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1.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Background
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Conclusions
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
doi:10.1371/journal.pmed.1000132
PMCID: PMC2722083  PMID: 19688045
2.  Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology 
PLoS Medicine  2006;3(7):e290.
Background
The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology.
Methods and Findings
Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased.
Conclusions
The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF.
Editors' Summary
Background.
Human cells (like those of other multicellular animals) use oxygen to provide the energy needed for daily life. Having not enough oxygen is a problem, but having too much is also dangerous because it damages proteins, DNA, and other large molecules that keep cells functioning. Consequently, the physiological systems—including the heart, lungs, and circulation—work together to balance oxygen supply and demand throughout the body. When oxygen is limiting (a condition called hypoxia), as happens at high altitudes, the cellular oxygen supply is maintained by increasing the heart rate, increasing the speed and depth of breathing (hyperventilation), constricting the blood vessels in the lung (pulmonary vasoconstriction), and increasing the number of oxygen-carrying cells in the blood. All these physiological changes increase the amount of oxygen that can be absorbed from the air, but how they are regulated is poorly understood. By contrast, researchers know quite a bit about how individual cells respond to hypoxia. When oxygen is limited, a protein called hypoxia-inducible factor (or HIF) activates a number of target proteins that help the cell get enough oxygen (for example, proteins that stimulate the growth of new blood vessels). When there is plenty of oxygen, another protein, called von Hippel–Lindau tumor suppressor (abbreviated VHL), rapidly destroys HIF. Recently, researchers discovered that a genetic condition called Chuvash polycythaemia, characterised by the overproduction of red blood cells, is caused by a specific defect in VHL that reduces its ability to destroy HIF. As a result, the expression of certain HIF target proteins is increased even when oxygen levels are normal.
Why Was This Study Done?
Chuvash polycythaemia is very rare, and so far little is known about how this genetic abnormality affects the physiology and long-term health of patients. By studying heart and lung function in patients with Chuvash polycythaemia, the researchers involved in this study hoped to discover more about the health consequences of the condition and to find out whether the VHL–HIF system controls systemic responses to hypoxia as well as cellular responses.
What Did the Researchers Do and Find?
The researchers recruited and studied three patients with Chuvash polycythaemia, and, as controls for the comparison, several normal individuals and patients with an unrelated form of polycythaemia. They then measured how the lungs and hearts of these people reacted to mild hypoxia (similar to that experienced on commercial air flights) and moderate hypoxia (equiv alent to being on the top of an Alpine peak). They found that patients with Chuvash polycythaemia naturally breathe slightly quicker and deeper than normal individuals, and that their breathing rate increased dramatically and abnormally when oxygen was reduced. They also found that at normal oxygen levels the pulmonary blood vessels of these patients were more constricted than those of control individuals, and that they reacted more extremely to hypoxia. Similarly, the normal heart rate of the patients was slightly higher than that of the controls and increased much more in response to mild hypoxia.
What Do These Findings Mean?
The physiological differences measured by the researchers between Chuvash polycythaemia patients and control individuals are similar to the adaptations seen in people traveling to high altitudes where oxygen is limited. Thus, the VHL–HIF proteins may regulate the response to different oxygen concentrations both in individual cells and at the systemic level, although more physiological studies are needed to confirm this. Because the pulmonary blood vessels of patients with Chuvash polycythaemia are always abnormally constricted, and even more so when oxygen is limited, these people should avoid living at high altitude and should minimise air travel, suggest the researchers. The increased blood pressure in their lungs (pulmonary hypertension) could conceivably cause heart failure under such circumstances. Finally, this study has implications for the development of drugs directed at the VHL–HIF system. Agents are currently being designed to promote the development of new blood vessels after strokes or heart attacks by preventing the destruction of HIF, but based on the findings here such agents might have undesirable physiological affects. Conversely, HIF inhibitors (which act as anti-cancer reagents by increasing hypoxia in the centre of tumors and so inhibiting their growth) might be useful in the treatment of pulmonary hypertension.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030290.
• Online Mendelian Inheritance in Man page on Chuvash polycythaemia
• Information from the VHL Family Alliance on von Hippel–Lindau disease, including information on Chuvash polycythaemia
• Wikipedia page on polycythaemia and von Hippel–Lindau disease (note: Wikipedia is a free online encyclopaedia that anyone can edit)
Physiological study of patients with Chuvash polycythemia (caused by mutation of VHL) reveals characteristics similar to those associated with acclimatization to the hypoxia of high altitude.
doi:10.1371/journal.pmed.0030290
PMCID: PMC1479389  PMID: 16768548
3.  Bench and mathematical modeling of the effects of breathing a helium/oxygen mixture on expiratory time constants in the presence of heterogeneous airway obstructions 
Background
Expiratory time constants are used to quantify emptying of the lung as a whole, and emptying of individual lung compartments. Breathing low-density helium/oxygen mixtures may modify regional time constants so as to redistribute ventilation, potentially reducing gas trapping and hyperinflation for patients with obstructive lung disease. In the present work, bench and mathematical models of the lung were used to study the influence of heterogeneous patterns of obstruction on compartmental and whole-lung time constants.
Methods
A two-compartment mechanical test lung was used with the resistance in one compartment held constant, and a series of increasing resistances placed in the opposite compartment. Measurements were made over a range of lung compliances during ventilation with air or with a 78/22% mixture of helium/oxygen. The resistance imposed by the breathing circuit was assessed for both gases. Experimental results were compared with predictions of a mathematical model applied to the test lung and breathing circuit. In addition, compartmental and whole-lung time constants were compared with those reported by the ventilator.
Results
Time constants were greater for larger minute ventilation, and were reduced by substituting helium/oxygen in place of air. Notably, where time constants were long due to high lung compliance (i.e. low elasticity), helium/oxygen improved expiratory flow even for a low level of resistance representative of healthy, adult airways. In such circumstances, the resistance imposed by the external breathing circuit was significant. Mathematical predictions were in agreement with experimental results. Time constants reported by the ventilator were well-correlated with those determined for the whole-lung and for the low-resistance compartment, but poorly correlated with time constants determined for the high-resistance compartment.
