Individualized Positive End-expiratory Pressure and Regional Gas Exchange in Porcine Lung Injury.

BACKGROUND: In acute respiratory failure elevated intraabdominal pressure aggravates lung collapse, tidal recruitment, and ventilation inhomogeneity. Low positive end-expiratory pressure (PEEP) may promote lung collapse and intrapulmonary shunting, whereas high PEEP may increase dead space by inspiratory overdistension. The authors hypothesized that an electrical impedance tomography-guided PEEP approach minimizing tidal recruitment improves regional ventilation and perfusion matching when compared to a table-based low PEEP/no recruitment and an oxygenation-guided high PEEP/full recruitment strategy in a hybrid model of lung injury and elevated intraabdominal pressure. METHODS: In 15 pigs with oleic acid-induced lung injury intraabdominal pressure was increased by intraabdominal saline infusion. PEEP was set in randomized order: (1) guided by a PEEP/inspired oxygen fraction table, without recruitment maneuver; (2) minimizing tidal recruitment guided by electrical impedance tomography after a recruitment maneuver; and (3) maximizing oxygenation after a recruitment maneuver. Single photon emission computed tomography was used to analyze regional ventilation, perfusion, and aeration. Primary outcome measures were differences in PEEP levels and regional ventilation/perfusion matching. RESULTS: Resulting PEEP levels were different (mean ± SD) with (1) table PEEP: 11 ± 3 cm H2O; (2) minimal tidal recruitment PEEP: 22 ± 3 cm H2O; and (3) maximal oxygenation PEEP: 25 ± 4 cm H2O; P < 0.001. Table PEEP without recruitment maneuver caused highest lung collapse (28 ± 11% vs. 5 ± 5% vs. 4 ± 4%; P < 0.001), shunt perfusion (3.2 ± 0.8 l/min vs. 1.0 ± 0.8 l/min vs. 0.7 ± 0.6 l/min; P < 0.001) and dead space ventilation (2.9 ± 1.0 l/min vs. 1.5 ± 0.7 l/min vs. 1.7 ± 0.8 l/min; P < 0.001). Although resulting in different PEEP levels, minimal tidal recruitment and maximal oxygenation PEEP, both following a recruitment maneuver, had similar effects on regional ventilation/perfusion matching. CONCLUSIONS: When compared to table PEEP without a recruitment maneuver, both minimal tidal recruitment PEEP and maximal oxygenation PEEP following a recruitment maneuver decreased shunting and dead space ventilation, and the effects of minimal tidal recruitment PEEP and maximal oxygenation PEEP were comparable.

Disentangling estimands and the intention-to-treat principle.

Randomized controlled trials (RCTs) aim at providing reliable estimates of treatment benefit. Missing data and nonadherence to treatment are distinct problems that can substantially impede this task. In practice, the fact that the handling of missing data due to nonadherence affects the question that is addressed is often ignored. Estimands allow precisely predefining the question of interest. Estimands are definitions of that which is being estimated with regard to population, endpoint, and handling of postrandomization events (eg, nonadherence). Depending on the situation, different estimands are of relevance. Therefore, it is important that the intention-to-treat (ITT) principle, which is considered the gold standard for analyzing RCTs, does not restrict an RCT's primary objective to only one of several relevant estimands. Although much ambiguity is involved around what is considered to constitute the ITT principle, many associate ITT with completely following up all patients and including all data of all randomized patients as allocated into the analysis. This would restrict primary objectives to estimating the effect of treatment policy and is certainly not warranted in all situations. To maintain the advantage of having the clear recommendation to follow the ITT principle while allowing for various relevant estimands as primary objective, we argue that the appropriate way forward is to define ITT as including all randomized patients into the analysis set and each patient is to be allocated to his or her randomized treatment. This definition comprises the actual intent of ITT and can be fully implemented also in settings where complete follow-up is impossible.

Spline-based procedures for dose-finding studies with active control.

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose-response relationship and to find the smallest target dose concentration d(*), which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose-response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose-response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs.

