventionsPatients were in prone position for 10 days for 6 hrs/day if they met ALI/ARDS criteria when assessed each morning. Respiratory variables were recorded before and after 6 hrs of pronation with unchanged ventilatory settings. Measurements and Main ResultsWe measured arterial blood gas alterations to the first pronation and the 28-day mortality rate. The independent risk factors for death in the general population were the Pao2/Fio2 ratio (odds ratio, 0.992; confidence interval, 0.986–0.998), the minute ventilation/Paco2 ratio (odds ratio, 1.003; confidence interval, 1.000–1.006), and the concentration of plasma creatinine (odds ratio, 1.385; confidence interval, 1.116–1.720). Pao2 responders (defined as the patients who increased their Pao2/Fio2 by ≥20 mm Hg, 150 patients, mean increase of 100.6 ± 61.6 mm Hg [13.4 ± 8.2 kPa]) had an outcome similar to the nonresponders (59 patients, mean decrease −6.3 ± 23.7 mm Hg [−0.8 ± 3.2 kPa]; mortality rate 44% and 46%, respectively; relative risk, 1.04; confidence interval, 0.74–1.45, p = .65). The Paco2 responders (defined as patients whose Paco2 decreased by ≥1 mm Hg, 94 patients, mean decrease −6.0 ± 6 mm Hg [−0.8 ± 0.8 kPa]) had an improved survival when compared with nonresponders (115 patients, mean increase 6 ± 6 mm Hg [0.8 ± 0.8 kPa]; mortality rate 35.1% and 52.2%, respectively; relative risk, 1.48; confidence interval, 1.07–2.05, p = .01). ConclusionALI/ARDS patients who respond to prone positioning with reduction of their Paco2 show an increased survival at 28 days. Improved efficiency of alveolar ventilation (decreased physiologic deadspace ratio) is an important marker of patients who will survive acute respiratory failure.

Prone position delays the progression of ventilator-induced lung injury in rats : Does lung strain distribution play a role?

Objective:To investigate if prone position delays the progression of experimental ventilator-induced lung injury, possibly due to a more homogeneous distribution of strain within lung parenchyma. Design:Prospective, randomized, controlled trial. Setting:Animal laboratory of a university hospital. Subjects:Thirty-five Sprague Dawley male rats (weight 257 ± 45 g). Interventions:Mechanical ventilation in either supine or prone position and computed tomography scan analysis. Measurements:Animals were ventilated in supine (n = 15) or prone (n = 15) position until a similar ventilator-induced lung injury was reached. To do so, experiments were interrupted when respiratory system elastance was 150% of baseline. Ventilator-induced lung injury was assessed as lung wet-to-dry ratio and histology. Time to reach lung injury was considered as a main outcome measure. In five additional animals, computed tomography scans (GE Light Speed QX/I, thickness 1.25 mm, interval 0.6 mm, 100 MA, 100 Kv) were randomly taken at end-expiration and end-inspiration in both positions, and quantitative analysis was performed. Data are shown as mean ± sd. Measurements and Main Results:Similar ventilator-induced lung injury was reached (respiratory system elastance, wet-to-dry ratio, and histology). The time taken to achieve the target ventilator-induced lung injury was longer with prone position (73 ± 37 mins vs. 112 ± 42, supine vs. prone, p = .011). Computed tomography scan analysis performed before lung injury revealed that at end-expiration, the lung was wider in prone position (p = .004) and somewhat shorter (p = .09), despite similar lung volumes (p = .455). Lung density along the vertical axis increased significantly only in supine position (p = .002). Lung strain was greater in supine as opposed to prone position (width strain, 7.8 ± 1.8% vs. 5.6 ± 0.9, supine vs. prone, p = .029). Conclusions:Prone position delays the progression of ventilator-induced lung injury. Computed tomography scan analysis suggests that a more homogeneous distribution of strain may be implicated in the protective role of prone position against ventilator-induced lung injury.

