Therapeutic hypothermia attenuates physiologic, histologic, and metabolomic markers of injury in a porcine model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a lung injury characterized by noncardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in inflammatory cytokines observed in the HI group compared to the I group. Changes to respiratory system mechanics in the injured groups were due to increases in lung elastance (E) and resistance (R) (ΔE from pre-injury = 46 ± 14 cmH2 O L-1 , p < 0.0001; ΔR from pre-injury: 3 ± 2 cmH2 O L-1  s- , p = 0.30) rather than changes to the chest wall (ΔE from pre-injury: 0.7 ± 1.6 cmH2 O L-1 , p = 0.99; ΔR from pre-injury: 0.6 ± 0.1 cmH2 O L-1  s- , p = 0.01). Both control groups had no change in respiratory mechanics. In conclusion, therapeutic hypothermia can reduce markers of injury and inflammation associated with experimentally induced short-term ARDS.

The Impact of Cycling Cadence on Respiratory and Hemodynamic Responses to Exercise.

PURPOSE: The physiological consequences of freely chosen cadence during cycling remains poorly understood. We sought to determine the effect of cadence on the respiratory and hemodynamic response to cycling exercise. METHODS: Eleven cyclists (10 males, 1 female; age, 27 ± 6 yr; V˙O2max = 60.8 ± 3.7 mL·kg·min) completed four, 6-min constant-load cycling trials at 10% below their previously determined gas exchange threshold (i.e., 63% ± 5% peak power) while pedaling at 60, 90, and 120 rpm, and a freely chosen cadence (94.3 ± 6.9 rpm) in randomized order. Standard cardiorespiratory parameters were measured and an esophageal electrode balloon catheter was used to assess electromyography of the diaphragm (EMGdi) and the work of breathing (Wb). Leg blood flow index (BFI) was determined on four muscles using near-infrared spectroscopy with indocyanine green dye injections. RESULTS: Oxygen uptake (V˙O2) increased as a function of increasing cadence (all pairwise comparisons, P < 0.05). The EMGdi and Wb were significantly greater at 120 rpm compared with all other conditions (all P < 0.01). Vastus medialis and semitendinosus BFI were significantly greater at 120 rpm compared with 60 and 90 rpm (all P < 0.05). Gastrocnemius BFI was higher at 120 rpm compared with all other cadences (all P < 0.01). No difference in BFI was found in the vastus lateralis (P = 0.06). Blood flow index was significantly correlated with the increase in V˙O2 with increasing cadence in the medial gastrocnemius (P < 0.001) and approached significance in the vastus lateralis (P = 0.09), vastus medialis (P = 0.06), and semitendinosus (P = 0.09). There was no effect of cadence on Borg 0-10 breathing or leg discomfort ratings (P > 0.05). CONCLUSIONS: High cadence cycling at submaximal exercise intensities is metabolically inefficient and increases EMGdi, Wb, and leg muscle blood flow relative to slower cadences.

Function of secreted phospholipase A2 group-X in asthma and allergic disease.

Elevated secreted phospholipase A2 (sPLA2) activity in the airways has been implicated in the pathogenesis of asthma and allergic disease for some time. The identity and function of these enzymes in asthma is becoming clear from work in our lab and others. We focused on sPLA2 group X (sPLA2-X) after identifying increased levels of this enzyme in asthma, and that it is responsible for a large portion of sPLA2 activity in the airways and that the levels are strongly associated with features of airway hyperresponsiveness (AHR). In this review, we discuss studies that implicated sPLA2-X in human asthma, and murine models that demonstrate a critical role of this enzyme as a regulator of type-2 inflammation, AHR and production of eicosanoids. We discuss the mechanism by which sPLA2-X acts to regulate eicosanoids in leukocytes, as well as effects that are mediated through the generation of lysophospholipids and through receptor-mediated functions. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.

Case Fatality and Adverse Outcomes Are Reduced in Pregnant Women With Severe Sepsis or Septic Shock Compared With Age-Matched Comorbid-Matched Nonpregnant Women.