Conclusions
It was concluded that breathing a low-density gas mixture, such as helium/oxygen, can improve expiratory flow from an obstructed lung compartment, but that such improvements will not necessarily affect time constants measured by the ventilator. Further research is required to determine if alternative measurements made at the ventilator level are predictive of regional changes in ventilation. It is anticipated that such efforts will be aided by continued development of mathematical models to include pertinent physiological and pathophysiological phenomena that are difficult to reproduce in mechanical test systems.
doi:10.1186/1475-925X-11-27
PMCID: PMC3497861  PMID: 22646835
Helium; Heliox; Exhalation; Time constant; Hyperinflation; Gas trapping; Ventilation distribution; Airway resistance; Mechanical ventilation; Lung
4.  Pattern of lung volumes in patients with sighing breathing. 
Thorax  1993;48(8):809-811.
BACKGROUND--Sighing breathing is observed in subjects suffering from anxiety with no apparent organic disease. METHODS--Lung volumes and expiratory flow rates were measured in 12 patients with a sighing pattern of breathing and in 10 normal subjects matched for age, gender, and anthropometric data. In both groups the measurements were made by spirographic and plethysmographic techniques. In normal subjects functional residual capacity (FRC) and residual volume (RV) were measured during normal breathing and again during simulated sighing breathing to exclude technical artifacts resulting from hyperventilation during measurement by the helium closed circuit method. RESULTS--Patients with a sighing pattern of breathing had a normal total lung capacity (TLC) but significantly different partitioning of lung compartments compared with normal subjects. The vital capacity (VC) was lower when measured by both spirographic and plethysmographic methods and RV was higher. The forced expiratory volume in one second (FEV1) was also lower in patients with sighing breathing. The FEV1/VC and the maximal expiratory flow rates at 50% and at 25% of the forced vital capacity (V50 and V25) were normal and similar in both groups. In normal subjects there were no differences in RV when measured during quiet or simulated sighing breathing. CONCLUSIONS--Subjects with sighing breathing have a normal TLC with a higher RV and lower VC than normal subjects. There was no obvious physiological or anatomical explanation for this pattern.
PMCID: PMC464706  PMID: 8211870
5.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
6.  Systems for Lung Volume Standardization during Static and Dynamic MDCT-based Quantitative Assessment of Pulmonary Structure and Function 
Academic radiology  2012;19(8):10.1016/j.acra.2012.03.017.
Rationale and Objectives
Multidetector-row Computed Tomography (MDCT) has emerged as a tool for quantitative assessment of parenchymal destruction, air trapping (density metrics) and airway remodeling (metrics relating airway wall and lumen geometry) in chronic obstructive pulmonary disease (COPD) and asthma. Critical to the accuracy and interpretability of these MDCT-derived metrics is the assurance that the lungs are scanned during a breath-hold at a standardized volume.
Materials and Methods
A computer monitored turbine-based flow meter system was developed to control patient breath-holds and facilitate static imaging at fixed percentages of the vital capacity. Due to calibration challenges with gas density changes during multi-breath xenon-CT an alternative system was required. The design incorporated dual rolling seal pistons. Both systems were tested in a laboratory environment and human subject trials.
Results
The turbine-based system successfully controlled lung volumes in 32/37 subjects, having a linear relationship for CT measured air volume between repeated scans: for all scans, the mean and confidence interval of the differences (scan1-scan2) was −9 ml (−169, 151); for TLC alone 6 ml (−164, 177); for FRC alone, −23 ml (−172, 126). The dual-piston system successfully controlled lung volume in 31/41 subjects. Study failures related largely to subject non-compliance with verbal instruction and gas leaks around the mouthpiece.
Conclusion
We demonstrate the successful use of a turbine-based system for static lung volume control and demonstrate its inadequacies for dynamic xenon-CT studies. Implementation of a dual-rolling seal spirometer has been shown to adequately control lung volume for multi-breath wash-in xenon-CT studies. These systems coupled with proper patient coaching provide the tools for the use of CT to quantitate regional lung structure and function. The wash-in xenon-CT method for assessing regional lung function, while not necessarily practical for routine clinical studies, provides for a dynamic protocol against which newly emerging single breath, dual-energy xenon-CT measures can be validated.
doi:10.1016/j.acra.2012.03.017
PMCID: PMC3825680  PMID: 22555001
Lung volume control; xenon-CT; dual-energy CT
7.  Noninvasive detection of lung cancer by analysis of exhaled breath 
BMC Cancer  2009;9:348.
Background
Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless.
Methods
Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers.
Results
Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons.
Conclusion
GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.
doi:10.1186/1471-2407-9-348
PMCID: PMC2761408  PMID: 19788722
8.  Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice 
eLife  2014;3:e02265.
All motor behaviors require precise temporal coordination of different muscle groups. Breathing, for example, involves the sequential activation of numerous muscles hypothesized to be driven by a primary respiratory oscillator, the preBötzinger Complex, and at least one other as-yet unidentified rhythmogenic population. We tested the roles of Atoh1-, Phox2b-, and Dbx1-derived neurons (three groups that have known roles in respiration) in the generation and coordination of respiratory output. We found that Dbx1-derived neurons are necessary for all respiratory behaviors, whereas independent but coupled respiratory rhythms persist from at least three different motor pools after eliminating or silencing Phox2b- or Atoh1-expressing hindbrain neurons. Without Atoh1 neurons, however, the motor pools become temporally disorganized and coupling between independent respiratory oscillators decreases. We propose Atoh1 neurons tune the sequential activation of independent oscillators essential for the fine control of different muscles during breathing.
DOI: http://dx.doi.org/10.7554/eLife.02265.001
eLife digest
A healthy adult at rest will breathe in and out around 20 times per minute. Each breath requires a complex series of coordinated muscle activity. Inhalation begins with the opening of the airway followed by the contraction of the diaphragm and the intercostal muscles between the ribs, causing the chest cavity to expand. As the lungs increase in volume, the pressure inside them drops and air is drawn in. Relaxation of the diaphragm and intercostal muscles compresses the lungs, causing us to exhale.