Effects of the Beach Chair Position, Positive End-expiratory Pressure, and Pneumoperitoneum on Respiratory Function in Morbidly Obese Patients during Anesthesia and Paralysis

Background:The authors studied the effects of the beach chair (BC) position, 10 cm H2O positive end-expiratory pressure (PEEP), and pneumoperitoneum on respiratory function in morbidly obese patients undergoing laparoscopic gastric banding. Methods:The authors studied 20 patients (body mass index 42 ± 5 kg/m2) during the supine and BC positions, before and after pneumoperitoneum was instituted (13.6 ± 1.2 mmHg). PEEP was applied during each combination of position and pneumoperitoneum. The authors measured elastance (E,rs) of the respiratory system, end-expiratory lung volume (helium technique), and arterial oxygen tension. Pressure–volume curves were also taken (occlusion technique). Patients were paralyzed during total intravenous anesthesia. Tidal volume (10.5 ± 1 ml/kg ideal body weight) and respiratory rate (11 ± 1 breaths/min) were kept constant throughout. Results:In the supine position, respiratory function was abnormal: E,rs was 21.71 ± 5.26 cm H2O/l, and end-expiratory lung volume was 0.46 ± 0.1 l. Both the BC position and PEEP improved E,rs (P < 0.01). End-expiratory lung volume almost doubled (0.83 ± 0.3 and 0.85 ± 0.3 l, BC and PEEP, respectively; P < 0.01 vs. supine zero end-expiratory pressure), with no evidence of lung recruitment (0.04 ± 0.1 l in the supine and 0.07 ± 0.2 in the BC position). PEEP was associated with higher airway pressures than the BC position (22.1 ± 2.01 vs. 13.8 ± 1.8 cm H2O; P < 0.01). Pneumoperitoneum further worsened E,rs (31.59 ± 6.73; P < 0.01) and end-expiratory lung volume (0.35 ± 0.1 l; P < 0.01). Changes of lung volume correlated with changes of oxygenation (linear regression, R2 = 0.524, P < 0.001) so that during pneumoperitoneum, only the combination of the BC position and PEEP improved oxygenation. Conclusions:The BC position and PEEP counteracted the major derangements of respiratory function produced by anesthesia and paralysis. During pneumoperitoneum, only the combination of the two maneuvers improved oxygenation.

Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients

Objectives: The aim of this research was to investigate endogenous concentrations and anti‐cytokine effects of the anti‐inflammatory peptide α‐melanocyte stimulating hormone (α‐MSH) in patients with systemic inflammation. The objectives were to determine the following: changes over time of plasma α‐MSH and relationship with patient outcome, correlation between plasma α‐MSH and tumor necrosis factor (TNF)‐α plasma concentration and production in whole blood samples, and influences of α‐MSH on production of TNF‐α and interleukin (IL)‐1β in whole blood samples stimulated with lipopolysaccharide (LPS). Design: Prospective, nonrandomized, clinical study. Setting: Intensive care unit of a university hospital. Patients: A total of 21 patients with sepsis syndrome/septic shock and an equal number of healthy volunteers. Interventions: Circulating α‐MSH and TNF‐α concentrations and TNF‐α production in supernatants of LPS (1 ng/mL)‐stimulated whole blood were measured repeatedly. To determine whether α‐MSH can modulate production of TNF‐α and IL‐1 β, these cytokines were measured in whole blood samples stimulated with LPS (1 ng/mL) in the presence or absence of concentrations of the peptide. Measurements and Main Results: Plasma α‐MSH was low in early samples and gradually increased in patients who recovered but not in those who died. There was a negative correlation between plasma concentrations of α‐MSH and TNF‐α. In blood samples taken at early phases of sepsis syndrome, production of TNF‐α was reduced relative to control values; such production increased in patients who recovered but not in those who died. Addition of α‐MSH to LPS‐stimulated whole blood samples inhibited production of TNF‐α and IL‐1β in a concentration‐dependent manner. Conclusions: In patients with systemic inflammation, there are substantial changes over time in plasma concentrations of α‐MSH that are reduced in early phases of the disease. Reduction of this endogenous modulator of inflammation could be detrimental to the host. Addition of α‐MSH to LPS‐stimulated blood samples reduces production of cytokines involved in development of septic syndrome. This inhibition by α‐MSH, a peptide that is beneficial in treatment of experimental models of sepsis, might therefore be useful to treat sepsis syndrome in humans.

Static and dynamic components of esophageal and central venous pressure during intra-abdominal hypertension.