OBJECTIVES: Case fatality in pregnancy-associated severe sepsis or septic shock appears reduced compared with nonpregnant women with severe sepsis or septic shock. It remains unclear if this difference is due to pregnancy or better baseline health status, among others. Our study compared adverse outcomes of pregnancy-associated severe sepsis or septic shock with nonpregnant women with severe sepsis or septic shock while controlling for age and chronic comorbidities. DESIGN: Retrospective cohort study. SETTING: Nationwide Inpatient Sample, a stratified sample of 20% acute care hospital admissions in the United States. Each entry includes patient and hospital characteristics as well as International Classification of Diseases, 9th revision, Clinical Modification, diagnoses and procedures. SUBJECTS: Women of childbearing age (15-44 yr) with severe sepsis or septic shock-related hospitalizations during 1998-2012 identified using International Classification of Diseases, 9th revision, Clinical Modification, codes. OUTCOMES: Case fatality, hospital length of stay, length of stay until death, number of organ failures, rates of mechanical ventilation, and hemodialysis were compared in women according to pregnancy status, controlling for age, and chronic comorbidities. MEASUREMENTS AND MAIN RESULTS: We identified 5,968 pregnancy-associated severe sepsis or septic shock and 85,240 nonpregnant women with severe sepsis or septic shock hospitalizations. Crude case fatality of pregnancy-associated severe sepsis or septic shock (9.6%) was lower than nonpregnant women with severe sepsis or septic shock (16.8%). The rate ratio for case fatality adjusted for socioeconomic status and race was 0.57 (95% CI, 0.52-0.62) while sequential adjustments for age and chronic comorbidities did not eliminate the association (rate ratio, 0.62 [95% CI, 0.57-0.68]) and 0.63 [95% CI, 0.57-0.68], respectively). Pregnancy-associated severe sepsis or septic shock was associated with shorter hospital length of stay (-0.83 d [95% CI, -1.32 to -0.34 d]), longer length of stay until death (2.61 d; [95% CI, 1.28-3.94 d]), and fewer organ failures (rate ratio, 0.95 [95% CI, 0.94-0.97]). CONCLUSIONS: Case fatality and adverse outcomes are reduced in women with pregnancy-associated severe sepsis or septic shock compared with nonpregnant women with severe sepsis or septic shock, and this is not explained by differences in age or chronic comorbidities alone. A less severe presentation of sepsis or protective effect of pregnancy may account for the difference observed with pregnancy-associated severe sepsis or septic shock.

Effect of Cerebral Perfusion Pressure on Acute Respiratory Distress Syndrome.

BACKGROUND: Increased cerebral perfusion pressure (CPP)>70 mmHg has been associated with acute respiratory distress syndrome (ARDS) after traumatic brain injury (TBI). Since this reported association, significant changes in ventilation strategies and fluid management have been accepted as routine critical care. Recently, individualized perfusion targets using autoregulation monitoring suggest CPP titration>70 mmHg. Given these clinical advances, the association between ARDS and increased CPP requires further delineation. OBJECTIVE: To determine the association between ARDS and increased CPP after TBI. METHODS: We conducted a single-center historical cohort study investigating the association of increased CPP and ARDS after TBI. We collected demographic data and physiologic data for CPP, intracranial pressure, mechanical ventilation, cumulative fluid balance and delta/driving pressure (ΔP). We collected outcomes measures pertaining to duration of ventilation, intensive care unit admission length, hospitalization length and 6-month neurological outcome. RESULTS: In total, 113 patients with severe TBI and multimodal neuromonitoring were included. In total, 16 patients (14%) developed ARDS according to the Berlin definition. There was no difference in the mean CPP during the first 7 days of admission between patients who developed ARDS (74 mmHg SD 18 vs. 73 mmHg SD 18, p=0.86) versus those who did not. Patients who developed ARDS had a higher ΔP (15 mmHg [5] vs. 12 mmHg [4], p=0.016) and lower lung compliance (35 ml/cmH2O [10] vs. 49 ml/cmH2O [18], p=0.024) versus those who did not. CONCLUSION: We did not observe an association between increased CPP and ARDS. Patients with ARDS had higher ΔP and lower lung compliance.

Impact of Critical Illness Polyneuromyopathy in Rehabilitation: A Prospective Observational Study.