Breathing is driven by the brainstem and it cannot be suppressed indefinitely: holding your breath eventually triggers a reflex that forces breathing to resume. The region of the brainstem that controls breathing is called the preBötzinger Complex. However, there is increasing evidence that a second region in the brainstem is also involved. This region, which is called the retrotrapezoid nucleus/parafacial respiratory group, consists of three types of excitatory neurons—Dbx1 neurons, Phox2b neurons, and Atoh1 neurons—but their roles had not been clear. Now, using multiple lines of genetically modified mice, Tupal et al. have teased apart the roles of these three cell types.
These experiments showed that the Dbx1 neurons—which are also found in the preBötzinger Complex—have an essential role in sending the signals from the brain that drive the different muscle activities needed to breathe. The Phox2b neurons modulate breathing based on the level of carbon dioxide in the blood. Atoh1 neurons help control the sequence of respiratory muscle activity during a breath, probably by selectively inhibiting different populations of Dbx1 neurons.
The work of Tupal et al. indicates that distinct populations of neurons within the brainstem independently control two different aspects of breathing: the generation of breathing rhythms, and the coordination of these rhythms. Given that many other physiological processes involve rhythmic activity patterns, this model may help us to understand how the brain generates and controls complex behaviors more generally.
DOI: http://dx.doi.org/10.7554/eLife.02265.002
doi:10.7554/eLife.02265
PMCID: PMC4060005  PMID: 24842997
breathing; central pattern generator; PreBötzinger Complex; oscillator; transcription; mouse
9.  Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study 
PLoS Medicine  2014;11(2):e1001599.
Tetyana Kendzerska and colleagues explore the association between physiological measures of obstructive sleep apnea other than the apnea-hypopnea index and the risk of cardiovascular events.
Please see later in the article for the Editors' Summary
Background
Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events.
Methods and Findings
A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence.
Conclusion
OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, particularly among middle-aged and elderly people. It is characterized by apnea—a brief interruption in breathing that lasts at least 10 seconds—and hypopnea—a decrease of more than 50% in the amplitude of breathing that lasts at least 10 seconds or clear but smaller decrease in amplitude associated with either oxygen desaturation or an arousal. Patients with OSA experience numerous episodes of apnea and hypopnea during the night; severe OSA is defined as having 30 or more episodes per hour (an apnea-hypopnea index [AHI] of >30). These breathing interruptions occur when relaxation of the upper airway muscles decreases the airflow, which lowers the amount of oxygen in the blood. As a result, affected individuals frequently wake from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air through a face mask into the airway to keep it open.
Why Was This Study Done?
OSA can be life-threatening. Most directly, daytime sleepiness can cause accidents, but OSA is also associated with an increased risk of developing cardiovascular disease (CVD, disease that affects the heart and the circulation). To date, studies that have investigated the association between OSA and the risk of myocardial infarction (heart attack), congestive heart failure, stroke, and other CVDs have used the AHI to diagnose and categorize the severity of OSA. However, by focussing on AHI, clinicians and researchers may be missing opportunities to improve their ability to predict which patients are at the highest risk of CVD. In this historical cohort study, the researchers investigate the association between other OSA-related variables (for example, blood oxygen saturation and sleep fragmentation) and the risk of cardiovascular events and all-cause mortality (death). A historical cohort study examines the medical records of groups of individuals who have different characteristics at baseline for the subsequent occurrence of specific outcomes.
What Did the Researchers Do and Find?
The researchers used administrative data (including hospitalization records and physicians' claims for services supplied to patients) to follow up adults referred for suspected OSA who underwent diagnostic polysomnography (a sleep study) at a single Canadian hospital between 1994 and 2010. A database of the polysomnography results provided information on OSA-related variables for all the study participants. Over an average follow-up of about 6 years, 11.5% of the 10,149 participants were hospitalized for a myocardial infarction, stroke, or congestive heart failure, underwent a revascularization procedure (an intervention that restores the blood supply to an organ or tissue after CVD has blocked a blood vessel), or had died from any cause. After adjusting for multiple established risk factors for CVD such as smoking and age in Cox regression models (a statistical approach that examines associations between patient variables and outcomes), several OSA-related variables (but not AHI) were significant predictors of CVD. The strongest OSA-related predictor of cardiovascular events or all-cause mortality was total sleep time spent with oxygen saturation below 90%, which increased the risk of a cardiovascular event or death by 50%. Other statistically significant OSA-related predictors (predictors that were unlikely to be associated with the outcome through chance) of cardiovascular events or death included total sleep time, number of awakenings, frequency of periodic leg movements, heart rate, and daytime sleepiness.
What Do These Findings Mean?
These findings indicate that OSA-related factors other than AHI are important predictors of the composite outcome of a cardiovascular event or all-cause mortality. Indeed, although AHI was significantly associated with the researchers' composite outcome in an analysis that did not consider other established risk factors for CVD (“confounders”), the association became non-significant after controlling for potential confounders. The accuracy of these findings, which need to be confirmed in other settings, is likely to be limited by the lack of information available about the use of CPAP by study participants and by the lack of adjustment for some important confounders. Importantly, however, these findings suggest that OSA-related factors other than AHI should be considered as predictors of CVD in future studies and in clinical practice.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001599.
The US National Heart Lung and Blood Institute has information (including several videos) about obstructive sleep apnea (in English and Spanish), sleep studies, heart disease, and other cardiovascular diseases (some information in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about sleep apnea and about cardiovascular disease
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and health-care professionals, including personal stories about the condition
The MedlinePlus encyclopedia has pages on obstructive sleep apnea and on polysomnography; MedlinePlus provides links to further information and advice about obstructive sleep apnea, heart diseases, and vascular diseases (in English and Spanish)
doi:10.1371/journal.pmed.1001599
PMCID: PMC3913558  PMID: 24503600
10.  Multi-slice Fractional Ventilation Imaging in Large Animals with Hyperpolarized Gas MRI 
NMR in biomedicine  2012;25(9):1015-1025.
