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Objective: To investigate the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their relationships with sepsis severity and oxygen transport/utilization impairment., Design: Retrospective analysis of PTX3, hsTnT, NT-proBNP levels at day 1, 2, and 7 after admission in the intensive care unit in a subset of the Albumin Italian Outcome Sepsis database., Setting: Forty Italian intensive care units., Patients: Nine hundred fifty-eight septic patients enrolled in the randomized clinical trial comparing albumin replacement plus crystalloids and crystalloids alone., Interventions: The patients were divided into sextiles of lactate (marker of severity), ScvO2 (marker of oxygen transport), and fluid balance (marker of therapeutic strategy)., Measurements and Main Results: PTX3 and hsTnT were remarkably similar in the two treatment arms, while NT-proBNP was almost double in the albumin treatment group. However, as the distribution of all these biomarkers was similar between control and treatment arms, for the sake of clarity, we analyzed the patients as a single cohort. PTX3 (71.8 [32.9-186.3] ng/mL), hsTnT (50.4 [21.6-133.6] ng/L), and NT-proBNP (4,393 [1,313-13,837] ng/L) were abnormally elevated in 100%, 84.5%, 93.4% of the 953 patients and all decreased from day 1 to day 7. PTX3 monotonically increased with increasing lactate levels. The hsTnT levels were significantly higher when ScvO2 levels were abnormally low (< 70%), suggesting impaired oxygen transport compared with higher ScvO2 levels, suggesting impaired oxygen utilization. NT-proBNP was higher with higher lactate and fluid balance. At ScvO2 levels < 70%, the NT-proBNP was higher than at higher ScvO2 levels. However, even with higher ScvO2, the NT-proBNP was remarkably elevated, suggesting volume expansion. Increased level of NT-proBNP showed the strongest association with 90-day mortality., Conclusions: The selected biomarkers seem related to different mechanisms during sepsis: PTX3 to sepsis severity, hsTnT to impaired oxygen transport, NT-proBNP to sepsis severity, oxygen transport, and aggressive fluid strategy.

Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable., Design: Multicenter, interventional randomized clinical trial., Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis)., Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis., Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone., Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes., Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.

Objective: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis., Design: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial)., Setting: Forty ICUs in Italy., Patients: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95)., Interventions: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1., Measurements and Main Results: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality., Conclusions: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

Purpose of Review: The review focuses on fluid resuscitation of critically ill patients with either colloid or crystalloid solutions., Recent Findings: In healthy patients, the volume expanding effect of colloids is greater than that of crystalloids. However, in critically ill patients, a similar amount of crystalloids and colloids is required for fluid resuscitation, suggesting a lower efficiency of colloids when capillary permeability is increased, and endothelial glycocalyx disrupted. Recent studies on synthetic colloids in surgical patients confirmed the increased risk of renal failure reported in large clinical trials performed in critically ill patients. Experimental studies suggest that albumin maintains plasma volume expansion efficiency even when the capillary permeability is impaired, and that extravasation of albumin to the interstitium is lower than that of hydroxyethyl starch., Summary: Fluid administration should be tailored to patient characteristics. Synthetic colloids should be avoided when possible, especially in patients at risk for kidney injury. In critically ill patients with suspected increased permeability, colloids may not be superior to crystalloids in expanding plasma volume. Albumin appears to be less harmful than synthetic colloids, although its beneficial effects need to be further investigated. The endothelial glycocalyx layer is the key structure finely regulating intravascular fluid distribution.

Objectives: Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement., Design: A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial)., Setting: Forty ICUs in Italy., Patients: Nine hundred and ninety-five patients with severe sepsis or septic shock., Interventions: Randomization to albumin and crystalloid solutions or crystalloid solutions alone., Measurements and Main Results: Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup., Conclusions: Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of supporting therapy.

Purpose of Review: The use of albumin-containing solutions in critically ill patients has been recently revisited, following evidence on harmful effects of synthetic colloids, and novel randomized controlled trials (RCTs) in sepsis. Here, we review the most recent findings on albumin administration in acutely ill and septic patients., Recent Findings: The revision of Starling's theory on microvascular fluid dynamics has highlighted the role of albumin in preserving intravascular compartment volume. In cirrhosis, albumin may be important in maintaining immune system reactivity and cardiac contractility. Preliminary analyses indicate albumin as beneficial in patients with burn, while being associated with increased risk of acute kidney injury after cardiac surgery. The first RCT (ALBIOS trial) testing the efficacy of albumin replacement in severe sepsis did not show a survival benefit associated with albumin, although observing at post-hoc analysis a benefit in septic shock. All the eight meta-analyses performed on albumin in sepsis reveal an absence of harm, and likely a benefit lower than expected, whereas suggesting an advantage, to be verified, in septic shock., Summary: Further studies are needed to clarify physiology and clinical impact of albumin in critically ill patients, considering specific phenotypes and secondary outcomes other than survival, yet clinically relevant.