Estimation of the treatment effect in the presence of non-compliance and missing data.

Treatment non-compliance and missing data are common problems in clinical trials. Non-compliance is a broad term including any kind of deviation from the assigned treatment protocol, such as dose modification, treatment discontinuation or switch, often resulting in missing values. Missing values and treatment non-compliance may bias study results. Follow-up of all patients until the planned end of treatment period irrespective of their protocol adherence may provide useful information on the effectiveness of a study drug, taking the actual compliance into account. In this paper, we consider non-compliance as discontinuation of treatment and assume that the endpoint of interest is recorded for some non-complying patients after treatment discontinuation. As a result, the patient's longitudinal profile is dividable into on- and off-treatment observations. Within the framework of depression trials, which usually show a considerably high amount of dropouts, we compare different analysis strategies including both on- and off-treatment observations to gain insight into how the additional use of off-treatment data may affect the trial's outcome. We compare naïve strategies, which simply ignore off-treatment data or treat on- and off-treatment data in the same way, with more complex strategies based on piecewise linear mixed models, which assume different treatment effects for on- and off-treatment data. We show that naïve strategies may considerably overestimate treatment effects. Therefore, it is worthwhile to follow up as many patients as possible until the end of their planned treatment period irrespective of compliance, including all available data in an analysis that accounts for the different treatment conditions.

Florbetapir (18F) for brain amyloid positron emission tomography: highlights on the European marketing approval.

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate ß-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir (18F).

Tidal recruitment assessed by electrical impedance tomography and computed tomography in a porcine model of lung injury*.

OBJECTIVES: To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung injury model. DESIGN: Randomized, controlled, prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Twelve anesthetized and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by central venous oleic acid injection and abdominal hypertension in seven animals. Five healthy pigs served as control group. Animals were ventilated with positive end-expiratory pressure of 0, 5, 10, 15, 20, and 25 cm H2O, respectively, in a randomized order. MEASUREMENTS AND MAIN RESULTS: At any positive end-expiratory pressure level, electrical impedance tomography was obtained during a slow inflation of 12 mL/kg of body weight. Regional-ventilation-delay indices quantifying the time until a lung region reaches a certain amount of impedance change were calculated for lung quadrants and for every single electrical impedance tomography pixel, respectively. Pixel-wise calculated regional-ventilation-delay indices were plotted in a color-coded regional-ventilation-delay map. Regional-ventilation-delay inhomogeneity that quantifies heterogeneity of ventilation time courses was evaluated by calculating the scatter of all pixel-wise calculated regional-ventilation-delay indices. End-expiratory and end-inspiratory computed tomography scans were performed at each positive end-expiratory pressure level to quantify tidal recruitment of the lung. Tidal recruitment showed a moderate inter-individual (r = .54; p < .05) and intra-individual linear correlation (r = .46 up to r = .73 and p < .05, respectively) with regional-ventilation-delay obtained from lung quadrants. Regional-ventilation-delay inhomogeneity was excellently correlated with tidal recruitment intra- (r = .90 up to r = .99 and p < .05, respectively) and inter-individually (r = .90; p < .001). CONCLUSIONS: Regional-ventilation-delay can be noninvasively measured by electrical impedance tomography during a slow inflation of 12 mL/kg of body weight and visualized using ventilation delay maps. Our experimental data suggest that the impedance tomography-based analysis of regional-ventilation-delay inhomogeneity provides a good estimate of the amount of tidal recruitment and may be useful to individualize ventilatory settings.

Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury.