Noninvasive assessment of regional lung ventilation is of critical importance in quantifying the severity of disease and evaluating response to therapy in many pulmonary diseases. This work presents for the first time the implementation of a hyperpolarized (HP) gas MRI technique for measuring whole-lung regional fractional ventilation (r) in Yorkshire pigs (n = 5) through the use of a gas mixing and delivery device in supine position. The proposed technique utilizes a series of back-to-back HP gas breaths with images acquired during short end-inspiratory breath-holds. In order to decouple the RF pulse decay effect from ventilatory signal build-up in the airways, regional distribution of flip angle (α) was estimated in the imaged slices by acquiring a series of back-to-back images with no inter-scan time delay during a breath-hold at the tail-end of the ventilation sequence. Analysis was performed to assess the multi-slice ventilation model sensitivity to noise, oxygen and number of flip angle images. The optimal α value was determined based on minimizing the error in r estimation; αopt = 5–6° for the set of acquisition parameters in pigs. The mean r values for the group of pigs were 0.27±0.09, 0.35±0.06, 0.40±0.04 for ventral, middle and dorsal slices, respectively, (excluding conductive airways r > 0.9). A positive gravitational (ventral-dorsal) ventilation gradient effect was present in all animals. The trachea and major conductive airways showed a uniform near-unity r value, with progressively smaller values corresponding to smaller diameter airways, and ultimately leading to lung parenchyma. Results demonstrate the feasibility of measurements of fractional ventilation in large species, and provides a platform to address technical challenges associated with long breathing time scales through the optimization of acquisition parameters in species with a pulmonary physiology very similar to that of human beings.
doi:10.1002/nbm.2763
PMCID: PMC3362674  PMID: 22290603
Pulmonary ventilation; Quantitative lung imaging; Fractional ventilation; Hyperpolarized gas MRI; Mechanical ventilation
11.  Anæsthesia in Chest Surgery, with Special Reference to Controlled Respiration and Cyclopropane 
Problems in chest surgery: Cases with prolonged toxæmia or amyloid disease require an anæsthetic agent of low toxicity. When sputum or blood are present in the tracheobronchial tree the anæsthesia should abolish reflex distrubances and excessive sputum be removed by suction. The technique should permit the use of a high oxygen atmosphere; controlled respiration with cyclopropane or ether fulfil these requirements. Open pneumothorax is present when a wound of the chest wall allows air to pass in and out of the pleural cavity. The lung on the affected side collapses and the mediastinum moves over and partly compresses the other lung.
The dangers of an open pneumothorax: (1) Paradoxical respiration—the lung on the affected side partially inflates on expiration and collapses on inspiration. Part of the air entering the good lung has been shuttled back from the lung on the affected side and is therefore vitiated. Full expansion of the sound lung is handicapped by the initial displacement of the mediastinum which increases on inspiration. The circulation becomes embarrassed.
(2) Vicious circle coughing. During a paroxysm of coughing dyspnœa will occur. This accentuates paradoxical respiration and starts a vicious circle. Death from asphyxia may result.
Special duties of the anæsthetist: (1) To carry out or supervise continuous circulatory resuscitation. During a thoracotomy a drip blood transfusion maintains normal blood-pressure and pulse-rate.
(2) To maintain effcient respiration.
Positive pressure anæsthesia: Risk of impacting secretions in smaller bronchi with subsequent atelectasis; eventual risk of CO2 poisoning without premonitory signs.
Controlled respiration: (1) How it is produced. (2) Its uses in chest surgery.
Controlled respiration means that the anæsthetist, having abolished the active respiratory efforts of the patient, maintains an efficient tidal exchange by rhythmic squeezing of the breathing bag. This may be done mechanically by Crafoord's modification of Frenkner's spiropulsator or by hand.
Active respiration will cease (i) if the patient's CO2 is lowered sufficiently by hyperventilation, (ii) if the patient's respiratory centre is depressed sufficiently by sedative and anæsthetic drugs, and (iii) by a combination of (i) and (ii) of less degree.
The author uses the second method, depressing the respiratory centre with omnoponscopolamine, pentothal sodium, and then cycloprȯpane. The CO2 absorption method is essential for this technique, and this and controlled respiration should be mastered by the anæsthetist with a familiar agent and used at first only in uncomplicated cases.
The significance of cardiac arrhythmias occuring with cyclopropane is discussed.
The place of the other available anæsthetic agents is discussed particularly on the advisability of using local anæsthesia for the drainage of empyema or lung abscess.
Pharyngeal airway or endotracheal tube? Anæsthesia may be maintained with a pharyngeal airway in many cases but intubation must be used when tracheobronchial suction may be necessary and when there may be difficulty in maintaining an unobstructed airway.
A one-lung anæsthesia is ideal for pneumonectomy. This may be obtained by endotracheal anæsthesia after bronchial tamponage of the affected side (Crafoord, v. fig. 6b) or by an endobronchial intubation of the sound side (v. figs. 9b and 9c). Endobronchial placing of the breathing tube may be performed “blind”. Before deciding on blind bronchial intubation, the anæsthetist must examine X-ray films for any abnormality deviating the trachea or bronchi. Though the right bronchus may be easily intubated blindly as a rule, there is the risk of occluding the orifice of the upper lobe bronchus (fig. 9d) when the patient will become cyanosed. If the tube bevel is facing its orifice the risk of occlusion will be decreased (fig. 9c).
Greater accuracy in placing the tube can be effected by inserting it under direct vision. Instruments for performing this manœuvre are described.
In lobectomy for bronchiectasis the anæsthetist must try to prevent the spread of infection to other parts. Ideally, the bronchus of the affected lobe should be plugged with ribbon gauze (Crafoord, v. fig. 6c) or a suction catheter with a baby balloon on it placed in the affected bronchus. In the presence of a large bronchopleural fistula controlled respiration cannot be established during operation. As the surgeon is rarely able to plug the fistula, if pneumonectomy is to be performed intubation for a one-lung anæsthesia is the best method. During other procedures it is essential to maintain quiet respiration.
In war casualties it is almost always possible, with the technique described, to leave the lung on the affected side fully expanded and thus frequently to restore normal respiratory physiology. Co-operation between surgeon and anæsthetist is essential.
PMCID: PMC1998132  PMID: 19992357
12.  Increased lung inflammation with oxygen supplementation in tracheotomized spontaneously breathing rabbits: an experimental prospective randomized study 
BMC Anesthesiology  2014;14(1):86.
Background
Mechanical ventilation is a well–known trigger for lung inflammation. Research focuses on tidal volume reduction to prevent ventilator-induced lung injury. Mechanical ventilation is usually applied with higher than physiological oxygen fractions. The purpose of this study was to investigate the after effect of oxygen supplementation during a spontaneous ventilation set up, in order to avoid the inflammatory response linked to mechanical ventilation.