BACKGROUND: Critical illness polyneuromyopathy (CIPNM) increasingly is recognized as a source of disability in patients requiring intensive care unit (ICU) admission. The prevalence and impact of CIPNM on patients in the rehabilitation setting has not been established. OBJECTIVES: To determine the proportion of at-risk rehabilitation inpatients with evidence of CIPNM and the functional sequelae of this disorder. DESIGN: Prospective observational study. SETTING: Tertiary academic rehabilitation hospital. PATIENTS: Rehabilitation inpatients with a history of ICU admission for at least 72 hours. METHODS: Electrodiagnostic studies were performed to evaluate for axonal neuropathy and/or myopathy in at least one upper and one lower limb. MAIN OUTCOME MEASUREMENTS: The primary outcome was prevalence of CIPNM. Secondary outcomes included Functional Independence Measure (FIM) scores, rehabilitation length of stay (RLOS), and discharge disposition. RESULTS: A total of 33 participants were enrolled; 70% had evidence of CIPNM. Admission FIM score, discharge FIM, FIM gain, and FIM efficiency were 64.1, 89.9, 25.5, and 0.31 in those with CIPNM versus 78.4, 94.6, 16.1, and 0.33 in those without CIPNM, respectively. Average RLOS was 123 days versus 76 days and discharge to home was 57% versus 90% in the CIPNM and non-CIPNM groups, respectively. CONCLUSIONS: CIPNM is very common in rehabilitation inpatients with a history of ICU admission. It was associated with a lower functional status at rehabilitation admission, but functional improvement was at a similar rate to those without CIPNM. Longer RLOS stay may be required to achieve the same functional level. LEVEL OF EVIDENCE: III.

Effects of respiratory muscle work on respiratory and locomotor blood flow during exercise.

NEW FINDINGS: What is the central question of this study? Does manipulation of the work of breathing during high-intensity exercise alter respiratory and locomotor muscle blood flow? What is the main finding and its importance? We found that when the work of breathing was reduced during exercise, respiratory muscle blood flow decreased, while locomotor muscle blood flow increased. Conversely, when the work of breathing was increased, respiratory muscle blood flow increased, while locomotor muscle blood flow decreased. Our findings support the theory of a competitive relationship between locomotor and respiratory muscles during intense exercise. Manipulation of the work of breathing (WOB) during near-maximal exercise influences leg blood flow, but the effects on respiratory muscle blood flow are equivocal. We sought to assess leg and respiratory muscle blood flow simultaneously during intense exercise while manipulating WOB. Our hypotheses were as follows: (i) increasing the WOB would increase respiratory muscle blood flow and decrease leg blood flow; and (ii) decreasing the WOB would decrease respiratory muscle blood flow and increase leg blood flow. Eight healthy subjects (n = 5 men, n = 3 women) performed a maximal cycle test (day 1) and a series of constant-load exercise trials at 90% of peak work rate (day 2). On day 2, WOB was assessed with oesophageal balloon catheters and was increased (via resistors), decreased (via proportional assist ventilation) or unchanged (control) during the trials. Blood flow was assessed using near-infrared spectroscopy optodes placed over quadriceps and the sternocleidomastoid muscles, coupled with a venous Indocyanine Green dye injection. Changes in WOB were significantly and positively related to changes in respiratory muscle blood flow (r = 0.73), whereby increasing the WOB increased blood flow. Conversely, changes in WOB were significantly and inversely related to changes in locomotor blood flow (r = 0.57), whereby decreasing the WOB increased locomotor blood flow. Oxygen uptake was not different during the control and resistor trials (3.8 ± 0.9 versus 3.7 ± 0.8 l min-1 , P > 0.05), but was lower on the proportional assist ventilator trial (3.4 ± 0.7 l min-1 , P < 0.05) compared with control. Our findings support the concept that respiratory muscle work significantly influences the distribution of blood flow to both respiratory and locomotor muscles.

Exercise-induced quadriceps muscle fatigue in men and women: effects of arterial oxygen content and respiratory muscle work.