BACKGROUND: Trials have provided conflicting results regarding the effect of different ventilatory strategies on the outcomes of patients with the acute respiratory distress syndrome (ARDS) and acute lung injury. PURPOSE: To determine whether ventilation with low tidal volume (Vt) and limited airway pressure or higher positive end-expiratory pressure (PEEP) improves outcomes for patients with ARDS or acute lung injury. DATA SOURCES: Multiple computerized databases (through March 2009), reference lists of identified articles, and queries of principal investigators. No language restrictions were applied. STUDY SELECTION: Randomized, controlled trials (RCTs) reporting mortality and comparing lower versus higher Vt ventilation, lower versus higher PEEP, or a combination of both in adults with ARDS or acute lung injury. DATA EXTRACTION: Using a standard protocol, 2 reviewer teams assessed trial eligibility and abstracted data on quality of study design and conduct, population characteristics, intervention, co-interventions, and confounding variables. DATA SYNTHESIS: 4 RCTs tested lower versus higher Vt ventilation at similar PEEP in 1149 patients, 3 RCTs compared lower versus higher PEEP at low Vt ventilation in 2299 patients, and 2 RCTs compared a combination of higher Vt and lower PEEP ventilation versus lower Vt and higher PEEP ventilation in 148 patients. Lower Vt ventilation reduced hospital mortality (odds ratio, 0.75 [95% CI, 0.58 to 0.96]; P = 0.02) compared with higher Vt ventilation at similar PEEP. Higher PEEP did not reduce hospital mortality (odds ratio, 0.86 [CI, 0.72 to 1.02]; P = 0.08) compared with lower PEEP using low Vt ventilation. Higher PEEP reduced the need for rescue therapy to prevent life-threatening hypoxemia (odds ratio, 0.51 [CI, 0.36 to 0.71]; P < 0.001) and death (odds ratio, 0.51 [CI, 0.36 to 0.71]; P < 0.001) in patients receiving rescue therapies. LIMITATIONS: Pooling according to similar ventilatory strategies resulted in few RCTs analyzed in each group. The benefit of low Vt is derived from only 1 study. CONCLUSION: Available evidence from a limited number of RCTs shows better outcomes with routine use of low Vt but not high PEEP ventilation in unselected patients with ARDS or acute lung injury. High PEEP may help to prevent life-threatening hypoxemia in selected patients.

Electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury.

OBJECTIVE: To determine the validity of functional electric impedance tomography to monitor regional ventilation distribution in experimental acute lung injury, and to develop a simple electric impedance tomography index detecting alveolar recruitment. DESIGN: Randomized prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Sixteen anesthetized, tracheotomized, and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced either by acid aspiration (direct acute lung injury) or by abdominal hypertension plus oleic acid injection (indirect acute lung injury) in ten pigs. Six pigs with normal lungs were studied as a control group and with endotracheal suction-related atelectasis. After 4 hrs of mechanical ventilation, a slow inflation was performed. MEASUREMENTS AND MAIN RESULTS: During slow inflation, simultaneous measurements of regional ventilation by electric impedance tomography and dynamic computed tomography were highly correlated in quadrants of a transversal thoracic plane (r2 = .63-.88, p < .0001, bias <5%) in both direct and indirect acute lung injury. Variability between methods was lower in direct than indirect acute lung injury (11 +/- 2% vs. 18 +/- 3%, respectively, p < .05). Electric impedance tomography indexes to detect alveolar recruitment were determined by mathematical curve analysis of regional impedance time curves. Empirical tests of different methods revealed that regional ventilation delay, that is, time delay of regional impedance time curve to reach a threshold, correlated well with recruited volume as measured by CT (r2 = .63). Correlation coefficients in subgroups were r2 = .71 and r2 = .48 in pigs with normal lungs with and without closed suction related atelectasis and r2 = .79 in pigs subject to indirect acute lung injury, respectively, whereas no significant correlation was found in pigs undergoing direct acute lung injury. CONCLUSIONS: Electric impedance tomography allows assessment of regional ventilation distribution and recruitment in experimental models of direct and indirect acute lung injury as well as normal lungs. Except for pigs with direct acute lung injury, regional ventilation delay determined during a slow inflation from impedance time curves appears to be a simple index for clinical monitoring of alveolar recruitment.

Spontaneous breathing during airway pressure release ventilation in experimental lung injury: effects on hepatic blood flow.

