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1.  Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis 
PLoS Medicine  2008;5(5):e97.
Background
Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.
Methods and Findings
Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors.
Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.
Conclusions
The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Frits Rosendaal and colleagues show that the combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Editors' Summary
Background.
When a blood vessel is injured, proteins in the blood called clotting factors “coagulate” (solidify) the blood at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. When the injury has healed, other proteins dissolve the clot, a process called “fibrinolysis.” Sometimes, however, a thrombus develops inside an undamaged blood vessel and partly or completely blocks the blood flow. A clot that occurs in one of the veins (vessels that take the blood to the heart) deep within the body (usually in the leg) is a deep vein thrombosis (DVT). Some DVTs have no symptoms; others cause pain, swelling, and tenderness in one leg. They are usually treated with heparin and warfarin, anticoagulant drugs that stop the clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called a pulmonary embolism (PE).
Why Was This Study Done?
Most people are very unlikely to develop venous thrombosis (the collective term for DVT and PE), but anything that makes blood “hypercoagulable” (prone to clotting) increases this risk. Genetic risk factors can be inherited changes in blood clotting proteins (for example, a mutation in a gene coding for one protein, factor V, which is involved in clotting, is known as factor V Leiden—Leiden, The Netherlands, was where it was first described). There are also acquired risk factors such as taking oral contraceptives or being immobilized (for example, during bed rest). These risk factors often act in such a way that the risk of developing venous thrombosis for a person with multiple risk factors is greater than the sum of the individual risks. Another recently identified but little studied risk factor for venous thrombosis is “hypofibrinolysis,” a decreased capacity to dissolve blood clots. In this study (part of the “MEGA” study on risk factors for venous thrombosis), the researchers investigate the combined effect of hypofibrinolysis and established risk factors associated with hypercoagulability on the risk of developing venous thrombosis.
What Did the Researchers Do and Find?
The researchers collected blood from more than 2,000 individuals after their first DVT or PE and from a similar number of persons without venous thrombosis (controls). For each blood sample, they measured the time it took to dissolve a clot generated from that blood in a test tube (the clot lysis time or CLT) and determined which participants had the factor V Leiden mutation or a genetic change in the clotting factor prothrombin that also increases blood coagulability. The study participants also completed a questionnaire about acquired risk factors for venous thrombosis. The researchers divided the participants into four equal-sized groups (quartiles) based on their CLT and used the quartile with the lowest CLT as the reference group for their statistical analyses; hypofibrinolysis was defined as a CLT in the highest quartile (the longest times). Participants with hypofibrinolysis alone were twice as likely to develop venous thrombosis as those with a CLT in the lowest quartile (the shortest times). Oral contraceptive use alone increased the risk of venous thrombosis 2.5-fold, whereas the combination of oral contraceptive use and hypofibrinolysis increased the risk 20-fold. The researchers also found synergistic effects on thrombosis risk for hypofibrinolysis combined with immobilization or with the factor V Leiden mutation but not with the prothrombin mutation.
What Do These Findings Mean?
These findings confirm that persons with hypofibrinolysis and hence longer CLTs have a greater risk of developing venous thrombosis than those with short CLTs. Because CLTs were measured after venous thrombosis had occurred, hypofibrinolysis could be an effect rather than a cause of this condition. However, this is unlikely because there was no association between how long after the venous thrombosis the blood sample was taken and the measured CLT. These findings also show that the combination of hypofibrinolysis with immobilization, the factor V Leiden mutation, and oral contraceptive use greatly increases the risk of venous thrombosis. This new information about the risk factors for venous thrombosis should help physicians to advise patients about reducing their chances of developing this life-threatening condition.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050097.
The MedlinePlus encyclopedia has pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis, including an animation about how DVT causes pulmonary embolisms
The UK National Health Service Direct health encyclopedia provides information for patients on deep vein thrombosis (in several languages)
More information about the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study is available on the Leiden University Medical Center Web site
Wikipedia has pages on coagulation and on fibrinolysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050097
PMCID: PMC2365975  PMID: 18462012
2.  Effectiveness of Chest Physiotherapy in Infants Hospitalized with Acute Bronchiolitis: A Multicenter, Randomized, Controlled Trial 
PLoS Medicine  2010;7(9):e1000345.
Vincent Gajdos and colleagues report results of a randomized trial conducted among hospitalized infants with bronchiolitis. They show that a physiotherapy technique (increased exhalation and assisted cough) commonly used in France does not reduce time to recovery in this population.
Background
Acute bronchiolitis treatment in children and infants is largely supportive, but chest physiotherapy is routinely performed in some countries. In France, national guidelines recommend a specific type of physiotherapy combining the increased exhalation technique (IET) and assisted cough (AC). Our objective was to evaluate the efficacy of chest physiotherapy (IET + AC) in previously healthy infants hospitalized for a first episode of acute bronchiolitis.
Methods and Findings
We conducted a multicenter, randomized, outcome assessor-blind and parent-blind trial in seven French pediatric departments. We recruited 496 infants hospitalized for first-episode acute bronchiolitis between October 2004 and January 2008. Patients were randomly allocated to receive from physiotherapists three times a day, either IET + AC (intervention group, n = 246) or nasal suction (NS, control group, n = 250). Only physiotherapists were aware of the allocation group of the infant. The primary outcome was time to recovery, defined as 8 hours without oxygen supplementation associated with minimal or no chest recession, and ingesting more than two-thirds of daily food requirements. Secondary outcomes were intensive care unit admissions, artificial ventilation, antibiotic treatment, description of side effects during procedures, and parental perception of comfort. Statistical analysis was performed on an intent-to-treat basis. Median time to recovery was 2.31 days, (95% confidence interval [CI] 1.97–2.73) for the control group and 2.02 days (95% CI 1.96–2.34) for the intervention group, indicating no significant effect of physiotherapy (hazard ratio [HR]  = 1.09, 95% CI 0.91–1.31, p = 0.33). No treatment by age interaction was found (p = 0.97). Frequency of vomiting and transient respiratory destabilization was higher in the IET + AC group during the procedure (relative risk [RR]  = 10.2, 95% CI 1.3–78.8, p = 0.005 and RR  = 5.4, 95% CI 1.6–18.4, p = 0.002, respectively). No difference between groups in bradycardia with or without desaturation (RR  = 1.0, 95% CI 0.2–5.0, p = 1.00 and RR  = 3.6, 95% CI 0.7–16.9, p = 0.10, respectively) was found during the procedure. Parents reported that the procedure was more arduous in the group treated with IET (mean difference  = 0.88, 95% CI 0.33–1.44, p = 0.002), whereas there was no difference regarding the assessment of the child's comfort between both groups (mean difference  = −0.07, 95% CI −0.53 to 0.38, p = 0.40). No evidence of differences between groups in intensive care admission (RR  = 0.7, 95% CI 0.3–1.8, p = 0.62), ventilatory support (RR  = 2.5, 95% CI 0.5–13.0, p = 0.29), and antibiotic treatment (RR  = 1.0, 95% CI 0.7–1.3, p = 1.00) was observed.
Conclusions
IET + AC had no significant effect on time to recovery in this group of hospitalized infants with bronchiolitis. Additional studies are required to explore the effect of chest physiotherapy on ambulatory populations and for infants without a history of atopy.
Trial registration
ClinicalTrials.gov NCT00125450
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Bronchiolitis, which is usually caused by the respiratory syncytial virus (RSV), is the commonest infection of the lower respiratory tract (the lungs and the passages through which air enters the lungs) in infants. A third of all children have bronchiolitis during their first year of life. The illness begins with stuffiness, a runny nose, a mild cough, and mild fever. Then, as the smallest airways in the lung (the bronchioles) become inflamed (swell) and blocked with mucus, the cough worsens, and the infant may develop a wheeze, shallow breathing, and a rapid heartbeat. Most cases of bronchiolitis are mild and clear up within two weeks without any treatment but some infants develop severe disease. Such infants struggle to get enough air into their lungs, drawing in their chest with each breath (chest recession). They have trouble eating and drinking, and the oxygen level in their blood can drop dangerously low. About 1% of previously healthy infants need hospitalization because of severe bronchiolitis. These severely affected infants are not normally given any medications but, where necessary, they are given oxygen therapy, fed through a tube into their stomach, and given fluids through a vein.