Methods
A prospective randomised study using New Zealand rabbits in a university research laboratory was carried out. Rabbits (n = 20) were randomly assigned to 4 groups (n = 5 each group). Groups 1 and 2 were submitted to 0.5 L/min oxygen supplementation, for 20 or 75 minutes, respectively; groups 3 and 4 were left at room air for 20 or 75 minutes. Ketamine/xylazine was administered for induction and maintenance of anaesthesia. Lungs were obtained for histological examination in light microscopy.
Results
All animals survived the complete experiment. Procedure duration did not influence the degree of inflammatory response. The hyperoxic environment was confirmed by blood gas analyses in animals that were subjected to oxygen supplementation, and was accompanied with lower mean respiratory rates. The non-oxygen supplemented group had lower mean oxygen arterial partial pressures and higher mean respiratory rates during the procedure. All animals showed some inflammatory lung response. However, rabbits submitted to oxygen supplementation showed significant more lung inflammation (Odds ratio = 16), characterized by more infiltrates and with higher cell counts; the acute inflammatory response cells was mainly constituted by eosinophils and neutrophils, with a relative proportion of 80 to 20% respectively. This cellular observation in lung tissue did not correlate with a similar increase in peripheral blood analysis.
Conclusions
Oxygen supplementation in spontaneous breathing is associated with an increased inflammatory response when compared to breathing normal room air. This inflammatory response was mainly constituted with polymorphonuclear cells (eosinophils and neutrophils). As confirmed in all animals by peripheral blood analyses, the eosinophilic inflammatory response was a local organ event.
doi:10.1186/1471-2253-14-86
PMCID: PMC4197313  PMID: 25320562
Lung inflammation; Oxygen supplemented spontaneous breathing
13.  Bench experiments comparing simulated inspiratory effort when breathing helium-oxygen mixtures to that during positive pressure support with air 
Background
Inhalation of helium-oxygen (He/O2) mixtures has been explored as a means to lower the work of breathing of patients with obstructive lung disease. Non-invasive ventilation (NIV) with positive pressure support is also used for this purpose. The bench experiments presented herein were conducted in order to compare simulated patient inspiratory effort breathing He/O2 with that breathing medical air, with or without pressure support, across a range of adult, obstructive disease patterns.
Methods
Patient breathing was simulated using a dual-chamber mechanical test lung, with the breathing compartment connected to an ICU ventilator operated in NIV mode with medical air or He/O2 (78/22 or 65/35%). Parabolic or linear resistances were inserted at the inlet to the breathing chamber. Breathing chamber compliance was also varied. The inspiratory effort was assessed for the different gas mixtures, for three breathing patterns, with zero pressure support (simulating unassisted spontaneous breathing), and with varying levels of pressure support.
Results
Inspiratory effort increased with increasing resistance and decreasing compliance. At a fixed resistance and compliance, inspiratory effort increased with increasing minute ventilation, and decreased with increasing pressure support. For parabolic resistors, inspiratory effort was lower for He/O2 mixtures than for air, whereas little difference was measured for nominally linear resistance. Relatively small differences in inspiratory effort were measured between the two He/O2 mixtures. Used in combination, reductions in inspiratory effort provided by He/O2 and pressure support were additive.
Conclusions
The reduction in inspiratory effort afforded by breathing He/O2 is strongly dependent on the severity and type of airway obstruction. Varying helium concentration between 78% and 65% has small impact on inspiratory effort, while combining He/O2 with pressure support provides an additive reduction in inspiratory effort. In addition, breathing He/O2 alone may provide an alternative to pressure support in circumstances where NIV is not available or poorly tolerated.
doi:10.1186/1471-2466-12-62
PMCID: PMC3527263  PMID: 23031537
Helium; Oxygen; Heliox; Inspiratory effort; Work of breathing; Airway resistance; Lung compliance; Non-invasive ventilation; Pressure support
14.  Habitual snoring and atopic state: correlations with respiratory function and teeth occlusion 
BMC Pediatrics  2012;12:175.
Background
Allergy represents a risk factor at the base of sleep-disordered breathing in pediatric age. Among allergic diseases, the atopy is characterized by a tendency to be “hyperallergic.” Sleep-disordered breathing is also known in orthodontics as correlated with the morphology of craniofacial complex. The aim of this study was to investigate the relation between atopy and sleep-disordered breathing (oral breathers with habitual snoring), comparing atopic children with sleep-disordered breathing (test group) with nonatopic ones with sleep-disordered breathing (control group), in the prevalence of dento-skeletal alterations and other risk factors that trigger sleep-disordered breathing, such as adenotonsillar hypertrophy, turbinate hypertrophy, obesity, and alteration of oxygen arterial saturation.
Methods
In a group of 110 subjects with sleep-disordered breathing (6 to 12 years old), we grouped the subjects into atopic (test group, 60 subjects) and nonatopic (control group, 50 subjects) children and compared the data on the following: skin allergic tests, rhinoscopy, rhinomanometry, night home pulsoxymetry, body mass index, and dento-facial alterations.
Results
Even if our results suggest that atopy is not a direct risk factor for sleep-disordered breathing, the importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing seems to be demonstrated in our study by the higher prevalence of hypertrophy in the adenotonsillar lymphatic tissue, odontostomatological alterations, alterations of the oxygen saturation to pulsoxymetry, and higher prevalence of obesity observed in our children with sleep-disordered breathing, in percentages higher than that of the general pediatric population previously observed in the literature.
Conclusions
The importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing is demonstrated in our study.
doi:10.1186/1471-2431-12-175
PMCID: PMC3506469  PMID: 23134563
Sleep-disordered breathing (SDB); Atopy; Dento-facial morphology; Allergy; Oral breathing; Snoring
15.  Effect of spontaneous breathing on ventilator-induced lung injury in mechanically ventilated healthy rabbits: a randomized, controlled, experimental study 
Critical Care  2011;15(5):R244.