KEY POINTS: High work of breathing and exercise-induced arterial hypoxaemia (EIAH) can decrease O2 delivery and exacerbate exercise-induced quadriceps fatigue in healthy men. Women have a higher work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles and develop EIAH. Despite a greater reduction in men's work of breathing, the attenuation of quadriceps fatigue was similar between the sexes. The degree of EIAH was similar between sexes, and regardless of sex, those who developed the greatest hypoxaemia during exercise demonstrated the most attenuation of quadriceps fatigue. Based on our previous finding that women have a greater relative oxygen cost of breathing, women appear to be especially susceptible to work of breathing-related changes in quadriceps muscle fatigue. ABSTRACT: Reducing the work of breathing or eliminating exercise-induced arterial hypoxaemia (EIAH) during exercise decreases the severity of quadriceps fatigue in men. Women have a greater work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles, and demonstrate EIAH, suggesting women may be especially susceptible to quadriceps fatigue. Healthy subjects (8 male, 8 female) completed three constant load exercise tests over 4 days. During the first (control) test, subjects exercised at ∼85% of maximum while arterial blood gases and work of breathing were assessed. Subsequent constant load exercise tests were iso-time and iso-work rate, but with EIAH prevented by inspiring hyperoxic gas or work of breathing reduced via a proportional assist ventilator (PAV). Quadriceps fatigue was assessed by measuring force in response to femoral nerve stimulation. For both sexes, quadriceps force was equally reduced after the control trial (-27 ± 2% baseline) and was attenuated with hyperoxia and PAV (-18 ± 1 and -17 ± 2% baseline, P < 0.01, respectively), with no sex difference. EIAH was similar between the sexes, and regardless of sex, subjects with the lowest oxyhaemoglobin saturation during the control test had the greatest quadriceps fatigue attenuation with hyperoxia (r2  = 0.79, P < 0.0001). For the PAV trial, despite reducing the work of breathing to a greater degree in men (men: 60 ± 5, women: 75 ± 6% control, P < 0.05), the attenuation of quadriceps fatigue was similar between the sexes (36 ± 4 vs. 37 ± 7%). Owing to a greater relative V̇O2 of the respiratory muscles in women, less of a change in work of breathing is needed to reduce quadriceps fatigue.

Fifty Years of Research in ARDS. Respiratory Mechanics in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome is a multifactorial lung injury that continues to be associated with high levels of morbidity and mortality. Mechanical ventilation, although lifesaving, is associated with new iatrogenic injury. Current best practice involves the use of small Vt, low plateau and driving pressures, and high levels of positive end-expiratory pressure. Collectively, these interventions are termed "lung-protective ventilation." Recent investigations suggest that individualized measurements of pulmonary mechanical variables rather than population-based ventilation prescriptions may be used to set the ventilator with the potential to improve outcomes beyond those achieved with standard lung protective ventilation. This review outlines the measurement and application of clinically applicable pulmonary mechanical concepts, such as plateau pressures, driving pressure, transpulmonary pressures, stress index, and measurement of strain. In addition, the concept of the "baby lung" and the utility of dynamic in addition to static measures of pulmonary mechanical variables are discussed.

Functional respiratory imaging, regional strain, and expiratory time constants at three levels of positive end expiratory pressure in an ex vivo pig model.

Heterogeneity in regional end expiratory lung volume (EELV) may lead to variations in regional strain (ε). High ε levels have been associated with ventilator-associated lung injury (VALI). While both whole lung and regional EELV may be affected by changes in positive end-expiratory pressure (PEEP), regional variations are not revealed by conventional respiratory system measurements. Differential rates of deflation of adjacent lung units due to regional variation in expiratory time constants (τE) may create localized regions of ε that are significantly greater than implied by whole lung measures. We used functional respiratory imaging (FRI) in an ex vivo porcine lung model to: (i) demonstrate that computed tomography (CT)-based imaging studies can be used to assess global and regional values of ε and τE and, (ii) demonstrate that the manipulation of PEEP will cause measurable changes in total and regional ε and τE values. Our study provides three insights into lung mechanics. First, image-based measurements reveal egional variation that cannot be detected by traditional methods such as spirometry. Second, the manipulation of PEEP causes global and regional changes in R, E, ε and τE values. Finally, regional ε and τE were correlated in several lobes, suggesting the possibility that regional τE could be used as a surrogate marker for regional ε.

Lipid Mediators in Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is a syndrome of severe asthma and rhinosinusitis with nasal polyposis with exacerbations of baseline eosinophil-driven and mast cell-driven inflammation after nonsteroidal antiinflammatory drug ingestion. Although the underlying pathophysiology is poorly understood, dysregulation of the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism is thought to be key. Central features of AERD pathogenesis are overproduction of proinflammatory and bronchoconstrictor cysteinyl leukotrienes and prostaglandin (PG) D2 and inhibition of bronchoprotective and antiinflammatory PGE2. Imbalance in the ratio of these lipid mediators likely leads to the increased eosinophilic and mast cell inflammatory responses in the respiratory tract.

Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma.