Why Was This Study Done?
In some countries, chest physiotherapy is routinely given to infants with bronchiolitis even though this is not a recommended treatment internationally. In France, for example, virtually all outpatients with bronchiolitis receive a form of chest physiotherapy known as increased exhalation technique with assisted cough (IET + AC). IET—manual chest compression—is designed to clear mucus from the bronchioles whereas AC—coughing triggered by applying pressure to the top of the breastbone—facilitates clearance of the large airways. But is IET + AC an effective treatment for bronchiolitis? In this study, the researchers undertook a multicenter, randomized, controlled trial to answer this question. A randomized trial is a study in which patients are randomly allocated to receive either the treatment under study or a control treatment. Usually in such trials, noone is aware of the treatment allocations until the trial has been completed. This is called blinding and avoids unconscious biases being introduced into the results. In this trial, although the parents, caregivers, and outcome assessors were blinded, the physiotherapists and the infants were aware of treatment allocations. The physiotherapists were not involved in patient assessment, however, and the infants were sufficiently young that their knowledge of their treatment was unlikely to bias the results.
What Did the Researchers Do and Find?
The researchers enrolled nearly 500 children aged 15 days to 2 years who were admitted to seven French hospitals for a first episode of acute bronchiolitis. They randomly allocated the patients to receive IET + AC (intervention group) or nasal suction (control group) three times a day from a physiotherapist working alone in a room with blacked-out windows. The primary outcome of the trial was the patients' time to recovery. Infants were judged to have recovered if they had not had oxygen therapy or showed signs of chest recession for 8 hours and had ingested more than two-thirds of their daily food requirement. Infants in the control group took an average of 2.31 days to recover whereas those in the intervention group took 2.02 days. However, this difference in recovery time was not statistically significant. That is, it could have happened by chance. The researchers also recorded several secondary outcomes such as admission to an intensive care unit, help with breathing, antibiotic treatment, and parental perceptions of their child's comfort. There were no significant differences between the two treatment groups for any of these secondary outcomes, although the parents did report that the IET + AC treatment was harder on their children than nasal suction while not reducing their overall comfort.
What Do These Findings Mean?
These findings show that IET + AC had no significant effect on the time to recovery of a large population of French infants admitted to hospital with severe bronchiolitis. These results cannot be extrapolated, however, to infants with mild or moderate bronchiolitis, and further studies are needed to assess whether chest physiotherapy is of any benefit in an outpatient setting. Three small trials of a different form of chest physiotherapy have also previously failed to find any effect of chest physiotherapy on recovery time. Thus, none of the currently available results support the routine use of chest physiotherapy in infants admitted to a hospital for severe bronchiolitis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000345
The UK National Health Service Choices Web site provides detailed information on all aspects of bronchiolitis
Kidshealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health) provides information for parents on bronchiolitis schizophrenia and on respiratory syncytial virus (in English and Spanish)
The British Lung Foundation also provides information on bronchiolitis schizophrenia and on respiratory syncytial virus
The MedlinePlus encyclopedia has a page on bronchiolitis schizophrenia (in English and Spanish)
The US Centers for Disease Control and Prevention has detailed information on respiratory syncytial virus
doi:10.1371/journal.pmed.1000345
PMCID: PMC2946956  PMID: 20927359
3.  Successful Removal of Endobronchial Blood Clots Using Bronchoscopic Cryotherapy at Bedside in the Intensive Care Unit 
Acute airway obstruction after hemoptysis occurs due to the presence of blood clots. These conditions may result in life-threatening ventilation impairment. We report a case of obstruction of the large airway by endobronchial blood clots which were removed using bronchoscopic cryotherapy at the bedside of intensive care unit. A 66-year-old female with endometrial cancer who had undergone chemotherapy, was admitted to the intensive care unit due to neutropenic fever. During mechanical ventilation, the minute ventilation dropped to inadequately low levels and chest radiography showed complete opacification of the left hemithorax. Flexible bronchoscopy revealed large blood clots obstructing the proximal left main bronchus. After unsuccessful attempts to remove the clots with bronchial lavage and forceps extraction, blood clots were removed using bronchoscopic cryotherapy. This report shows that cryotherapy via flexible bronchoscopy at the bedside in the intensive of intensive care unit is a simple and effective alternative for the removal of endobronchial blood clots.
doi:10.4046/trd.2014.77.4.193
PMCID: PMC4217037  PMID: 25368667
Bronchi; Bronchoscopy; Cryotherapy; Hemorrhage
4.  Acoustic Analysis of a Mechanical Circulatory Support 
Artificial Organs  2013;38(7):593-598.
Mechanical circulatory support technology is continually improving. However, adverse complications do occur with devastating consequences, for example, pump thrombosis that may develop in several parts of the pump system. The aim of this study was to design an experimental clot/thrombosis model to register and analyze acoustic signals from the left ventricular assist device (LVAD) HeartMate II (HMII) (Thoratec Corporation, Inc., Pleasanton, CA, USA) and detect changes in sound signals correlating to clots in the inflow, outflow, and pump housing. Using modern telecom techniques, it was possible to register and analyze the HMII pump-specific acoustic fingerprint in an experimental model of LVAD support using a mock loop. Increase in pump speed significantly (P < 0.005) changed the acoustic fingerprint at certain frequency (0–23 000 Hz) intervals (regions: R1–3 and peaks: P1,3–4). When the ball valves connected to the tubing were narrowed sequentially by ∼50% of the inner diameter (to mimic clot in the out- and inflow tubing), the frequency spectrum changed significantly (P < 0.005) in P1 and P2 and R1 when the outflow tubing was narrowed. This change was not seen to the same extent when the lumen of the ball valve connected to the inflow tube was narrowed by ∼50%. More significant (P < 0.005) acoustic changes were detected in P1 and P2 and R1 and R3, with the largest dB figs. in the lower frequency ranges in R1 and P2, when artificial clots and blood clots passed through the pump system. At higher frequencies, a significant change in dB figs. in R3 and P4 was detected when clots passed through the pump system. Acoustic monitoring of pump sounds may become a valuable tool in LVAD surveillance.
doi:10.1111/aor.12244
PMCID: PMC4209799  PMID: 24372095
Mechanical circulatory support; Frequency analysis; Thrombosis
5.  Travel-Related Venous Thrombosis: Results from a Large Population-Based Case Control Study (MEGA Study) 
PLoS Medicine  2006;3(8):e307.
Background
Recent studies have indicated an increased risk of venous thrombosis after air travel. Nevertheless, questions on the magnitude of risk, the underlying mechanism, and modifying factors remain unanswered.
Methods and Findings
We studied the effect of various modes and duration of travel on the risk of venous thrombosis in a large ongoing case-control study on risk factors for venous thrombosis in an unselected population (MEGA study). We also assessed the combined effect of travel and prothrombotic mutations, body mass index, height, and oral contraceptive use.
Since March 1999, consecutive patients younger than 70 y with a first venous thrombosis have been invited to participate in the study, with their partners serving as matched control individuals. Information has been collected on acquired and genetic risk factors for venous thrombosis. Of 1,906 patients, 233 had traveled for more than 4 h in the 8 wk preceding the event. Traveling in general was found to increase the risk of venous thrombosis 2-fold (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.5–3.0). The risk of flying was similar to the risks of traveling by car, bus, or train. The risk was highest in the first week after traveling. Travel by car, bus, or train led to a high relative risk of thrombosis in individuals with factor V Leiden (OR 8.1; 95% CI 2.7–24.7), in those who had a body mass index of more than 30 kg/m2 (OR 9.9; 95% CI 3.6–27.6), in those who were more than 1.90 m tall (OR 4.7; 95% CI 1.4–15.4), and in those who used oral contraceptives (estimated OR > 20). For air travel these synergistic findings were more apparent, while people shorter than 1.60 m had an increased risk of thrombosis after air travel (OR 4.9; 95% CI 0.9–25.6) as well.