OBJECTIVE: Positive pressure ventilation can affect systemic haemodynamics and regional blood flow distribution with negative effects on hepatic blood flow. We hypothesized that spontaneous breathing (SB) with airway pressure release ventilation (APRV) provides better systemic and hepatic blood flow than APRV without SB. DESIGN: Animal study with a randomized cross-over design. SETTING: Animal laboratory of Bonn University Hospital. SUBJECTS: Twelve pigs with oleic-acid-induced lung injury. INTERVENTIONS: APRV with or without SB in random order. Without SB, either the upper airway pressure limit or the ventilator rate was increased to maintain constant pH and PaCO2. MEASUREMENTS AND RESULTS: Systemic haemodynamics were determined by double-indicator dilution, organ blood flow by coloured microspheres. Systemic blood flow was best during APRV with SB. During APRV with SB blood flow (ml g(-1) min(-1)) was 0.91+/-0.26 (hepatic arterial), 0.29+/-0.05 (stomach), 0.64+/-0.08 (duodenum), 0.62+/-0.10 (jejunum), 0.53+/-0.07 (ileum), 0.53+/-0.07 (colon), 0.46+/-0.09 (pancreas) and 3.59+/-0.55 (spleen). During APRV without SB applying high P(aw) it decreased to 0.13+/-0.01 (stomach), 0.37+/-0.03 (duodenum), 0.29+/-0.03 (jejunum), 0.31+/-0.05 (ileum), 0.32+/-0.03 (colon) and 0.23+/-0.04 (pancreas) p<0.01, respectively. During APRV without SB applying same Paw limits it decreased to 0.18+/-0.03 (stomach, p<0.01), 0.47+/-0.06 (duodenum, p<0.05), 0.38+/-0.05 (jejunum, p<0.01), 0.36+/-0.03 (ileum, p<0.05), 0.39+/-0.05 (colon, p<0.05), and 0.27+/-0.04 (pancreas, p<0.01). Arterial liver blood flow did not change significantly when SB was abolished (0.55+/-0.11 and 0.63+/-0.11, respectively). CONCLUSIONS: Maintaining SB during APRV was associated with better systemic and pre-portal organ blood flow. Improvement in hepatic arterial blood flow was not significant.

Cardiorespiratory effects of spontaneous breathing in two different models of experimental lung injury: a randomized controlled trial.

INTRODUCTION: Acute lung injury (ALI) can result from various insults to the pulmonary tissue. Experimental and clinical data suggest that spontaneous breathing (SB) during pressure-controlled ventilation (PCV) in ALI results in better lung aeration and improved oxygenation. Our objective was to evaluate whether the addition of SB has different effects in two different models of ALI. METHODS: Forty-four pigs were randomly assigned to ALI resulting either from hydrochloric acid aspiration (HCl-ALI) or from increased intra-abdominal pressure plus intravenous oleic acid injections (OA-ALI) and were ventilated in PCV mode either with SB (PCV + SB) or without SB (PCV - SB). Cardiorespiratory variables were measured at baseline after induction of ALI and after 4 hours of treatment (PCV + SB or PCV - SB). Finally, density distributions and end-expiratory lung volume (EELV) were assessed by thoracic spiral computed tomography. RESULTS: PCV + SB improved arterial partial pressure of oxygen/inspiratory fraction of oxygen (PaO2/FiO2) by a reduction in intrapulmonary shunt fraction in HCl-ALI from 27% +/- 6% to 23% +/- 13% and in OA-ALI from 33% +/- 19% to 26% +/- 18%, whereas during PCV - SB PaO2/FiO2 deteriorated and shunt fraction increased in the HCl group from 28% +/- 8% to 37% +/- 17% and in the OA group from 32% +/- 12% to 47% +/- 17% (P < 0.05 for interaction time and treatment, but not ALI type). PCV + SB also resulted in higher EELV (HCl-ALI: 606 +/- 171 mL, OA-ALI: 439 +/- 90 mL) as compared with PCV - SB (HCl-ALI: 372 +/- 130 mL, OA-ALI: 192 +/- 51 mL, with P < 0.05 for interaction of time, treatment, and ALI type). CONCLUSIONS: SB improves oxygenation, reduces shunt fraction, and increases EELV in both models of ALI.