Objectives: The Berlin definition of acute respiratory distress syndrome has introduced three classes of severity according to PaO2/FIO2 thresholds. The level of positive end-expiratory pressure applied may greatly affect PaO2/FIO2, thereby masking acute respiratory distress syndrome severity, which should reflect the underlying lung injury (lung edema and recruitability). We hypothesized that the assessment of acute respiratory distress syndrome severity at standardized low positive end-expiratory pressure may improve the association between the underlying lung injury, as detected by CT, and PaO2/FIO2-derived severity., Design: Retrospective analysis., Setting: Four university hospitals (Italy, Germany, and Chile)., Patients: One hundred forty-eight patients with acute lung injury or acute respiratory distress syndrome according to the American-European Consensus Conference criteria., Interventions: Patients underwent a three-step ventilator protocol (at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure). Whole-lung CT scans were obtained at 5 and 45 cm H2O airway pressure., Measurements and Main Results: Nine patients did not fulfill acute respiratory distress syndrome criteria of the novel Berlin definition. Patients were then classified according to PaO2/FIO2 assessed at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure. At clinical positive end-expiratory pressure (11±3 cm H2O), patients with severe acute respiratory distress syndrome had a greater lung tissue weight and recruitability than patients with mild or moderate acute respiratory distress syndrome (p<0.001). At 5 cm H2O, 54% of patients with mild acute respiratory distress syndrome at clinical positive end-expiratory pressure were reclassified to either moderate or severe acute respiratory distress syndrome. In these patients, lung recruitability and clinical positive end-expiratory pressure were higher than in patients who remained in the mild subgroup (p<0.05). When patients were classified at 5 cm H2O, but not at clinical or 15 cm H2O, lung recruitability linearly increases with acute respiratory distress syndrome severity (5% [2-12%] vs 12% [7-18%] vs 23% [12-30%], respectively, p<0.001). The potentially recruitable lung was the only CT-derived variable independently associated with ICU mortality (p=0.007)., Conclusions: The Berlin definition of acute respiratory distress syndrome assessed at 5 cm H2O allows a better evaluation of lung recruitability and edema than at higher positive end-expiratory pressure clinically set.

Objective: Positive end-expiratory pressure exerts its effects keeping open at end-expiration previously collapsed areas of the lung; consequently, higher positive end-expiratory pressure should be limited to patients with high recruitability. We aimed to determine which bedside method would provide positive end-expiratory pressure better related to lung recruitability., Design: Prospective study performed between 2008 and 2011., Setting: Two university hospitals (Italy and Germany)., Patients: Fifty-one patients with acute respiratory distress syndrome., Interventions: Whole lung CT scans were taken in static conditions at 5 and 45 cm H2O during an end-expiratory/end-inspiratory pause to measure lung recruitability. To select individual positive end-expiratory pressure, we applied bedside methods based on lung mechanics (ExPress, stress index), esophageal pressure, and oxygenation (higher positive end-expiratory pressure table of lung open ventilation study)., Measurements and Main Results: Patients were classified in mild, moderate and severe acute respiratory distress syndrome. Positive end-expiratory pressure levels selected by the ExPress, stress index, and absolute esophageal pressures methods were unrelated with lung recruitability, whereas positive end-expiratory pressure levels selected by the lung open ventilation method showed a weak relationship with lung recruitability (r = 0.29; p < 0.0001). When patients were classified according to the acute respiratory distress syndrome Berlin definition, the lung open ventilation method was the only one which gave lower positive end-expiratory pressure levels in mild and moderate acute respiratory distress syndrome compared with severe acute respiratory distress syndrome (8 ± 2 and 11 ± 3 cm H2O vs 15 ± 3 cm H2O; p < 0.05), whereas ExPress, stress index, and esophageal pressure methods gave similar positive end-expiratory pressure values in mild, moderate, and severe acute respiratory distress syndrome. The positive end-expiratory pressure selected by the different methods were unrelated to each other with the exception of the two methods based on lung mechanics (ExPress and stress index)., Conclusions: Bedside positive end-expiratory pressure selection methods based on lung mechanics or absolute esophageal pressures provide positive end-expiratory pressure levels unrelated to lung recruitability and similar in mild, moderate, and severe acute respiratory distress syndrome, whereas the oxygenation-based method provided positive end-expiratory pressure levels related with lung recruitability progressively increasing from mild to moderate and severe acute respiratory distress syndrome.