Conclusions
The risk of venous thrombosis after travel is moderately increased for all modes of travel. Subgroups exist in which the risk is highly increased.
In a large case-control study of travelers, the risk of venous thrombosis was increased 3-fold with a similar risk for flying or travelling by car, bus, or train.
Editors' Summary
Background.
Recently there has been increasing concern that blood clots (thromboses) in the leg or lungs occur with greater frequency after air travel. Several theories have been put forward to explain why this increase might happen, including the fact that air passengers tend to not move around much, or possibly that reduced amounts of oxygen in the blood make the blood more likely to clot. Understanding what causes such clots is important as it would help us come up with suggestions of ways to prevent them.
Why Was This Study Done?
It is not possible to test in a controlled trial whether travel causes an increase in blood clots, so the next best way of studying this problem is to do a case-control study, in which people with blood clots (cases) are compared with similar people who don't have a blood clot (controls—in this case, the partners of the cases), and the differences in a number of contributing factors are assessed.
What Did the Researchers Do and Find?
Since 1999, the MEGA (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis) study has aimed to identify all people in an area of the Netherlands who develop a blood clot for the first time, by seeking out people who receive treatment for blood clots. At the time of this report, 1,906 people with clots had been found; of these, 233 had traveled for more than four hours in the eight weeks preceding the event. Traveling in general was found to increase the risk of clots two-fold, and the risk was highest in the week after traveling. The risk of flying was similar to the risk of traveling by car, bus, or train, and was highest in the first week after traveling. Certain other factors increased the risk of a blood clot even more, such as having a particular mutation (known as factor V Leiden) in a gene involved in blood clotting, having a body mass index of more than 30 kg/m2 (over 30 kg/m2 is defined as being obese), being more than 1.90 meters tall, and using oral contraceptives. All these factors made the risk of clots especially after air travel worse; in addition, people shorter than 1.60 meters also had an increased risk of thrombosis after air travel. However, it should be borne in mind that the number of cases in each of these various groups was quite small, and the overall risk of getting a thrombosis is still low.
What Do These Findings Mean?
Since the risks of thrombosis are increased for all types of long travel, it seems that the main factor causing the thrombosis is immobility. However, since the risk is even higher for air travel, the relative lack of oxygen may also play a part. One interesting aspect of this study is that the researchers used partners as controls; in order to be sure that doing this did not make the results invalid, the researchers had to carefully adjust for differences between the cases and controls, such as the fact that partners were generally of the opposite sex. In a related Perspective (DOI: 10.1371/journal.pmed.0030300), Kenneth Rothman discusses the study further.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030307.
MedlinePlus encyclopedia entries on deep venous thrombosis and pulmonary embolus
OMNI, a health information service in the UK run by the Resource Discovery Network, has links to pages of information on venous thrombosis
The Web site for the MEGA study in this paper gives further background and information
The Web site of the World Health Organization Research Initiative into Global Hazards of Travel has information on research into the connection between air travel and venous thrombosis
doi:10.1371/journal.pmed.0030307
PMCID: PMC1551914  PMID: 16933962
6.  Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this health technology assessment was to determine the effectiveness and cost-effectiveness of noninvasive ventilation for stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Noninvasive ventilation is used for COPD patients with chronic respiratory failure. Chronic respiratory failure in COPD patients may be due to the inability of the pulmonary system to coordinate ventilation, leading to adverse arterial levels of oxygen and carbon dioxide. Noninvasive ventilation in stable COPD patients has the potential to improve quality of life, prolong survival, and improve gas exchange and sleep quality in patients who are symptomatic after optimal therapy, have hypercapnia or nocturnal hypoventilation and mild hypercapnia, and are frequently hospitalized.
Technology
Noninvasive positive pressure ventilation (NPPV) is any form of positive ventilatory support without the use of an endotracheal tube. For stable COPD, the standard of care when using noninvasive ventilation is bilevel positive airway pressure (BiPAP). Bilevel positive airway pressure involves both inspiratory and expiratory pressure, high during inspiration and lower during expiration. It acts as a pressure support to accentuate a patient’s inspiratory efforts. The gradient between pressures maintains alveolar ventilation and helps to reduce carbon dioxide levels. Outpatients typically use BiPAP at night. Additional advantages of using BiPAP include resting of respiratory muscles, decreased work of breathing, and control of obstructive hypopnea.
Research Question
What is the effectiveness and cost-effectiveness of noninvasive ventilation, compared with no ventilation while receiving usual care, for stable COPD patients?
Research Methods
Literature Search
Search Strategy
A literature search was performed on December 3, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 2004 to December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. When the reviewer was unsure of the eligibility of articles, a second clinical epidemiologist and then a group of epidemiologists reviewed these until consensus was reached.
Inclusion Criteria
full-text English language articles,
studies published between January 1, 2004 and December 3, 2010,
journal articles that report on the effectiveness or cost-effectiveness of noninvasive ventilation,
clearly described study design and methods, and
health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs).
Exclusion Criteria
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
cross-over RCTs
studies on noninvasive negative pressure ventilation (e.g., iron lung)
studies that combine ventilation therapy with other regimens (e.g., daytime NPPV plus exercise or pulmonary rehabilitation)
studies on heliox with NPPV
studies on pulmonary rehabilitation with NPPV
Outcomes of Interest
mortality/survival
hospitalizations/readmissions
length of stay in hospital
forced expiratory volume
arterial partial pressure of oxygen
arterial partial pressure of carbon dioxide
dyspnea
exercise tolerance
health-related quality of life
Note: arterial pressure of oxygen and carbon dioxide are surrogate outcomes.
Statistical Methods
A meta-analysis and an analysis of individual studies were performed using Review Manager Version 5. For continuous data, a mean difference was calculated, and for dichotomous data, a relative risk ratio was calculated for RCTs. For continuous variables with mean baseline and mean follow-up data, a change value was calculated as the difference between the 2 mean values.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Conclusions
The following conclusions refer to stable, severe COPD patients receiving usual care.
Short-Term Studies
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation on oxygen gas exchange, carbon dioxide gas exchange, and exercise tolerance measured using the 6 Minute Walking Test.
Based on very low quality of evidence, there is no effect of NPPV therapy on lung function measured as forced expiratory volume in 1 second (Type II error not excluded).
Long-Term Studies
Based on moderate quality of evidence, there is no effect of NPPV therapy for the outcomes of mortality, lung function measured as forced expiratory volume in 1 second, and exercise tolerance measured using the 6 Minute Walking Test.
Based on low quality of evidence, there is no effect of NPPV therapy for the outcomes of oxygen gas exchange and carbon dioxide gas exchange (Type II error not excluded).
Qualitative Assessment
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation for dyspnea based on reduced Borg score or Medical Research Council dyspnea score.
Based on moderate quality of evidence, there is no effect of NPPV therapy for hospitalizations.
Health-related quality of life could not be evaluated.
PMCID: PMC3384378  PMID: 23074437
7.  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
8.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
9.  The Absolute Risk of Venous Thrombosis after Air Travel: A Cohort Study of 8,755 Employees of International Organisations 
PLoS Medicine  2007;4(9):e290.
Background
The risk of venous thrombosis is approximately 2- to 4-fold increased after air travel, but the absolute risk is unknown. The objective of this study was to assess the absolute risk of venous thrombosis after air travel.