Electrical impedance tomography guided ventilation therapy.

PURPOSE OF REVIEW: Computed tomography (CT) in patients with acute respiratory distress syndrome has shown that intrapulmonary gas is not homogeneously distributed. Although regional ventilation can be studied by isotope and magnetic resonance techniques while aeration of the lungs can be imaged using CT, these techniques are not available at the bedside. Recently, electrical impedance tomography has been introduced as a true bedside technique which provides information on regional ventilation distribution. RECENT FINDINGS: Electrical impedance tomography can reliably determine regional ventilation in healthy lungs and various models of induced lung injury when compared with CT, electron beam CT, and single photon emission CT. In healthy volunteers and patients with acute lung injury, relative impedance changes on the electrical impedance tomography image demonstrate an excellent correlation with regional changes in lung air content detected by CT. In a limited number of patients with respiratory dysfunction, gas exchange was found to improve when electrical impedance tomography was used to adjust ventilator settings, improving regional ventilation and avoiding tidal alveolar collapse. SUMMARY: In view of recently published data, it can be concluded that, in critically ill patients, electrical impedance tomography determines reliable regional ventilation. Therefore, this technique has the potential to become a valuable bedside tool.

The performance of a target-controlled infusion of propofol in combination with remifentanil: a clinical investigation with two propofol formulations.

Target-controlled infusion (TCI) incorporates the pharmacokinetic variables of an IV drug to facilitate safe and reliable administration. In this clinical study we investigated the performance of propofol TCI in combination with remifentanil. Fifty-four adult patients scheduled for general surgery lasting longer than 1 h received a combined TCI of propofol (Marsh parameter set; propofol randomly either dissolved with long- or middle-/long-chain triglycerides) and remifentanil. Arterial propofol plasma concentrations and hemodynamic and derived electroencephalogram variables were determined at various stages before, during, and after surgery. Measured propofol plasma concentrations exceeded the predicted values by 59%, and 48% when recalculated with the Schnider parameter set. Pharmacokinetic population analysis showed a small central volume of distribution (3.55 L) and reduced clearance (1.31 L/min) for propofol. ASA status and sex were the only variables that had a significant influence on propofol pharmacokinetics. In a second step, a new pharmacokinetic variable set for propofol was determined in the first 27 patients. Post hoc performance analysis of the remaining 27 patients showed improved accuracy using the new variable set. Our results show that when remifentanil and propofol are combined, the Marsh and Schnider parameter sets systematically underestimate propofol plasma concentrations. Presented, in part, at the Annual Meeting of the European Society of Anesthesiologists, Amsterdam, The Netherlands, June 1, 1999, and the Annual Meeting of the American Society of Anesthesiologists, Dallas, Texas, October 12, 1999.

Methodologic aspects of attenuation distributions from static and dynamic thoracic CT techniques in experimental acute lung injury.

BACKGROUND: In acute lung injury, thoracic CT is used to gain information about lung aeration and consolidation. This can be done either during breath-holding by spiral CT scanning of the entire lung or dynamically by scanning lung slices without interrupting ventilation. We hypothesized that attenuation distribution is dependent on static or dynamic scanning techniques. We also studied whether a variation in the CT cut level, corresponding to the diaphragm movement over a breath, had any effect on the attenuation distribution. METHODS: Twenty-two pigs with oleic acid-induced lung injury were randomly assigned to receive pressure-controlled mechanical ventilation with or without spontaneous breathing. Transversal dynamic CT scans of the chest were performed in apical and juxtadiaphragmatic regions, and end-expiratory and end-inspiratory slices were selected. In addition, after clamping the tube at end-expiration and end-inspiration, respectively, spiral CTs were performed. Guided by morphologic structures, spiral CT slices matching the dynamic scan slice and three additional neighbored slices above the diaphragm were selected. Distributions of CT attenuation were calculated and summarized in ranges for comparison. RESULTS: No significant difference in attenuation distributions between the two scanning methods or an interaction with the factors ventilation mode, ventilation phase, and attenuation range were found. In addition, attenuation distributions of four neighbored juxtadiaphragmatic slices, 8 mm thick, from the spiral CT did not differ statistically. CONCLUSION: In an animal model of oleic acid-induced lung injury, analyses of transverse thoracic slices based on dynamic or static CT scanning showed comparable distributions of attenuation. Variations on the CT cut level of 24 mm had no significant effect on the distribution of Hounsfield unit numbers. CT attenuation distributions of transversal juxtadiaphragmatic slices were not dependent on exact position.