Secreted phospholipase A2s (sPLA2s) regulate eicosanoid formation and have been implicated in asthma. Although sPLA2s function as enzymes, some of the sPLA2s bind with high affinity to a C-type lectin receptor, called PLA2R1, which has functions in both cellular signaling and clearance of sPLA2s. We sought to examine the expression of PLA2R1 in the airway epithelium of human subjects with asthma and the function of the murine Pla2r1 gene in a model of asthma. Expression of PLA2R1 in epithelial brushings was assessed in two distinct cohorts of children with asthma by microarray and quantitative PCR, and immunostaining for PLA2R1 was conducted on endobronchial tissue and epithelial brushings from adults with asthma. C57BL/129 mice deficient in Pla2r1 (Pla2r1-/-) were characterized in an ovalbumin (OVA) model of allergic asthma. PLA2R1 was differentially overexpressed in epithelial brushings of children with atopic asthma in both cohorts. Immunostaining for PLA2R1 in endobronchial tissue localized to submucosal glandular epithelium and columnar epithelial cells. After OVA sensitization and challenge, Pla2r1-/- mice had increased airway hyperresponsiveness, as well as an increase in cellular trafficking of eosinophils to the peribronchial space and bronchoalveolar lavage fluid, and an increase in airway permeability. In addition, Pla2r1-/- mice had more dendritic cells in the lung, higher levels of OVA-specific IgG, and increased production of both type-1 and type-2 cytokines by lung leukocytes. PLA2R1 is increased in the airway epithelium in asthma, and serves as a regulator of airway hyperresponsiveness, airway permeability, antigen sensitization, and airway inflammation.

Using the relationship between brain tissue regional saturation of oxygen and mean arterial pressure to determine the optimal mean arterial pressure in patients following cardiac arrest: A pilot proof-of-concept study.

INTRODUCTION: Prospectively assess cerebral autoregulation and optimal mean arterial pressure (MAPOPT) using the dynamic relationship between MAP and regional saturation of oxygen (rSO2) using near-infrared spectroscopy. METHODS: Feasibility study of twenty patients admitted to the intensive care unit following a cardiac arrest. All patients underwent continuous rSO2 monitoring using the INVOS(®) cerebral oximeter. ICM+(®) brain monitoring software calculates the cerebral oximetry index (COx) in real-time which is a moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of MAP and correspond rSO2 signals. When rSO2 increases with increasing MAP (COx ≥0.3), cerebral autoregulation is dysfunctional. Conversely, when rSO2 remains constant or decreases with increasing MAP (COx <0.3), autoregulation is preserved. ICM+(®) fits a U-shaped curve through the COx values plotted vs. MAP. The MAPOPT is nadir of this curve. RESULTS: The median age was 59 years (IQR 54-67) and 7 of 20 were female. The cardiac arrest was caused by myocardial infarction in 12 (60%) patients. Nineteen arrests were witnessed and return of spontaneous circulation occurred in a median of 15.5min (IQR 8-33). Patients underwent a median of 30h (IQR 23-46) of monitoring. COx curves and MAPOPT were generated in all patients. The mean overall MAP and MAPOPT were 76mmHg (SD 10) and 76mmHg (SD 7), respectively. MAP was outside of 5mmHg from MAPOPT in 50% (SD 15) of the time. Out of the 7672 5-min averaged COx measurements, 1182 (15%) were at 0.3 or above, indicating absence of autoregulation. Multivariable polynomial fractional regression demonstrated an increase in COx with increasing temperature (P=0.008). CONCLUSIONS: We demonstrated the feasibility to determine a MAPOPT using cerebral oximetry in patients after cardiac arrest.

The effect of continuous hypertonic saline infusion and hypernatremia on mortality in patients with severe traumatic brain injury: a retrospective cohort study.