Methods and Findings
We conducted a cohort study among employees of large international companies and organisations, who were followed between 1 January 2000 and 31 December 2005. The occurrence of symptomatic venous thrombosis was linked to exposure to air travel, as assessed by travel records provided by the companies and organisations. A long-haul flight was defined as a flight of at least 4 h and participants were considered exposed for a postflight period of 8 wk. A total of 8,755 employees were followed during a total follow-up time of 38,910 person-years (PY). The total time employees were exposed to a long-haul flight was 6,872 PY. In the follow-up period, 53 thromboses occurred, 22 of which within 8 wk of a long-haul flight, yielding an incidence rate of 3.2/1,000 PY, as compared to 1.0/1,000 PY in individuals not exposed to air travel (incidence rate ratio 3.2, 95% confidence interval 1.8–5.6). This rate was equivalent to a risk of one event per 4,656 long-haul flights. The risk increased with exposure to more flights within a short time frame and with increasing duration of flights. The incidence was highest in the first 2 wk after travel and gradually decreased to baseline after 8 wk. The risk was particularly high in employees under age 30 y, women who used oral contraceptives, and individuals who were particularly short, tall, or overweight.
Conclusions
The risk of symptomatic venous thrombosis after air travel is moderately increased on average, and rises with increasing exposure and in high-risk groups.
In a cohort study of 8,755 employees of large international organizations followed for 38,910 person-years, Suzanne Cannegieter and colleagues find a risk of one thrombosis per 4,656 long-haul flights.
Editors' Summary
Background.
Blood normally flows smoothly throughout the human body, supplying the brain and other vital organs with oxygen and nutrients. When an injury occurs, proteins called clotting factors make the blood gel or coagulate at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood to the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the deep veins of the leg) include pain, swelling, and redness in one leg. DVT is usually treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called pulmonary embolism (PE). Fortunately, DVT and PE are rare but having an inherited blood clotting disorder, taking an oral contraceptive, and some types of surgery are all risk factors for them. In addition, long-haul plane travel increases the risk of DVT and PE, known collectively as venous thrombosis (VT) 2- to 4-fold, in part because the enforced immobilization during flights slows down blood flow.
Why Was This Study Done?
Although the link between air travel and VT was first noticed in the 1950s, exactly how many people will develop DVT and PE (the absolute risk of developing VT) after a long flight remains unknown. This information is needed so that travelers can be given advice about their actual risk and can make informed decisions about trying to reduce that risk by, for example, taking small doses of anticoagulant medicine before a flight. In this study, the researchers have determined the absolute risk of VT during and after long-haul air travel in a large group of business travelers.
What Did the Researchers Do and Find?
The researchers enrolled almost 9,000 employees from several international companies and organizations and followed them for an average of 4.4 years. The details of flights taken by each employee were obtained from company records, and employees completed a Web-based questionnaire about whether they had developed VT and what risk factors they had for the condition. Out of 53 thrombi that occurred during the study, 22 occurred within eight weeks of a long-haul flight (a flight of more than four hours). From this and data on the total time employees spent on long-haul flights, the researchers calculated that these flights tripled the risk of developing VT, and that the absolute risk (the probability of something occurring in a certain time period) of a VT occurring shortly after such travel was one event per 4,656 flights. They also calculated that the risk of VT was increased by exposure to more flights during a short period and to longer flights and was greatest in the first two weeks after a flight. In addition, the risk of VT was particularly high in young employees, women taking oral contraceptives, and people who were short, tall or overweight.
What Do These Findings Mean?
The main finding of this study is that the absolute risk of VT after of a long-haul flight is low—only one passenger out of nearly 5,000 is likely to develop VT because of flying. However, the study included only healthy people without previous VT whose average age was 40 years, so the absolute risk of VT after long-haul flights might be higher in the general traveling population. Even so, this finding strongly suggests that prophylactic (preventative) use of anticoagulants by all long-haul travelers may not be justified because these drugs have potentially dangerous side effects (for example, they can cause uncontrolled bleeding). Subgroups of travelers with additional risk factors for VT might, however, benefit from the use of this and other prophylactic measures, but randomized trials are needed to find out who would benefit most from which prophylactic measure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040290.
MedlinePlus encyclopedia pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
Information from the US National Heart Lung and Blood Institute on deep vein thrombosis, including an animation of how DVT causes pulmonary embolisms
Information for patients from the UK National Health Service Direct health encyclopedia on deep vein thrombosis (in several languages)
Information for travelers on DVT from the US Centers for Disease Control and Prevention and from the UK National Travel Health Network and Centre
This study came out of the WHO Research Into Global Hazards of Travel (WRIGHT) project, and WHO's WRIGHT project on Air Travel and Venous Thromboembolism, of which his study forms a part, has a Web site
doi:10.1371/journal.pmed.0040290
PMCID: PMC1989755  PMID: 17896862
10.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Background
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
Conclusions
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
Background
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000098.
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
11.  A new device for 100 per cent humidification of inspired air 
Critical Care  2000;4(1):54-60.
A new humidifier for use during mechanical ventilation in endotracheally intubated patients is described and tested. The humidifier is based on a heat-moisture exchanger, which absorbs the expired heat and moisture and releases it into the inspired air. External heat and water are then added at the patient side of the heat-moisture exchanger, so that the inspired gas should reach 100% humidity (44 mg/l) at 37°C. In bench tests using constant and decelerating inspiratory flow and minute volumes of 3–25 l the device gave an absolute humidity of 41–44 mg/l, and it reduced the amount of water consumed in eight mechanically ventilated patients compared with a conventional active humidifier. During a 24-h test period there was no water condensation in the ventilator tubing with the new device.
Introduction:
Devices for active humidification of the inspired air in mechanically ventilated patients cause water condensation in the ventilator tubing, which may become contaminated or interfere with the function of the ventilator. The present study describes and tests the performance of a new humidifier, which is designed to eliminate water condensation.
Objectives:
To test the performance of the new humidifier at different ventilator settings in a lung model, and to compare this new humidifier with a conventional active humidifier in ventilator-treated critically ill patients.
Materials and methods:
The humidifier (Humid-Heat; Louis Gibeck AB, Upplands Väsby, Sweden) consists of a supply unit with a microprocessor and a water pump, and a humidification device, which is placed between the Y-piece and the endotracheal tube. The humidification device is based on a hygroscopic heat-moisture exchanger (HME), which absorbs the expired heat and moisture and releases it into the inspired gas. External heat and water are then added to the patient side of the HME, so the inspired gas should reach 100% humidity at 37°C (44 mg H2O/l air). The external water is delivered to the humidification device via a pump onto a wick and then evaporated into the inspired air by an electrical heater. The microprocessor controls the water pump and the heater by an algorithm using the minute ventilation (which is fed into the microprocessor) and the airway temperature measured by a sensor mounted in the flex-tube on the patient side of the humidification device.
The performance characteristics were tested in a lung model ventilated with a constant flow (inspiratory:expiratory ratio 1:2, rate 12–20 breaths/min and a minute ventilation of 3–25 l/min) or with a decelerating flow (inspiratory:expiratory ratio 1:2, rate 12–15 breaths/min and a minute ventilation of 4.7–16.4 l/min). The device was also tested prospectively and in a randomized order compared with a conventional active humidifier (Fisher & Paykel MR730, Auckland, New Zealand) in eight mechanically ventilated, endotracheally intubated patients in the intensive care unit. The test period with each device was 24 h. The amount of fluid consumed and the amount of water in the water traps were measured. The number of times that the water traps were emptied, changes of machine filters, the suctions and quality of secretions, nebulizations, and the amount of saline instillations and endotracheal tube obstruction were recorded. In order to evaluate increased expiratory resistance due to the device, the airway pressure was measured at the end of a prolonged end-expiratory pause at 1 h of use and at the end of the test, and was compared with the corresponding pressure before the experiment. The body temperature of the patient was measured before and after the test of each device.
Results:
Both with constant flow and decelerating flow, the Humid-Heat gave an absolute humidity of 41–44 mgH2O/l at 37°C, with the lower level at the highest ventilation. In the patients, both Humid-Heat and the conventional active humidifier (MR730) maintained temperatures, indicating that they provided the intended heat and moisture to the inspired air. With both devices, the body temperature was maintained during the test period. There was no difference in the amount of secretions, the quality of the secretions and the frequency of suctions, saline instillations or nebulizations between the test periods with the two devices. There was no endotracheal tube obstruction, and after 1 h of use and at the end of the test no increased airway resistance was found with either device. When the MR730 was used, however, the water traps needed to be emptied six to 14 (mean eight) times (total amount of fluid in the traps was 100–300 ml) and the machine filters were changed two to six (mean four) times due to an excessive amount of condensed water with flow obstruction. No condensation of water was found in the tubing with the Humid-Heat. The water consumption was 23–65 ml/h (mean 30 ml/h) with the MR730 and 4–8 ml/h (mean 6 ml/h) with the Humid-Heat (P < 0.0008). The same relations were found when the water consumption was corrected for differences in minute ventilation.