Effects of spontaneous breathing during airway pressure release ventilation on respiratory work and muscle blood flow in experimental lung injury.

STUDY OBJECTIVES: To evaluate the effects of spontaneous breathing at ambient airway pressure (Paw) and during airway pressure release ventilation (APRV) on respiratory work and respiratory muscle blood flow (RMBF) in experimental lung injury. DESIGN: Prospective experimental study. SETTING: Research laboratory of a university hospital. SUBJECTS: Twelve hemodynamically stable, analgosedated, and tracheotomized domestic pigs. MEASUREMENTS: Respiratory work was estimated by the inspiratory pressure time product (PTPinsp) of esophageal pressure, and RMBF was measured with colored microspheres. Lung injury was induced with IV boli of oleic acid. The first set of measurements was performed before induction of lung injury while pigs were breathing spontaneously at ambient Paw, the second after induction of lung injury while breathing spontaneously at ambient Paw, and the third with lung injury and spontaneous breathing with APRV. RESULTS: After induction of lung injury PTPinsp increased from 138 +/- 14 to 214 +/- 32 cm H2O s/min when pigs breathed spontaneously at ambient Paw (p < 0.05) and returned to 128 +/- 27 cm H2O s/min during APRV. While systemic hemodynamics and blood flow to the psoatic and intercostal muscles did not change, diaphragmatic blood flow increased from 0.34 +/- 0.05 before to 0.54 +/- 0.08 mL/g/min after induction of lung injury and spontaneous breathing at ambient Paw (p < 0.05) and returned to 0.32 +/- 0.05 mL/g/min during APRV (p < 0.05 vs spontaneous breathing at ambient Paw [lung injury]). CONCLUSION: Respiratory work and RMBF are increased in acute lung injury when subjects breathe spontaneously at ambient Paw. Supporting spontaneous breathing with APRV decreases respiratory work and RMBF to physiologic values.

Mechanical ventilation strategies and inflammatory responses to cardiac surgery: a prospective randomized clinical trial.

OBJECTIVE: To examine whether postoperative mechanical ventilation with lower tidal volumes (V(T)) has protective effects on inflammatory responses induced by cardiopulmonary bypass (CPB) surgery in smokers and nonsmokers. DESIGN AND SETTING: Prospective, randomized, controlled clinical trial in the intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: We examined 44 patients (22 smokers, 22 nonsmokers) immediately after uncomplicated CPB surgery. INTERVENTIONS: Ventilation was applied for 6 h with either V(T) of either 6 or 12 ml/kg ideal body weight. MEASUREMENTS AND RESULTS: The time course of serum tumor necrosis factor (TNF) alpha, interleukin (IL) 6, and IL-8 determined 0, 2, 4, and 6 h after randomization did not differ significantly between the ventilatory strategies. By contrast, in bronchoalveolar lavage fluids sampled after 6 h only TNF-alpha levels were significantly higher in the high V(T) group than the low V(T) group (50+/-111 pg/ml vs. 1+/-7 pg/ml). IL-6 and IL-8 concentrations did not differ between groups. Subgroup analysis of patients with serum TNF-alpha level higher than 0 pg/ml after surgery revealed lower TNF-alpha serum levels during lower V(T) ventilation. All observed effects were small, independent of patients' history of smoking, and were not correlated with duration of ventilation and ICU stay. CONCLUSIONS: Ventilation with lower V(T) had no or only minor effect on systemic and pulmonary inflammatory responses in patients with healthy lungs after uncomplicated CPB surgery. Our data do not suggest a clinical benefit of using low V(T) ventilation in these selected patients.