PURPOSE: Hypertonic saline (HTS) is used to control intracranial pressure (ICP) in patients with traumatic brain injury (TBI); however, in prior studies, the resultant hypernatremia has been associated with increased mortality. We aimed to study the effect of HTS on ICP and mortality in patients with severe TBI. METHODS: We performed a retrospective cohort study of 231 patients with severe TBI (Glasgow Coma Scale [GCS] ≤ 8) admitted to two neurotrauma units from 2006-2012. We recorded daily HTS, ICP, and serum sodium (Na) concentration. We used Cox proportional regression modelling for hospital mortality and incorporated the following time-dependent variables: use of HTS, hypernatremia, and desmopressin administration. RESULTS: The mean [standard deviation (SD)] age of patients was 34 (17) and the median (interquartile range [IQR]) GCS was 6 [3-8]. Hypertonic saline was administered as a continuous infusion in 124 of 231 (54%) patients over 788 of 2,968 (27%) patient-days. Hypernatremia (Na > 145 mmol·L(-1)) developed in 151 of 231 (65%) patients over 717 of 2,968 (24%) patients-days. In patients who developed hypernatremia, the median [IQR] Na was 146 [142-147] mmol·L(-1). Overall hospital mortality was 26% (59 of 231 patients). After adjusting for baseline covariates, neither HTS (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.56 to 2.05; P = 0.84) nor hypernatremia (HR, 1.31; 95% CI, 0.68 to 2.55; P = 0.42) was associated with hospital mortality. There was no effect modification by either HTS or hypernatremia on each another. Patients who received HTS observed a significant decrease in ICP during their ICU stay compared with those who did not receive HTS (4 mmHg; 95% CI, 2 to 6; P < 0.001 vs 2 mmHg; 95% CI, -1 to 5; P = 0.14). CONCLUSIONS: Hypertonic saline and hypernatremia are not associated with hospital mortality in patients with severe TBI.

Effect of tidal volume and positive end-expiratory pressure on expiratory time constants in experimental lung injury.

We utilized a multicompartment model to describe the effects of changes in tidal volume (VT) and positive end-expiratory pressure (PEEP) on lung emptying during passive deflation before and after experimental lung injury. Expiratory time constants (τE) were determined by partitioning the expiratory flow-volume (V˙EV) curve into multiple discrete segments and individually calculating τE for each segment. Under all conditions of PEEP and VT, τE increased throughout expiration both before and after injury. Segmented τE values increased throughout expiration with a slope that was different than zero (P < 0. 01). On average, τE increased by 45.08 msec per segment. When an interaction between injury status and τE segment was included in the model, it was significant (P < 0.05), indicating that later segments had higher τE values post injury than early τE segments. Higher PEEP and VT values were associated with higher τE values. No evidence was found for an interaction between injury status and VT, or PEEP. The current experiment confirms previous observations that τE values are smaller in subjects with injured lungs when compared to controls. We are the first to demonstrate changes in the pattern of τE before and after injury when examined with a multiple compartment model. Finally, increases in PEEP or VT increased τE throughout expiration, but did not appear to have effects that differed between the uninjured and injured state.

A proportional assist ventilator to unload respiratory muscles experimentally during exercise in humans.

What is the central question of this study? Can a modern proportional assist ventilator (PAV) function sufficiently well to unload the respiratory muscles during exercise? What is the main finding and its importance? A PAV can be constructed with contemporary hardware and software and be used at all exercise intensities to unload the respiratory muscles by up to 70%. Previously, PAVs have allowed researchers to address many fundamental physiological problems in clinical and healthy populations, but those versions are no longer functional or available. We describe the creation of a PAV that permits researchers to use it as an experimental tool. Manipulation of the normally occurring work of breathing (WOB) during exercise can provide insights into whole-body regulatory mechanisms in clinical patients and healthy subjects. One method to reduce the WOB uses a proportional assist ventilator (PAV). Suitable commercially available units are not capable of being used during heavy exercise. This investigation was undertaken in order to create a PAV and assess the degree to which the WOB could be reduced during exercise. A PAV works by creating a positive mouth pressure (Pm ) during inspiration, which consequently reduces the WOB. Spontaneous breathing patterns can be maintained, and the amplitude of Pm is calculated using the equation of motion and predetermined proportionality constants. We generated positive Pm using a breathing apparatus consisting of rigid tubing, solenoid valves to control the airflow direction and a proportional valve connected to compressed gas. Healthy male and female subjects were able to use the PAV successfully while performing cycling exercise over a range of intensities (50-100% of maximal workload) for different durations (from 30 s to 20 min) and different protocols (constant versus progressive workload). Inspiratory WOB was reduced up to 90%, while total WOB was reduced by 70%. The greatest reduction in WOB (50-75%) occurred during submaximal exercise, but at maximal ventilations (>180 l min(-1) ) a 50% reduction was still possible. The calculated change in WOB and subsequent reduction in respiratory muscle oxygen consumption resulted in equivalent reductions in whole-body oxygen consumption. With adequate familiarization and practice, our PAV can consistently reduce the WOB across a range of exercise intensities.