Discussion:
The new humidifier, the Humid-Heat, gave an absolute humidity of 41–44 mg/l at 37°C in the bench tests. The tests in ventilated patients showed that the device was well tolerated and that condensation in the tubing was eliminated. There was no need to empty water traps. The test period was too short to evaluate whether the new device had any other advantages or disadvantages compared with conventional humidifiers.
PMCID: PMC29037  PMID: 11056746
airway humidification; heated humidifier; intensive care; mechanical ventilation
12.  Development of an in vitro model to study clot lysis activity of thrombolytic drugs 
Thrombosis Journal  2006;4:14.
Background
Thrombolytic drugs are widely used for the management of cerebral venous sinus thrombosis patients. Several in vitro models have been developed to study clot lytic activity of thrombolytic drugs, but all of these have certain limitations. There is need of an appropriate model to check the clot lytic efficacy of thrombolytic drugs. In the present study, an attempt has been made to design and develop a new model system to study clot lysis in a simplified and easy way using a thrombolytic drug, streptokinase.
Methods
Whole blood from healthy individuals (n = 20) was allowed to form clots in a pre-weighed sterile microcentrifuge tubes; serum was removed and clot was weighed. After lysis by streptokinase fluid was removed and remnants of clot were again weighed along with the tube. Percentage of Clot lysis was calculated on the basis of the weight difference of microcentrifuge tubes obtained before and after clot lysis.
Results
There was a significant percentage of clot lysis observed when streptokinase was used. On the other hand with water (negative control), minimal (2.5%) clot lysis was observed. There was a significant difference between clot lysis done by streptokinase and water.
Conclusion
Our study could be a rapid and effective methodology to study clot-lytic effect of newly developed drugs as well as known drugs.
doi:10.1186/1477-9560-4-14
PMCID: PMC1570448  PMID: 16968529
13.  A COMPARISON OF THE ACTION OF PLASMA AND SERUM ON CERTAIN OBJECTS USED IN BIOLOGICAL TESTS FOR EPINEPHRIN 
Apparently, then, we are confronted with this result,—that citrate plasma which causes little or no constriction of the stretched artery ring, little or no slowing of the flow through the frog perfusion preparation, while the corresponding serum produces a marked effect on both preparations, will affect the intestine or uterus preparation practically in the same way as the corresponding serum. Hirudin plasma and serum exert on the intestine and uterus preparations practically the same effect, causing a marked increase of tone. On the artery ring preparation, there is a difference although it is not so strongly marked as in the case of the citrate material. The frog perfusion preparation, as regards the effect of the hirudin material, seems to occupy an intermediate position between the intestine and uterus on the one hand, and the artery ring on the other. Of the three plasmas, the peptone plasma most closely resembles serum in its action on the artery rings. Like the other plasmas its effect on the intestine and uterus does not differ appreciably from that of the serum. From these observations the following conclusions seem justified. A change occurs in shed blood which confers on it the property of constricting artery rings and of slowing the flow through the perfused frog preparation. If this property is in any degree possessed by circulating blood it is at least markedly increased after the blood is shed. The change, whatever it may be, does not entail any essential alteration in the action of the blood on intestine and uterus segments. The tone-increasing property developed in the shed blood may, therefore, so far as the four test objects included in the present survey are concerned, be looked upon as especially affecting the blood vessels and probably their smooth muscle directly. This need not imply that the pressor substance, if it is a single definite substance developed in the shed blood, exerts no action on the smooth muscle of the intestine and uterus preparations, but merely that its action on these objects is masked by the general action of the serum and plasma, so that in the presence of the other constituents common to serum and plasma, its effect is inconspicuous or not to be detected at all, while on the blood vessel preparations, especially the artery rings, the effect of the pressor substance is the dominant one, and the general action of the serum and plasma is feeble or undetectable. It is not the clotting process as such, i.e., the actual change of fibrinogen into fibrin, that is responsible for the differences between serum and plasma revealed by the biological tests employed but some process which precedes or accompanies the clotting and which may or may not be causally related to it. Changes in formed elements of the blood under the influence of the changed conditions (contact with foreign bodies, restriction of gaseous exchange, etc.). which blood encounters as soon as it leaves the living vessels, are known to occur. Among these it is to be assumed are the changes which condition the differences between plasma and serum under discussion.16 Even if these changes represent preliminary stages in coagulation (liberation of the factors necessary to the formation of thrombin, for instance), they may still occur to a greater or less extent in blood which is prevented in certain ways from clotting since it is known that the procedures by which the various non-coagulable plasmas are obtained break at different points the chain of events which normally ends in coagulation. A procedure which simply supplies sufficient antithrombin to neutralize the thrombin which has been allowed to form in normal amount may not interfere at all with the changes in the formed elements, and the pressor property of the resulting plasma may then be as marked as that of the serum. On the other hand, a procedure which binders clotting by preventing or diminishing the alterations in the cells, for example, the addition of a substance which acts as a preservative for blood platelets, will very likely yield a plasma with little or no pressor effect in comparison with the serum. The mere prevention of clotting, then, except in so far as it is an index of the prevention of changes in the formed elements may have little significance in preventing the development of the pressor property. Indeed it is conceivable that the alterations in the cells which are connected with the development of this property may even be wholly or partially independent of the cell changes concerned in coagulation. In this case it might be possible to obtain blood which would clot without developing the pressor property. The main results which seem to follow from our observations may be thus summarized: 1. The substance, or property, developed in shed blood by which it causes constriction of artery rings, is not developed, or at least not mainly developed, in connection with the actual change of fibrinogen to fibrin, since the constrictor action of different plasmas differs greatly, while the absence of coagulation is common to all. 2. The development of the constrictor substance, or property, is associated with changes undergone probably by formed elements of the blood when it is shed. These changes may be identical with the alterations, or with some of the alterations, preliminary to clotting. It is possible, however, that there may be changes connected with the development of the pressor property which, although concomitant with the liberation of the substances concerned in the production of thrombin, are yet quite independent of the clotting process. Our observations do not enable us to decide definitely between these possibilities. 3. The constrictor substance, or property, developed in shed blood acts especially on blood vessels and does not equally affect the other organs examined. This follows from the fact that a plasma and serum which differ markedly in their action on the blood vessels may have practically the same action on the intestine or uterus segments, an action which must therefore reside mainly, at least, in the original plasma itself. 4. The indication that the serum acts especially on blood vessels increases the interest of the suggestion that this action may play an important part in the prompt sealing of wounded vessels in addition to the mechanical effect of the clot, or by coming into operation before the clot has fully formed.
PMCID: PMC2125024  PMID: 19867632
14.  Tonsillitis and sore throat in children 
Surgery of the tonsils is still one of the most frequent procedures during childhood. Due to a series of fatal outcomes after hemorrhage in children in Austria in 2006, the standards and indications for tonsillectomy have slowly changed in Germany. However, no national guidelines exist and the frequency of tonsil surgery varies across the country. In some districts eight times more children were tonsillectomized than in others.