Spontaneous breathing with airway pressure release ventilation favors ventilation in dependent lung regions and counters cyclic alveolar collapse in oleic-acid-induced lung injury: a randomized controlled computed tomography trial.

INTRODUCTION: Experimental and clinical studies have shown a reduction in intrapulmonary shunt with spontaneous breathing during airway pressure release ventilation (APRV) in acute lung injury. This reduction was related to reduced atelectasis and increased aeration. We hypothesized that spontaneous breathing will result in better ventilation and aeration of dependent lung areas and in less cyclic collapse during the tidal breath. METHODS: In this randomized controlled experimental trial, 22 pigs with oleic-acid-induced lung injury were randomly assigned to receive APRV with or without spontaneous breathing at comparable airway pressures. Four hours after randomization, dynamic computed tomography scans of the lung were obtained in an apical slice and in a juxtadiaphragmatic transverse slice. Analyses of regional attenuation were performed separately in nondependent and dependent halves of the lungs on end-expiratory scans and end-inspiratory scans. Tidal changes were assessed as differences between inspiration and expiration of the mechanical breaths. RESULTS: Whereas no differences were observed in the apical slices, spontaneous breathing resulted in improved tidal ventilation of dependent lung regions (P < 0.05) and less cyclic collapse (P < 0.05) in the juxtadiaphragmatic slices. In addition, with spontaneous breathing, the end-expiratory aeration increased and nonaerated tissue decreased in dependent lung regions close to the diaphragm (P < 0.05 for the interaction ventilator mode and lung region). CONCLUSION: Spontaneous breathing during APRV redistributes ventilation and aeration to dependent, usually well-perfused, lung regions close to the diaphragm, and may thereby contribute to improved arterial oxygenation. Spontaneous breathing also counters cyclic collapse, which is a risk factor for ventilation-associated lung injury.

Choosing Appropriate Estimands in Clinical Trials.

Lack of adherence to study protocol and missing data are often unavoidable in clinical trials, and both increase the need to differentiate between the ideal treatment effect if the medication is taken as directed and the treatment effect in presence of the actual adherence pattern. In this regard, estimands have become the focus of attention. An estimand is simply that which is being estimated. In the context of treatment benefit, an estimand may address either efficacy or effectiveness aspects. Defining the estimand of interest is an essential step to take before deciding on trial design and primary analysis. The choice of estimand has consequences for various other factors to be considered during any clinical trial's planning phase. This study presents a process chart including all aspects to consider during planning. After deciding on the primary estimand, the trial design should be specified, followed by the primary analysis. Both should appropriately address the chosen estimand. Finally, sensitivity analyses should be taken into account. Provided are suggestions for all the planning steps involved, especially on choosing between efficacy and effectiveness, and relevant examples from clinical practice to illustrate them. It is recommended that one bear in mind the process chart during planning of any clinical trial and give reasonable justification for each decision in the study protocol.

CD66b Overexpression and Loss of C5a Receptors as Surface Markers for Staphylococcus aureus-Induced Neutrophil Dysfunction.

Neutrophil granulocytes constitute the main component of innate immunity in the clearance of bacterial infections. However, during systemic inflammation, immunoparalysis may occur resulting in neutrophil dysfunction. This study presents a new in vitro model for analyzing the dysfunction of human peripheral blood neutrophils resulting from the interaction with Staphylococcus aureus components in whole blood. After induction of a massive complement activation by S. aureus supernatant, the neutrophils exhibit a reduced phagocytic capacity resulting in a dramatic reduction of the antibacterial activity similar to that of neutrophils isolated from septic patients. The number of phagocytozing neutrophils is drastically reduced as well as the phagocytic capacity designated by a significantly lower number of ingested microbes. This dysfunction correlates with the loss of complement component 5a receptor 1 from the neutrophil cell surface and can be further characterized by a C5a-induced CD66b overexpression. The presented in vitro model offers a new platform for preclinical testing of immunosuppressive drugs and delivers new information for the understanding of neutrophil dysfunctions under the conditions described.