Objective:To investigate the effects of intra-abdominal hypertension on esophageal and central venous pressure considering values obtained at end-expiration (i.e., in static conditions) and during tidal volume delivery (i.e., in dynamic conditions). Design:Retrospective (pigs) and prospective, randomized, controlled (rats) trial. Setting:Animal laboratory of a university hospital. Subjects:Six female pigs and 15 Sprague Dawley male rats. Interventions:During anesthesia and paralysis, animals’ abdomens were inflated with helium. Measurements and Main Results:Abdominal pressure was measured by intraperitoneal catheter. In pigs, esophageal pressure and central venous pressure were continuously measured while inflating the abdomen together with hemodynamic assessment. In rats, the abdomen was inflated after the random application of three levels of positive end-expiratory pressure. Data are shown as mean ± sd. At end-expiration, esophageal pressures were similar before and after abdominal inflation (p = .177). In contrast, the dynamic component significantly rose after intra-abdominal hypertension, from 3.2 ± 0.7 cm H2O to 10.0 ± 2.3 cm H2O (p < .001), and was correlated with peritoneal pressure (linear regression, R2 = .708, p < .001). Positive end-expiratory pressure significantly influenced static esophageal pressure during intra-abdominal hypertension (p = .002) but not dynamic pressures.Static central venous pressure rose with intra-abdominal hypertension from 4.1 ± 1.5 cm H2O to 6.7 ± 1.8 cm H2O (p = .043), more so the dynamic component (from 2.9 ± 0.8 cm H2O to 9.3 ± 3.1 cm H2O, p = .02). Dynamic changes of esophageal pressures correlated with dynamic changes of central venous pressure (linear regression, R2 = .679, p < .001). Mean values of central venous pressure significantly increased with intra-abdominal hypertension from 7.7 ± 1.5 cm H2O to 12.7 ± 2.6 cm H2O (p = .006), whereas transmural central venous pressure and intrathoracic blood volume did not change significantly. Conclusions:Dynamic changes of esophageal pressure occurred during intra-abdominal hypertension, whereas end-expiratory pressure was affected by high positive end-expiratory pressure levels. Provided that central venous pressure changes reflect esophageal pressure, central venous pressure itself cannot be relied on to guide resuscitation in patients with intra-abdominal hypertension, particularly when abdominal pressures are changing over short periods of time.

Positive end-expiratory pressure delays the progression of lung injury during ventilator strategies involving high airway pressure and lung overdistention.

ObjectiveMany studies have investigated the protective role of positive end-expiratory pressure (PEEP) on ventilator-induced lung injury. Most assessed lung injury in protocols involving different ventilation strategies applied for the same length of time. This study, however, set out to investigate the protective role of PEEP with respect to the time needed to reach similar levels of lung injury. DesignProspective, randomized laboratory animal investigation. SettingThe University Laboratory of Ospedale Maggiore, Milano, IRCCS. SubjectsAnesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats. InterventionsThree groups of five Sprague-Dawley rats were ventilated using zero end-expiratory pressure ZEEP (PEEP of 0 cm H2O) and PEEP of 3 and 6 cm H2O and a similar index of lung overdistension (Pawp/P100 ≅ 1.1; where Pawp is peak airway pressure and P100 is the pressure corresponding to total lung capacity). To obtain this, tidal volume was reduced depending on the PEEP. To reach similar levels of lung injury, we measured respiratory system elastance while ventilating the animals and killed them when respiratory system elastance was 150% of baseline. Once target respiratory system elastance was reached, the lung wet-to-dry ratio was obtained. ResultsRats were ventilated with comparable high airway pressure (Pawp of 42.8 ± 3.1, 43.5 ± 2.6, and 46.2 ± 4.4, respectively, for PEEP 0, 3, and 6) obtaining similar overdistension (Pawp/P100 − index of overdistension: 1.17 ± 0.2, 1.06 ± 0.1, and 1.19 ± 0.2). The respiratory system elastance target was reached and wet-to-dry ratio was not different in the three groups, suggesting a similar degree of lung damage. The time taken to achieve the target respiratory system elastance was three times longer with PEEP 3 and 6 (55 ± 14 mins and 60 ± 17) as compared with zero end-expiratory pressure (18 ± 3 mins, p < .001). ConclusionThese findings confirm that PEEP is protective against ventilator-induced lung injury and may enable the clinician to “buy time” in the progression of lung injury.