A tonsillectomy in children under six years should only be done if the child suffers from recurrent acute bacterially tonsillitis. In all other cases (i.e. hyperplasia of the tonsils) the low risk partial tonsillectomy should be the first line therapy. Postoperative pain and the risk of hemorrhage are much lower in partial tonsillectomy (=tonsillotomy). No matter whether the tonsillotomy is done by laser, radiofrequency, shaver, coblation, bipolar scissor or Colorado needle, as long as the crypts are kept open and some tonsil tissue is left behind. Total extracapsular tonsillectomy is still indicated in severely affected children with recurrent infections of the tonsils, allergy to antibiotics, PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) and peritonsillar abscess. With regard to the frequency and seriousness of the recurrent tonsillitis the indication for tonsillectomy in children is justified if 7 or more well-documented, clinically important, adequately treated episodes of throat infection occur in the preceding year, or 5 or more of such episodes occur in each of the 2 preceding years (according to the paradise criteria). Diagnosis of acute tonsillitis is clinical, but sometimes it is hard to distinguish viral from bacterial infections. Rapid antigen testing has a very low sensitivity in the diagnosis of bacterial tonsillitis and swabs are highly sensitive but take a long time. In all microbiological tests the treating physician has to keep in mind, that most of the bacterials, viruses and fungi belong to the healthy flora and do no harm. Ten percent of healthy children even bear strepptococcus pyogenes all the time in the tonsils with no clinical signs. In these children decolonization is not necessary. Therefore, microbiological screening tests in children without symptoms are senseless and do not justify an antibiotic treatment (which is sometimes postulated by the kindergartens).
The acute tonsillitis should be treated with steroids (e.g. dexamethasone), NSAIDs (e.g. ibuprofene) and betalactam antibiotics (e.g. penicillin or cefuroxime). With respect to the symptom reduction and primary healing the short-term late-generation antibiotic therapy (azithromycin, clarithromycin or cephalosporine for three to five days) is comparable to the long-term penicilline therapy. There is no difference in the course of healing, recurrence or microbiological resistance between the short-term penicilline therapy and the standard ten days therapy.
On the other hand, only the ten days antibiotic therapy has proven to be effective in the prevention of rheumatic fever and glomerulonephritic diseases. The incidence of rheumatic heart disease is currently 0.5 per 100,000 children of school age.
The main morbidity after tonsillectomy is pain and the late haemorrhage. Posttonsillectomy bleeding can occur till the whole wound is completely healed, which is normally after three weeks. Life-threatening haemorrhages occur often after smaller bleedings, which can spontaneously cease. That is why every haemorrhage, even the smallest, has to be treated properly and in ward. Patients and parents have to be informed about the correct behaviour in case of haemorrhage with a written consent before the surgery.
The handout should contain important addresses, phone numbers and contact persons. Almost all cases of fatal outcome after tonsillectomy were due to false management of haemorrhage. Haemorrhage in small children can be especially life-threatening because of the lower blood volume and the danger of aspiration with asphyxia. A massive haemorrhage is an extreme challenge for every paramedic or emergency doctor because of the difficult airway management. Intubation is only possible with appropriate inflexible suction tubes.
All different surgical techniques have the risk of haemorrhage and even the best surgeon will experience a postoperative haemorrhage. The lowest risk of haemorrhage is after cold dissection with ligature or suturing. All “hot” techniques with laser, radiofrequency, coblation, mono- or bipolar forceps have a higher risk of late haemorrhage.
Children with a hereditary coagulopathy have a higher risk of haemorrhage. It is possible, that these children were not identified before surgery. Therefore it is recommended by the Society of paediatrics, anaesthesia and ENT, that a standardised questionnaire should be answered by the parents before tonsillectomy and adenoidectomy. This 17-point-checklist questionnaire is more sensitive and easier to perform than a screening with blood tests (e.g. INR and PTT). Unfortunately, a lot of surgeons still screen the children preoperatively by coagulative blood tests, although these tests are inappropriate and incapable of detecting the von Willebrand disease, which is the most frequent coagulopathy in Europe.
The preoperative information about the surgery should be done with the child and the parents in a calm and objective atmosphere with a written consent. A copy of the consent with the signature of the surgeon and both custodial parents has to be handed out to the parents.
doi:10.3205/cto000110
PMCID: PMC4273168  PMID: 25587367
tonsillitis; tonsillectomy; intracapsular; extracapsular; antibiotics
15.  Intermediate Term Evaluation of Starr-Edwards Ball Valves in the Mitral Position 
Texas Heart Institute Journal  1985;12(1):43-47.
The Model 6120 ball valve prosthesis introduced in 1965 is still strongly supported as a mitral valve substitute in many centers around the world. A current reassessment of the performance of this prosthesis is therefore pertinent to current medical practice.
In this institution since 1974, 227 Starr-Edwards caged ball valves have been implanted in the mitral position during isolated valve replacement. Two models of caged ball valves were used concurrently: the silastic ball valve in 108 patients (48%) and the composite strut “tract” valve in 119 (52%).
Hospital mortality was 7%, and 8-year survival (standard error) was 74 (6%), with 100% follow-up, documenting 752 total patient-years. No late deaths were known to be valve related, and there were no cases of prosthetic thrombosis. The actuarial estimate of patients free from thromboembolism at 8 years was 89 (4%) with a linearized rate of 1.3% per year. At the most recent follow-up, 95% of the patients were in the New York Heart Association (NYHA) Classes I or II. These good results were partly due to an awareness at operation of ventricular outflow tract size requirements and to strict control of postoperative anticoagulation.
We conclude that the Starr-Edwards ball valve is the mitral valve of choice in the young patient who is able to take anticoagulation drugs and has a left ventricular outflow tract of satisfactory size.
PMCID: PMC341791  PMID: 15227040
16.  Suction Curettage for Removal of Retained Intrathoracic Blood Clots and Pleural Lesions 
Objective:
To develop a thoracoscopic technique for correcting and/or removing an intrathoracic disease process using our existing operating room equipment and without a “small thoracotomy.”
Methods and Procedures:
Fifty-eight patients from October 1994 to April 1998 were prospectively studied. All were undergoing procedures involving the removal of a suspected benign (or infectious) pleural process or a retained blood clot. Three or four thoracic ports were used in all cases. Straight and curved suction curettage cannulae (with finger valve attachment) ranging from 8 to 16 French were available for use. Intermittent variable suction (between zero and 60 mm Hg) was used in all cases. Dependent upon the size and adherence of the lesion to be removed, the pressure was determined by the surgeon and regulated by the circulating nurse in the room. In each case, a trap system was used for retrieval of the specimen. One lung ventilation was used in every case, and when suction was used one of the ports was kept “open” to allow room air to enter the chest cavity.
Results:
All patients in our series had their procedures completed without the need for any kind of open thoracotomy. Pre and postoperative diagnosis concurred in all 10 patients, and no complications occurred (specifically, no injury to the lung tissue or chest wall structures). Operative time ranged from 45 minutes to 180 minutes with a mean of 75 minutes. In all cases of a hemothorax, a cell saver system was used for an average of one unit of blood autotransfused per case.
Conclusions:
New techniques do not always require the purchase of new equipment. Tight hospital budgets are forcing surgeons to rely on redefining uses of instrumentation already available in solving surgical problems. We believe that the use of this instrumentation will provide another avenue for surgeons to successfully complete a procedure thoracoscopically without the need for a thoracotomy. It is through multidisciplinary conferences such as the Society of Laparoendoscopic Surgeons that ideas such as this are propagated.
PMCID: PMC3015315  PMID: 10444010
Thoracoscopy; Retained clot; Pleural lesion
17.  STUDIES IN EXPERIMENTAL EXTRACORPOREAL THROMBOSIS  
The effects of environmental temperature on thrombosis in circulating blood were tested in the extracorporeal loop by the method previously described. Cold (7° to 15°C.) about the collodion tube retards the clotting of circulating blood. Obstruction of the arterial cannula occurs after from 15 to 25 minutes. Heat (40° and 55°C.) tends to hasten clotting; obstruction by red clot takes place after from 4 to 6 minutes and from 2 to 4 minutes, respectively. In the latter case no characteristic thrombus structure may be seen. These results were what might be expected. The formation of white thrombi occurs even under the influence of cold, and they continue to form and grow as long as the circulation continues. When the carotid artery is partially occluded and the blood stream slowed, after the injection of the anticoagulant, the blood has a tendency to form red thrombi on the foreign surface of the vascular loop. The thrombi are deposited chiefly in the arterial half of the apparatus, especially at the bottom of the arterial end of the collodion tube, just as in the case of Aschoff's sand experiments. In spite of incoagulability of heparinized blood, red clots, with interwoven fibrin bands, are found. Also very tiny white thrombi may form in other parts of the collodion tube. The effect of complete obstruction of the carotid artery and jugular vein on thrombus formation was studied after the use of anticoagulant. When the carotid artery is obstructed the formation of white thrombi is negligible and sedimentation of erythrocytes and deposition of fibrin appear throughout the apparatus; then the blood, at a standstill, clots very slowly. When the jugular vein is obstructed, dislodgment of platelet thrombi probably results from the pulsating movement, and sedimentation of erythrocytes follows, forming mixed thrombi. The dislodged white thrombi tend to gather in the bottom of the tubes of the widest caliber, especially in the collodion tube.