Purpose of Review: To describe the physiological meaning and the clinical application of the lung stress and strain concepts., Recent Findings: The end-inspiratory plateau pressure and ratio of tidal volume/ideal body weight are inadequate surrogates for the end-inspiratory stress (equal to the transpulmonary pressure) and the end-inspiratory strain (change in lung volume relative to the resting volume). For a given plateau pressure or tidal volume/ideal body weight, stress and strain may vary largely due to the variability of chest wall elastance and the resting lung volume. The injurious limits of stress and strain in healthy lungs are reached when stress and strain reach the total lung capacity. This occurs when the resting lung volume (the baby lung in case of acute respiratory distress syndrome) is increased by two-fold to three-fold. As these limits are rarely reached in clinical practice and damage has been reported with stress and strain well below this upper limit, this implies the presence in the lung parenchyma of regions which act as stress raisers or pressure multipliers. These are primarily linked to the inhomogeneous distribution of local stress and strain., Summary: End-inspiratory stress and strain, as well as the lung inhomogeneity and the stress raisers, must be taken in account when setting mechanical ventilation.

Since its introduction into the management of the acute respiratory distress syndrome, mechanical ventilation has been so strongly interwoven with its side effects that it came to be considered as invariably dangerous. Over the decades, attention has shifted from gross barotrauma to volutrauma and, more recently, to atelectrauma and biotrauma. In this article, we describe the anatomical and physiologic framework in which ventilator-induced lung injury may occur. We address the concept of lung stress/strain as applied to the whole lung or specific pulmonary regions. We challenge some common beliefs, such as separately studying the dangerous effects of different tidal volumes (end inspiration) and end-expiratory positive pressures. Based on available data, we suggest that stress at rupture is only rarely reached and that high tidal volume induces ventilator-induced lung injury by augmenting the pressure heterogeneity at the interface between open and constantly closed units. We believe that ventilator-induced lung injury occurs only when a given threshold is exceeded; below this limit, mechanical ventilation is likely to be safe.

Purpose of Review: In the last 2 years, several reports have dealt with recruitment/positive end-expiratory pressure (PEEP) selection. Most of them confirm previous results and few add new information., Recent Findings: It has been definitely confirmed that opening pressures are different throughout the acute respiratory distress syndrome lung parenchyma, ranging from 5-10 up to 30-40 cmH2O. The highest opening pressures are required to open the most dependent lung regions. It has been found that in 2 s, most of the recruitable lung regions may be open when a proper pressure is applied. The best way to assess recruitment is computed tomography scanning, whereas lung mechanics are a reasonable bedside surrogate. Impedance tomography has been increasingly tested, whereas gas exchange is the less reliable indicator of recruitment. A large outcome study showed that higher PEEP might provide survival benefit in a subgroup of more severe patients as compared with lower PEEP. To set PEEP in each individual patient, the use of the expiratory limb of the pressure-volume curve has been suggested. Setting PEEP according to transpulmonary pressure has a robust physiological background, although it requires confirmatory study., Summary: Indiscriminate application of recruitment maneuver in unselected acute respiratory distress syndrome population does not provide benefits. However, in the most severe patients, recruitment maneuver has to be considered and higher PEEP applied. To individualize PEEP, the expiratory phase has to be considered, and the esophageal pressure measurement to compute the transpulmonary pressure should be progressively introduced in clinical practice.