Introduction
Ventilator-induced lung injury (VILI), one of the most serious complications of mechanical ventilation (MV), can impact patients' clinical prognoses. Compared to control ventilation, preserving spontaneous breathing can improve many physiological features in ventilated patients, such as gas distribution, cardiac performance, and ventilation-perfusion matching. However, the effect of spontaneous breathing on VILI is unknown. The goal of this study was to compare the effects of spontaneous breathing and control ventilation on lung injury in mechanically-ventilated healthy rabbits.
Methods
Sixteen healthy New Zealand white rabbits were randomly placed into a spontaneous breathing group (SB Group) and a control ventilation group (CV Group). Both groups were ventilated for eight hours using biphasic positive airway pressure (BIPAP) with similar ventilator parameters: inspiration pressure (PI) resulting in a tidal volume (VT) of 10 to 15 ml/kg, inspiratory-to-expiratory ratio of 1:1, positive end-expiration pressure (PEEP) of 2 cmH2O, and FiO2 of 0.5. Inflammatory markers in blood serum, lung homogenates and bronchoalveolar lavage fluid (BALF), total protein levels in BALF, mRNA expressions of selected cytokines in lung tissue, and lung injury histopathology scores were determined.
Results
Animals remained hemodynamically stable throughout the entire experiment. After eight hours of MV, compared to the CV Group, the SB Group had lower PaCO2 values and ratios of dead space to tidal volume, and higher lung compliance. The levels of cytokines in blood serum and BALF in both groups were similar, but spontaneous breathing led to significantly lower cytokine mRNA expressions in lung tissues and lower lung injury histological scores.
Conclusions
Preserving spontaneous breathing can not only improve ventilatory function, but can also attenuate selected markers of VILI in the mechanically-ventilated healthy lung.
doi:10.1186/cc10502
PMCID: PMC3334795  PMID: 22018091
16.  Enhanced External Counterpulsation (EECP) 
Executive Summary
Objective
To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery).
To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure.
Clinical Need
Angina
Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.
Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2)
Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1)
Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.
Heart Failure
Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.
A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6)
The Technology
Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.
External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely “enhanced external counterpulsation” (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1)
Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.
2003 Health Technology Assessment by the Medical Advisory Secretariat
The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.
A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 – March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation.
BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.
On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (13) Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:
Canadian Cardiovascular Society Classification (CCSC) II angina
Heart failure
NYHA class II/III stable HF symptoms with an EF≤35%
NYHA class II/III stable HF symptoms with an EF≤40%
NYHA class IV HF
Acute HF
Cardiogenic shock
Acute MI
In January 2005, ECRI (14) stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).
GRADE Quality of the Studies
According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1). (11)
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and followup.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence. (11)
GRADE Quality of Studies
Economic Analysis - Literature Review
No economic analysis of EECP was identified in the published literature.
Estimated Prevalence of Angina in Ontario
3,800 patients with chronic refractory angina:
The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000 (4), this corresponds to about 3,800 patients in Ontario (3.8% × 100,000) with refractory angina.
3,800 patients × $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.
Estimated Prevalence of Heart Failure in Ontario
23,700 patients EF ≤ 0.35:
This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.
23,700 patients with EF ≤35% × $7,000 Cdn ~ $166 M Cdn.
Conclusions
There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.
As per the GRADE Working Group, overall recommendations consider 4 main factors. (11)
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence.
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. (11) Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For angina and heart failure, the overall GRADE and strength of the recommendations is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379533  PMID: 23074496
17.  Dynamic Multiscale Boundary Conditions for 4D CT of Healthy and Emphysematous Rats 
PLoS ONE  2013;8(6):e65874.
Changes in the shape of the lung during breathing determine the movement of airways and alveoli, and thus impact airflow dynamics. Modeling airflow dynamics in health and disease is a key goal for predictive multiscale models of respiration. Past efforts to model changes in lung shape during breathing have measured shape at multiple breath-holds. However, breath-holds do not capture hysteretic differences between inspiration and expiration resulting from the additional energy required for inspiration. Alternatively, imaging dynamically – without breath-holds – allows measurement of hysteretic differences. In this study, we acquire multiple micro-CT images per breath (4DCT) in live rats, and from these images we develop, for the first time, dynamic volume maps. These maps show changes in local volume across the entire lung throughout the breathing cycle and accurately predict the global pressure-volume (PV) hysteresis. Male Sprague-Dawley rats were given either a full- or partial-lung dose of elastase or saline as a control. After three weeks, 4DCT images of the mechanically ventilated rats under anesthesia were acquired dynamically over the breathing cycle (11 time points, ≤100 ms temporal resolution, 8 cmH2O peak pressure). Non-rigid image registration was applied to determine the deformation gradient – a numerical description of changes to lung shape – at each time point. The registration accuracy was evaluated by landmark identification. Of 67 landmarks, one was determined misregistered by all three observers, and 11 were determined misregistered by two observers. Volume change maps were calculated on a voxel-by-voxel basis at all time points using both the Jacobian of the deformation gradient and the inhaled air fraction. The calculated lung PV hysteresis agrees with pressure-volume curves measured by the ventilator. Volume maps in diseased rats show increased compliance and ventilation heterogeneity. Future predictive multiscale models of rodent respiration may leverage such volume maps as boundary conditions.
doi:10.1371/journal.pone.0065874
PMCID: PMC3683027  PMID: 23799057
18.  Biomarkers of progression of chronic obstructive pulmonary disease (COPD) 
Journal of Thoracic Disease  2014;6(11):1532-1547.
Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor α (TNF-α)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD.
doi:10.3978/j.issn.2072-1439.2014.11.33
PMCID: PMC4255159  PMID: 25478195
Pulmonary disease; chronic obstructive; disease progression; biological markers (biomarkers); lung; sputum; blood
19.  Clinical update on the use of biomarkers of airway inflammation in the management of asthma 
Biological markers are already used in the diagnosis and treatment of cardiovascular disease and cancer. Biomarkers have great potential use in the clinic as a noninvasive means to make more accurate diagnoses, monitor disease progression, and create personalized treatment regimes. Asthma is a heterogeneous disease with several different phenotypes, generally triggered by multiple gene-environment interactions. Pulmonary function tests are most often used objectively to confirm the diagnosis. However, airflow obstruction can be variable and thus missed using spirometry. Furthermore, lung function measurements may not reflect the precise underlying pathological processes responsible for different phenotypes. Inhaled corticosteroids and β2-agonists have been the mainstay of asthma therapy for over 30 years, but the heterogeneity of the disease means not all asthmatics respond to the same treatment. High costs and undesired side effects of drugs also drive the need for better targeted treatment of asthma. Biomarkers have the potential to indicate an individual’s disease phenotype and thereby guide clinicians in their decisions regarding treatment. This review focuses on biomarkers of airway inflammation which may help us to identify, monitor, and guide treatment of asthmatics. We discuss biomarkers obtained from multiple physiological sources, including sputum, exhaled gases, exhaled breath condensate, serum, and urine. We discuss the inherent limitations and benefits of using biomarkers in a heterogeneous disease such as asthma. We also discuss how we may modify our study designs to improve the identification and potential use of potential biomarkers in asthma.
doi:10.2147/JAA.S15081
PMCID: PMC3140298  PMID: 21792321
asthma; inflammation; airway biomarkers; urinary biomarkers; serum biomarkers
20.  Influenza Vaccination in Adults with Chronic Obstructive Pulmonary Disease: The Impact of a Diagnostic Breathing Test on Vaccination Rates 
PLoS ONE  2013;8(6):e67600.
Introduction
Influenza vaccination rates are low in adults with chronic obstructive pulmonary disease (COPD). A diagnostic breathing test in adults with COPD may increase vaccination rates; however, research has not demonstrated this relationship. The purpose of this research was to determine if adults with COPD diagnosed by a breathing test were more likely to have had an influenza vaccination during the past 12 months when compared to those with COPD diagnosed without a breathing test.
Methods
This was a cross-sectional study using data from the 2011 Behavioral Risk Factor Surveillance System. Logistic regression examined the relationship between influenza vaccination among adults with COPD diagnosed with a breathing test (n = 13,201) compared to those diagnosed without a breathing test (n = 3,108), after controlling for all potential confounders.
Results
Overall, 49% of respondents with COPD received an influenza vaccination within the past 12 months and 78% reported their COPD was diagnosed by a breathing test. The prevalence of influenza vaccination in the past 12 months was greater in those with COPD diagnosed by a breathing test (53%) compared to those diagnosed without a breathing test (36%). In adjusted analysis, adults with COPD who had a breathing test were 31% (confidence interval 1.1, 1.6) more likely to have received an influenza vaccination in the past 12 months compared to those without a breathing test.
Discussion
A diagnostic breathing test for COPD was associated with increased likelihood of having had an influenza vaccination in the past 12 months. This may be an indicator of the relationship between knowledge of lung function and the need for preventative care, a sign of quality healthcare, or good health-seeking behaviors in patients with COPD. This research is the first to use a nationally representative sample to suggest that spirometry diagnosis of COPD may increase rates of influenza vaccination.
doi:10.1371/journal.pone.0067600
PMCID: PMC3695872  PMID: 23840746
21.  Virtual respiratory system in investigation of CPAP influence on optimal breathing frequency in obstructive lungs disease 
Background
Continuous Positive Airway Pressure (CPAP) is a commonly accepted method of spontaneous breathing support in obstructive lung disease. Previous work suggested that the cause of the CPAP efficacy in the obstructive lung disease localized in bronchi of middle order (OLDMO) is not as obvious as, for example, in the obstructive sleep apnea. Since CPAP reduces obstruction and the optimal breathing frequency (BF) depends on the obstruction level, it seems to be important to analyze the dependence of the optimal BF on CPAP.
Aim
To analyze the support efficacy cause in OLDMO, esp. the relationship between the CPAP value and optimal BF.
Method
Investigations utilized previously built virtual respiratory system. Its most important factors: nonlinear lungs compliance and changeability of nonlinear airway resistance (Raw). Influence of BF and the CPAP value on the tidal volume and minute ventilation was analyzed for four exemplary virtual patients: healthy ("standard") and suffering from moderate, severe, and the very severe OLDMO (the other parameters, esp. respiratory muscles effort, were unchanged). Minute inspiratory work as a criterion of the BF optimization.
Results
CPAP decreased Raw making breathing easier, however, it shifted the working point of the respiratory system towards the smaller lungs compliance making breathing harder. The final result depended on the Raw value: CPAP improved breathing of patients with the serious OLDMO while it worsened healthy person breathing. The optimal CPAP value depended on the Raw value. If a virtual patient suffering from the serious OLDMO was not supported with CPAP, he had to breathe with low frequency because minute ventilation did not rise with BF increase. The optimal BF depended on the CPAP value (the greater the value, the greater the frequency).
Conclusion
The CPAP efficacy depends on the level of OLDMO. CPAP is efficient in the severe OLDMO because it increases the optimal BF, which makes possible less energy-consuming breathing with frequency close to the normal one (greater BF means smaller tidal volume and thus smaller work against lungs compliance).
doi:10.1186/1753-4631-1-6
PMCID: PMC1997125  PMID: 17908339
22.  Is a large scale community programme as effective as a community rehabilitation programme delivered in the setting of a clinical trial? 
Background
The rationale for commissioning community pulmonary rehabilitation programmes is based on evidence from randomised clinical trials. However, there are a number of reasons why similar programmes might be less effective outside the environment of a clinical trial. These include a less highly selected patient group and less control over the fidelity of intervention delivery. The main objective of this study was therefore to test the hypothesis that the real-world programme would have similar outcomes to an intervention delivered in the context of a clinical trial.
Methods
As part of the evaluation of an innovative community-based pulmonary rehabilitation programme (“BreathingSpace”), clinical and quality of life measures were collected before and after delivery of a rehabilitation programme. Baseline characteristics of participants and the change in symptoms and quality of life after the BreathingSpace programme were compared to measures collected in the community-based arm of a separate randomised trial of pulmonary rehabilitation.
Results
Despite differences between the BreathingSpace participants and research participants in clinical status at baseline, patient reported symptoms and quality of life measures were similar. Improvements in both symptoms and quality of life were of the same order of magnitude despite the different contexts, setting and scale of the two intervention programmes. Whilst 73% (326/448) of those considered suitable for community rehabilitation in the trial and 80% (393/491) assessed as suitable for the BreathingSpace programme agreed to participate, less than half of participants completed rehabilitation, whether in a research or “real world” setting ( 47% and 45% respectively).