PMCID: PMC2131319  PMID: 19869385
18.  Bronchial obstruction by tumor embolus of contralateral lung during pneumonectomy: report of a case 
Bronchial obstruction due to a tumor embolus of the contralateral lung during pneumonectomy is an uncommon and fatal complication. According to previous cases, a bronchial balloon of double-lumen endotracheal tube (DLT) could prevent a dislodged tumor from traveling to the contralateral lung. We experienced a tumor embolism from the bronchus with cancer to the other bronchus despite applying DLT. A 59-year-old male with endobronchial lung cancer underwent a left pneumonectomy. One-lung ventilation was established by the right-sided DLT. After a left bronchial division, a sudden increase of peak airway pressure and reduction of the expired tidal volume to 50 ml was observed. Intraoperative fiberoptic bronchoscopy showed a near total obstruction of the right main bronchus due to tumor emboli. It was not possible to remove the tumor embolus through bronchoscopic suction and forceps. Therefore, we reopened the left bronchial stump and successfully extracted tumor embolus under bronchoscopic guidance.
doi:10.1186/1749-8090-8-26
PMCID: PMC3598947  PMID: 23421935
Airway obstruction; Bronchial neoplasm; Pneumonectomy; Double-lumen endotracheal tube
19.  Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets 
Journal of Clinical Investigation  1970;49(11):2068-2085.
Dilute whole blood clots were prepared by addition of thrombin to blood diluted 1:10 in phosphate buffer. The pH of this buffer was 7.4 and the ionic strength was 0.084. Though the ionic strength was low, there was no hemolysis of red corpuscles due to the contribution to the osmotic gradient by plasma salts and proteins. In the standard assay the clot was formed by addition of thrombin at 4°C then incubated at 37°C. Retraction and lysis of these clots were inhibited by removal of platelets and by increasing concentrations of purified thrombin. Retraction and lysis were also inhibited by inactivation of any one of the following factors: γM globulin, complement components C4 and 3, and (in the case of lysis) plasminogen.
Evidence that some of the above serum factors were adsorbed to the platelet membrane was obtained by aggregation of washed platelets by antisera to these factors (i.e. fibrinogen, γM, and C4 or C3). These platelets were not aggregated by antisera to other serum proteins (by albumin, transferrin, γG globulin).
These and other studies suggested that platelets, thrombin, fibrinogen, γM globulin (cold agglutinin), complement components, and plasminogen influenced and facilitated retraction and lysis of clots. These studies also suggested that platelets and some of these factors were physically associated.
Because of this physical association, and because of the fact that clot retraction is associated with aggregation and retraction of platelets, we extended the above observations to include a study of the effect of these same serum factors on serum-induced aggregation and retraction of washed platelets. (Other terms which have been in use in the past to describe serum-induced platelet aggregation and retraction have included those such as platelet “fusion” and “viscous metamorphosis,” neither of which fully described the phenomena.)
Platelet aggregation and retraction induced by serum was markedly accelerated by addition of increasing concentrations of thrombin and (or) cold agglutinin. Hirudin and antisera to γM globulin inhibited seruminduced aggregation and retraction of platelets. Reconstitution of inactivated serum with purified C4, 3, and 5 and thrombin restored its capacity to induce aggregation and retraction of platelets.
Therefore, we postulated that platelet aggregation and retraction were necessary for clot retraction and that platelet aggregation and clot retraction facilitated clot lysis. More specifically we postulated that thrombin, in addition to catalyzing clot formation, also modified the platelet membrane such that γM globulin (cold agglutinin) and complement components can act on the platelet membrane leading to (a) aggregation and retraction of the platelets, (b) retraction of the clot, and (c) to the activation of plasminogen either on the surface of the platelet by C8i and (or) by release of platelet activators of plasminogen.
Images
PMCID: PMC535783  PMID: 4248913
20.  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
21.  Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to examine the effectiveness, safety, and cost-effectiveness of noninvasive positive pressure ventilation (NPPV) in the following patient populations: patients with acute respiratory failure (ARF) due to acute exacerbations of chronic obstructive pulmonary disease (COPD); weaning of COPD patients from invasive mechanical ventilation (IMV); and prevention of or treatment of recurrent respiratory failure in COPD patients after extubation from IMV.
Clinical Need and Target Population
Acute Hypercapnic Respiratory Failure
Respiratory failure occurs when the respiratory system cannot oxygenate the blood and/or remove carbon dioxide from the blood. It can be either acute or chronic and is classified as either hypoxemic (type I) or hypercapnic (type II) respiratory failure. Acute hypercapnic respiratory failure frequently occurs in COPD patients experiencing acute exacerbations of COPD, so this is the focus of this evidence-based analysis. Hypercapnic respiratory failure occurs due to a decrease in the drive to breathe, typically due to increased work to breathe in COPD patients.
Technology
There are several treatment options for ARF. Usual medical care (UMC) attempts to facilitate adequate oxygenation and treat the cause of the exacerbation, and typically consists of supplemental oxygen, and a variety of medications such as bronchodilators, corticosteroids, and antibiotics. The failure rate of UMC is high and has been estimated to occur in 10% to 50% of cases.
The alternative is mechanical ventilation, either invasive or noninvasive. Invasive mechanical ventilation involves sedating the patient, creating an artificial airway through endotracheal intubation, and attaching the patient to a ventilator. While this provides airway protection and direct access to drain sputum, it can lead to substantial morbidity, including tracheal injuries and ventilator-associated pneumonia (VAP).
While both positive and negative pressure noninvasive ventilation exists, noninvasive negative pressure ventilation such as the iron lung is no longer in use in Ontario. Noninvasive positive pressure ventilation provides ventilatory support through a facial or nasal mask and reduces inspiratory work. Noninvasive positive pressure ventilation can often be used intermittently for short periods of time to treat respiratory failure, which allows patients to continue to eat, drink, talk, and participate in their own treatment decisions. In addition, patients do not require sedation, airway defence mechanisms and swallowing functions are maintained, trauma to the trachea and larynx are avoided, and the risk for VAP is reduced. Common complications are damage to facial and nasal skin, higher incidence of gastric distension with aspiration risk, sleeping disorders, and conjunctivitis. In addition, NPPV does not allow direct access to the airway to drain secretions and requires patients to cooperate, and due to potential discomfort, compliance and tolerance may be low.
In addition to treating ARF, NPPV can be used to wean patients from IMV through the gradual removal of ventilation support until the patient can breathe spontaneously. Five to 30% of patients have difficultly weaning. Tapering levels of ventilatory support to wean patients from IMV can be achieved using IMV or NPPV. The use of NPPV helps to reduce the risk of VAP by shortening the time the patient is intubated.
Following extubation from IMV, ARF may recur, leading to extubation failure and the need for reintubation, which has been associated with increased risk of nosocomial pneumonia and mortality. To avoid these complications, NPPV has been proposed to help prevent ARF recurrence and/or to treat respiratory failure when it recurs, thereby preventing the need for reintubation.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of NPPV for the treatment of acute hypercapnic respiratory failure due to acute exacerbations of COPD compared with
usual medical care, and
invasive mechanical ventilation?
What is the effectiveness, cost-effectiveness, and safety of NPPV compared with IMV in COPD patients after IMV for the following purposes:
weaning COPD patients from IMV,
preventing ARF in COPD patients after extubation from IMV, and
treating ARF in COPD patients after extubation from IMV?