Objectives: The lung-protective strategy employs positive end-expiratory pressure to keep open otherwise collapsed lung regions (anatomical recruitment). Improvement in venous admixture with positive end-expiratory pressure indicates functional recruitment to better gas exchange, which is not necessarily related to anatomical recruitment, because of possible global/regional perfusion modifications. Therefore, we aimed to assess the value of venous admixture (functional shunt) in estimating the fraction of nonaerated lung tissue (anatomical shunt compartment) and to describe their relationship., Design: Retrospective analysis of a previously published study., Setting: Intensive care units of four university hospitals., Patients: Fifty-nine patients with acute lung injury/acute respiratory distress syndrome., Interventions: Positive end-expiratory pressure trial at 5 and 15 cm H2O positive end-expiratory pressures., Measurements and Main Results: Anatomical shunt compartment (whole-lung computed tomography scan) and functional shunt (blood gas analysis) were assessed at 5 and 15 cm H2O positive end-expiratory pressures. Apparent perfusion ratio (perfusion per gram of nonaerated tissue/perfusion per gram of total lung tissue) was defined as the ratio of functional shunt to anatomical shunt compartment. Functional shunt was poorly correlated to the anatomical shunt compartment (r2 = .174). The apparent perfusion ratio at 5 cm H2O positive end-expiratory pressure was widely distributed and averaged 1.25 +/- 0.80. The apparent perfusion ratios at 5 and 15 cm H2O positive end-expiratory pressures were highly correlated, with a slope close to identity (y = 1.10.x -0.03, r2 = .759), suggesting unchanged blood flow distribution toward the nonaerated lung tissue, when increasing positive end-expiratory pressure., Conclusions: Functional shunt poorly estimates the anatomical shunt compartment, due to the large variability in apparent perfusion ratio. Changes in anatomical shunt compartment with increasing positive end-expiratory pressure, in each individual patient, may be estimated from changes in functional shunt, only if the anatomical-functional shunt relationship at 5 cm H2O positive end-expiratory pressure is known.

Purpose of Review: Although many years have passed since its first application in acute respiratory distress syndrome, computed tomography remains widely employed for research and clinical purposes. Here, we review recent findings derived from computed tomography scanning during acute respiratory distress syndrome, particularly concerning setting positive end-expiratory pressure and mechanisms of ventilator-induced lung injury., Recent Findings: Several studies have provided evidence for the validity of monitoring dynamic mechanics of the respiratory system to estimate the balance between beneficial (i.e. reduction of alveolar derecruitment) and harmful (i.e. lung hyperinflation) effects, consequent to positive end-expiratory pressure increase. The combination of different respiratory variables to estimate lung recruitment has become a more accepted approach. Computed tomography scanning has provided important evidence of lung hyperinflation even after the use of low tidal volume in a specific category of patients. Alternative techniques, such as electrical impedance tomography and lung ultrasound, appear as promising tools potentially available at the bedside., Summary: As far as setting positive end-expiratory pressure is concerned, further randomized clinical studies are warranted to verify the pathophysiologic findings recently observed with computed tomography scanning. Similarly, the safety of the widespread use of low tidal volume should be brought into question, possibly pointing out a category of patients who may benefit from alternative techniques of respiratory support.

Purpose of Review: Bedside assessment of lung recruitment is critical for setting mechanical ventilation during acute respiratory distress syndrome. We review recent findings on this topic and attempt to provide a clinical approach to estimating lung recruitment., Recent Findings: Because of intrinsic limitations in considering single parameters of gas exchange as tools to estimate lung recruitment, investigators have combined different respiratory variables, including respiratory mechanics, to enhance the likelihood of predicting lung recruitment. Confusions on interpreting the physiologic rationale of gas-exchange variations as associated with lung recruitment are still widespread. Techniques of lung imaging, in particular computed-tomography scanning, are still the most applied for reference measurement. Dynamic computed-tomography scanning may allow continuous monitoring of the effects of mechanical ventilation on lung parenchyma. Among the new techniques proposed, electric impedance and positron emission tomography are the most promising. Despite progress, computed-tomography scanning still represents the best technique to measure lung recruitment in clinical practice., Summary: Two approaches should be considered to estimate lung recruitment: the use of computed-tomography scanning and indices combining different respiratory variables. Future studies, especially on lung-perfusion distribution, are warranted to improve our knowledge of the pathophysiology of lung recruitment.