Measurement of functional residual capacity by nitrogen washout during partial ventilatory support.

OBJECTIVE: Evaluation of an open circuit multiple breath nitrogen washout (MBNW) technique for measurement of functional residual capacity (FRC) during partial ventilatory support using corrections for gas viscosity, sampling delay time, and re-inspired nitrogen. DESIGN: Measurements in a lung model with known reference volume simulating spontaneous breathing and duplicate measurements in patients breathing spontaneously with partial ventilatory support. SETTING. Experimental laboratory and intensive care units of a university hospital. PATIENTS: Eighteen patients with acute respiratory failure. INTERVENTIONS: Change of FiO(2) from baseline to 1.0. MEASUREMENTS AND MAIN RESULTS: FRC was measured by MBNW during spontaneous breathing with continuous positive airway pressure, pressure support ventilation, proportional assist ventilation, automatic tube compensation, and airway pressure release ventilation. In the lung model, repeated measurements at three volumes were done with all partial ventilatory support modalities, and baseline FiO(2 )was varied with one mode and FRC. The mean of differences between MBNW (FRC(MBNW)) and reference was 28 ml (1.6%), and the 2.SD-interval was 84 ml (4.9%) for all modes. Measurements up to a baseline FiO(2) of 0.8 showed differences of 5 ml (-0.3%) and the 2.SD-interval of 38 ml (2.2%) between reference and FRC(MBNW). In 18 patients, 66 duplicate measurements revealed a mean difference of 30 ml (0.9%) with a coefficient of repeatability of 358 ml (13%) independent of ventilatory mode and chronological order. CONCLUSION: This study suggests that, using corrections for gas viscosity, sampling delay time, and re-inspired nitrogen, FRC can be determined with good repeatability in patients and good accuracy in a lung model during partial ventilatory support.

Effects of spontaneous breathing during airway pressure release ventilation on renal perfusion and function in patients with acute lung injury.

OBJECTIVE: Controlled mechanical ventilation can impair systemic and renal blood flow and function, which may be aggravated by respiratory acidosis. We hypothesized that partial ventilatory support using airway pressure release ventilation (APRV) with spontaneous breathing provides better cardiopulmonary and renal function than full ventilatory support using APRV without spontaneous breathing. DESIGN: Prospective randomized study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twelve patients with acute lung injury (ALI). INTERVENTIONS: Airway pressure release ventilation with and without spontaneous breathing, maintaining either the same minute ventilation (V(E)) or the same airway pressure (Paw) limits. MEASUREMENTS: Systemic hemodynamics were estimated by double-indicator dilution, effective renal blood flow (ERBF) by para-aminohippurate, and glomerular filtration rate (GFR) by inulin clearance. RESULTS: Compared to APRV with spontaneous breathing, cardiac index (CI) was decreased when the upper Paw limit was increased to provide the same V(E) (4.26+/-1.21 l min(-1) m(-2)vs 3.72+/-0.99 l min(-1) m(-2); p<0.05) while CI was increased when Paw limits were held constant (4.91+/-1.41 l min(-1) m(-2); p<0.05). Effective renal blood flow and GFR were higher during APRV with spontaneous breathing (858+/-388 ml min(-1) m(-2) and 94+/-47 ml min(-1) m(-2)) than during APRV without spontaneous breathing and the same V(E) (714+/-236 ml min(-1) m(-2)and 82+/-35 ml min(-1) m(-2)) or the same Paw (675+/-287 ml min(-1) m(-2) and 80+/-41 ml min(-1) m(-2); p<0.05). Urine volume did not change. CONCLUSIONS: Spontaneous breathing during APRV was associated with better renal perfusion and function than APRV without spontaneous breathing applying either the same V(E) or the same Paw limits. Maintaining spontaneous breathing during ventilatory support may, therefore, be advantageous in preventing deterioration of renal function in patients with ALI.