Conclusion
The before-after changes in outcomes seen in a “real world” community rehabilitation programme are similar in magnitude to those seen in the intervention arm of a clinical trial. However suboptimal uptake and high dropout rates from rehabilitation amongst eligible participants occurs in both clinical trials and community based programmes and must be addressed if the benefits of rehabilitation for people with chronic lung disease are to be maximised.
doi:10.1186/1471-2288-13-103
PMCID: PMC3751120  PMID: 23941580
Pulmonary rehabilitation; Randomised controlled trials; Community programmes; Quality of life
23.  A multiscale MDCT image-based breathing lung model with time-varying regional ventilation 
A novel algorithm is presented that links local structural variables (regional ventilation and deforming central airways) to global function (total lung volume) in the lung over three imaged lung volumes, to derive a breathing lung model for computational fluid dynamics simulation. The algorithm constitutes the core of an integrative, image-based computational framework for subject-specific simulation of the breathing lung. For the first time, the algorithm is applied to three multi-detector row computed tomography (MDCT) volumetric lung images of the same individual. A key technique in linking global and local variables over multiple images is an in-house mass-preserving image registration method. Throughout breathing cycles, cubic interpolation is employed to ensure C1 continuity in constructing time-varying regional ventilation at the whole lung level, flow rate fractions exiting the terminal airways, and airway deformation. The imaged exit airway flow rate fractions are derived from regional ventilation with the aid of a three-dimensional (3D) and one-dimensional (1D) coupled airway tree that connects the airways to the alveolar tissue. An in-house parallel large-eddy simulation (LES) technique is adopted to capture turbulent-transitional-laminar flows in both normal and deep breathing conditions. The results obtained by the proposed algorithm when using three lung volume images are compared with those using only one or two volume images. The three-volume-based lung model produces physiologically-consistent time-varying pressure and ventilation distribution. The one-volume-based lung model under-predicts pressure drop and yields un-physiological lobar ventilation. The two-volume-based model can account for airway deformation and non-uniform regional ventilation to some extent, but does not capture the non-linear features of the lung.
doi:10.1016/j.jcp.2012.12.007
PMCID: PMC3685439  PMID: 23794749
Multiscale; pulmonary air flow; boundary condition; regional ventilation; image registration; MDCT
24.  Repeatability and Sample Size Assessment Associated with Computed Tomography-Based Lung Density Metrics 
Rationale and Objectives
Density-based metrics assess severity of lung disease but vary with lung inflation and method of scanning. The aim of this study was to evaluate the repeatability of single center, CT-based density metrics of the lung in a normal population and assess study sample sizes needed to detect meaningful changes in lung density metrics when scan parameters and volumes are tightly controlled.
Materials and Methods
Thirty-seven subjects (normal smokers and non-smokers) gave consent to have randomly assigned repeated, breath-held scans at either inspiration (90% vital capacity: TLC) or expiration (20% vital capacity: FRC). Repeated scans were analyzed for: mean lung density (MLD), 15th percentile point of the density histogram (P15), low attenuation areas (LAA) and alpha (fractal measure of hole size distribution). Using inter-subject differences and previously reported bias, sample size was estimated from month or yearly change in density metrics obtained from published literature (i.e. meaningful change).
Results
Inter-scan difference measurements were small for density metrics (ICC > 0.80) and average ICCs for whole lung alpha−910 and alpha−950 were 0.57 and 0.64, respectively. Power analyses demonstrated that, under the control conditions with minimal extrinsic variation, population sizes needed to detect meaningful changes in density measures for TLC or FRC repeated scans ranged from a few (20–40) to a few hundred subjects, respectively.
Conclusion
A meaningful sample size was predicted from this study using volume-controlled normal subjects in a controlled imaging environment. Under proper breath-hold conditions, high repeatability was obtained in cohorts of normal smokers and non-smokers.
doi:10.15326/jcopdf.1.1.2014.0111#sthash.nxTDeRi7.dpuf
PMCID: PMC4278434  PMID: 25553338
Quantitative Computed Tomography; Pulmonary Imaging; COPD; Air Trap ping; Lung Volume Control
25.  Origin of Exhaled Breath Particles from Healthy and Human Rhinovirus-Infected Subjects 
Abstract
Background
Exhaled breath studies suggest that humans exhale fine particles during tidal breathing, but little is known of their physical origin in the respiratory system during health or disease.
Methods
Particles generated by 3 healthy and 16 human rhinovirus (HRV)-infected subjects were counted using an optical particle counter with nominal diameter-size bins ranging between 0.3 and 10 μm. Data were collected from HRV-infected subjects during tidal breathing. In addition, data from healthy subjects were collected during coughs, swallows, tidal breathing, and breathing to total lung capacity (TLC) and residual volume (RV). Using general additive models, we graphed exhaled particle concentration versus airflow during exhalation. Exhaled particles were collected from expired air on gelatin filters and analyzed for HRV via quantitative PCR.
Results
HRV-infected subjects exhaled from 0.1 to 7200 particles per liter of exhaled air during tidal breathing (geometric mean = 32 part/L). A small fraction (24%) of subjects exhaled most (81%) of the particles measured and 82% of particles detected were 0.300–0.499 μm. Minute ventilation, maximum airflow during exhalation, and forced expiratory volume 1 second (FEV1 % predicted) were positively correlated with particle production. No human rhinovirus was detected in exhaled breath samples. Three healthy subjects exhaled less than 100 particles per liter of exhaled air during tidal breathing and increased particle concentrations more with exhalation to RV than with coughing, swallowing, or rapid exhalation.
Conclusions
Submicron particles were detected in the exhaled breath of healthy and HRV-infected subjects. Particle concentrations were correlated with airflow during the first half of exhalation, and peaked at the end of exhalation, indicating both lower and upper airways as particle sources. The effect of breathing maneuver suggested a major contribution from lower airways, probably the result of opening collapsed small airways and alveoli.
doi:10.1089/jamp.2010.0815
PMCID: PMC3123971  PMID: 21361786
exhaled breath; aerosols; particles; human rhinovirus

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