Purpose of Review: This paper reviews recent findings regarding the respiratory mechanics during acute respiratory distress syndrome as a tool for tailoring its ventilatory management., Recent Findings: The pressure-volume curve has been used for many years as a descriptor of the respiratory mechanics in patients affected by acute respiratory distress syndrome. The use of the sigmoidal equation introduced by Venegas for the analysis of the pressure-volume curve seems to be the most rigorous mathematical approach to assessing lung mechanics. Increasing attention has been focused on the deflation limb for titration of positive end-expiratory pressure. Based on physiologic reasoning, a novel parameter, the stress index, has been proposed for tailoring a safe mechanical ventilation, although its clinical impact has still to be proved. Evidence has confirmed that a variety of underlying pathologies may lead to acute respiratory distress syndrome, making unrealistic any attempt to unify the ventilatory approach. Although extensively proposed to tailor mechanical ventilation during acute respiratory distress syndrome, there is no evidence that the pressure-volume curve may be useful in setting a lung-protective strategy in the presence of different potentials for recruitment., Summary: The Venegas approach should be the standard analysis of pressure-volume curves. In any patient, the potential for recruitment should be assessed, as a basis for tailoring the most effective mechanical ventilation. Further studies are needed to clarify the potential use of the pressure-volume curve to guide a lung-protective ventilatory strategy.

Purpose of Review: The purpose of this paper is to review the mechanisms of ventilator-induced lung injury as a basis for providing the less damaging mechanical ventilation in patients with acute respiratory failure., Recent Findings: In normal lungs, high tidal volume causes an immediate gene upregulation and downregulation. Although the importance of alveolar inflammatory reaction is well known, recent findings suggest the potential role of airway distension in causing ventilator-induced lung injury. The initial activation has been shown to occur in the airways, accounting for the damages induced by high peak flow. The healthier lung regions are more exposed to the injury, since they may be subjected to strain. Challenge with endotoxin enhances in a synergistic manner the pulmonary inflammation induced by mechanical ventilation. However, mechanical strain and endotoxin seem to trigger lung inflammation through two different pathways. Despite convincing experimental and clinical evidences of lung injury, the clinical implementation of low tidal volume ventilation is still limited and has not yet become part of standard clinical practice. Setting positive end-expiratory pressure remains an open problem because the ALVEOLI study did not provide any exhaustive answers, likely because of methodologic problems and, unphysiologic design., Summary: Gentle lung ventilation must be standard practice. Because stress and strain are the triggers of ventilator-induced lung injury, their clinical equivalents should be measured (transpulmonary pressure and the ratio between tidal volume and end-expiratory lung volume). For a rational application of positive end-expiratory pressure, the potential for recruitment in any single patient should be estimated.

Objective: The "helmet" has been used as a novel interface to deliver noninvasive ventilation without applying direct pressure on the face. However, due to its large volume, the helmet may predispose to CO2 rebreathing. We hypothesized that breathing with the helmet is similar to breathing in a semiclosed environment, and therefore the PCO2 inside the helmet is primarily a function of the subject's CO2 production and the flow of fresh gas through the helmet., Design: Human volunteer study., Setting: Laboratory in a university teaching hospital., Subjects: Eight healthy volunteers., Interventions: We delivered continuous positive airway pressure (CPAP) with the helmet under a variety of ventilatory conditions in a lung model and in volunteers., Measurements and Main Results: Gas flow and CO2 concentration at the airway were measured continuously. End-tidal PCO2, CO2 production, and ventilatory variables were subsequently computed. We found that a) when CPAP was delivered with a ventilator, the inspired CO2 of the volunteers was high (12.4 +/- 3.2 torr [1.7 +/- 0.4 kPa]); b) when CPAP was delivered with a continuous high flow system, inspired CO2 of the volunteers was low (2.5 +/- 1.2 torr [0.3 +/- 0.2 kPa]); and c) the inspired CO2 calculated mathematically for a semiclosed system model of CO2 rebreathing was highly correlated with the values measured in a lung model (r = .97, slope = 0.92, intercept = -1.17, p < .001) and in the volunteers (r = .94, slope = 0.96, intercept = 0.90, p < .001)., Conclusions: a) The helmet predisposes to CO2 rebreathing and should not be used to deliver CPAP with a ventilator; b) continuous high flow minimizes CO2 rebreathing during CPAP with the helmet; and c) minute ventilation and Pco2 should be monitored during CPAP with the helmet.

Objective: To 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)., Design: Retrospective 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., Setting: Twenty-eight Italian and two Swiss intensive care units., Patients: We studied 225 patients meeting the criteria for ALI or ARDS., Interventions: Patients 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 Results: We 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 > or =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 > or =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)., Conclusion: ALI/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.