Research Methods
Literature Search
A literature search was performed on December 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), Wiley Cochrane, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Since there were numerous studies that examined the effectiveness of NPPV for the treatment of ARF due to exacerbations of COPD published before 2004, pre-2004 trials which met the inclusion/exclusion criteria for this evidence-based review were identified by hand-searching reference lists of included studies and systematic reviews.
Inclusion Criteria
English language full-reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies performed with patients with a mix of conditions if results are reported for COPD patients separately;
patient population: (Question 1) patients with acute hypercapnic respiratory failure due to an exacerbation of COPD; (Question 2a) COPD patients being weaned from IMV; (Questions 2b and 2c) COPD patients who have been extubated from IMV.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
studies examining noninvasive negative pressure ventilation
studies comparing modes of ventilation
studies comparing patient-ventilation interfaces
studies examining outcomes not listed below, such as physiologic effects including heart rate, arterial blood gases, and blood pressure
Outcomes of Interest
mortality
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
breathlessness
duration of mechanical ventilation
weaning failure
complications
NPPV tolerance and compliance
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1, otherwise, the results were summarized descriptively. Dichotomous data were pooled into relative risks using random effects models and continuous data were pooled using weighted mean differences with a random effects model. Analyses using data from RCTs were done using intention-to-treat protocols; P values < 0.05 were considered significant. A priori subgroup analyses were planned for severity of respiratory failure, location of treatment (ICU or hospital ward), and mode of ventilation with additional subgroups as needed based on the literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
NPPV for the Treatment of ARF due to Acute Exacerbations of COPD
NPPV Plus Usual Medical Care Versus Usual Medical Care Alone for First Line Treatment
A total of 1,000 participants were included in 11 RCTs1; the sample size ranged from 23 to 342. The mean age of the participants ranged from approximately 60 to 72 years of age. Based on either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria or the mean percent predicted forced expiratory volume in 1 second (FEV1), 4 of the studies included people with severe COPD, and there was inadequate information to classify the remaining 7 studies by COPD severity. The severity of the respiratory failure was classified into 4 categories using the study population mean pH level as follows: mild (pH ≥ 7.35), moderate (7.30 ≤ pH < 7.35), severe (7.25 ≤ pH < 7.30), and very severe (pH < 7.25). Based on these categories, 3 studies included patients with a mild respiratory failure, 3 with moderate respiratory failure, 4 with severe respiratory failure, and 1 with very severe respiratory failure.
The studies were conducted either in the ICU (3 of 11 studies) or general or respiratory wards (8 of 11 studies) in hospitals, with patients in the NPPV group receiving bilevel positive airway pressure (BiPAP) ventilatory support, except in 2 studies, which used pressure support ventilation and volume cycled ventilation, respectively. Patients received ventilation through nasal, facial, or oronasal masks. All studies specified a protocol or schedule for NPPV delivery, but this varied substantially across the studies. For example, some studies restricted the amount of ventilation per day (e.g., 6 hours per day) and the number of days it was offered (e.g., maximum of 3 days); whereas, other studies provided patients with ventilation for as long as they could tolerate it and recommended it for much longer periods of time (e.g., 7 to 10 days). These differences are an important source of clinical heterogeneity between the studies. In addition to NPPV, all patients in the NPPV group also received UMC. Usual medical care varied between the studies, but common medications included supplemental oxygen, bronchodilators, corticosteroids, antibiotics, diuretics, and respiratory stimulators.
The individual quality of the studies ranged. Common methodological issues included lack of blinding and allocation concealment, and small sample sizes.
Need for Endotracheal Intubation
Eleven studies reported the need for endotracheal intubation as an outcome. The pooled results showed a significant reduction in the need for endotracheal intubation in the NPPV plus UMC group compared with the UMC alone group (relative risk [RR], 0.38; 95% confidence interval [CI], 0.28−0.50). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Inhospital Mortality
Nine studies reported inhospital mortality as an outcome. The pooled results showed a significant reduction in inhospital mortality in the NPPV plus UMC group compared with the UMC group (RR, 0.53; 95% CI, 0.35−0.81). When subgrouped by severity of respiratory failure, the results remained significant for the moderate and severe respiratory failure groups.
GRADE: moderate
Hospital Length of Stay
Eleven studies reported hospital length of stay (LOS) as an outcome. The pooled results showed a significant decrease in the mean length of stay for the NPPV plus UMC group compared with the UMC alone group (weighted mean difference [WMD], −2.68 days; 95% CI, −4.41 to −0.94 days). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Complications
Five studies reported complications. Common complications in the NPPV plus UMC group included pneumonia, gastrointestinal disorders or bleeds, skin abrasions, eye irritation, gastric insufflation, and sepsis. Similar complications were observed in the UMC group including pneumonia, sepsis, gastrointestinal disorders or bleeds, pneumothorax, and complicated endotracheal intubations. Many of the more serious complications in both groups occurred in those patients who required endotracheal intubation. Three of the studies compared complications in the NPPV plus UMC and UMC groups. While the data could not be pooled, overall, the NPPV plus UMC group experienced fewer complications than the UMC group.
GRADE: low
Tolerance/Compliance
Eight studies reported patient tolerance or compliance with NPPV as an outcome. NPPV intolerance ranged from 5% to 29%. NPPV tolerance was generally higher for patients with more severe respiratory failure. Compliance with the NPPV protocol was reported by 2 studies, which showed compliance decreases over time, even over short periods such as 3 days.
NPPV Versus IMV for the Treatment of Patients Who Failed Usual Medical Care
A total of 205 participants were included in 2 studies; the sample sizes of these studies were 49 and 156. The mean age of the patients was 71 to 73 years of age in 1 study, and the median age was 54 to 58 years of age in the second study. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, patients in 1 study had very severe COPD. The COPD severity could not be classified in the second study. Both studies had study populations with a mean pH less than 7.23, which was classified as very severe respiratory failure in this analysis. One study enrolled patients with ARF due to acute exacerbations of COPD who had failed medical therapy. The patient population was not clearly defined in the second study, and it was not clear whether they had to have failed medical therapy before entry into the study.
Both studies were conducted in the ICU. Patients in the NPPV group received BiPAP ventilatory support through nasal or full facial masks. Patients in the IMV group received pressure support ventilation.
Common methodological issues included small sample size, lack of blinding, and unclear methods of randomization and allocation concealment. Due to the uncertainty about whether both studies included the same patient population and substantial differences in the direction and significance of the results, the results of the studies were not pooled.
Mortality
Both studies reported ICU mortality. Neither study showed a significant difference in ICU mortality between the NPPV and IMV groups, but 1 study showed a higher mortality rate in the NPPV group (21.7% vs. 11.5%) while the other study showed a lower mortality rate in the NPPV group (5.1% vs. 6.4%). One study reported 1-year mortality and showed a nonsignificant reduction in mortality in the NPPV group compared with the IMV group (26.1% vs. 46.1%).
GRADE: low to very low
Intensive Care Unit Length of Stay
Both studies reported LOS in the ICU. The results were inconsistent. One study showed a statistically significant shorter LOS in the NPPV group compared with the IMV group (5 ± 1.35 days vs. 9.29 ± 3 days; P < 0.001); whereas, the other study showed a nonsignificantly longer LOS in the NPPV group compared with the IMV group (22 ± 19 days vs. 21 ± 20 days; P = 0.86).
GRADE: very low
Duration of Mechanical Ventilation
Both studies reported the duration of mechanical ventilation (including both invasive and noninvasive ventilation). The results were inconsistent. One study showed a statistically significant shorter duration of mechanical ventilation in the NPPV group compared with the IMV group (3.92 ± 1.08 days vs. 7.17 ± 2.22 days; P < 0.001); whereas, the other study showed a nonsignificantly longer duration of mechanical ventilation in the NPPV group compared with the IMV group (16 ± 19 days vs. 15 ± 21 days; P = 0.86). GRADE: very low
Complications
Both studies reported ventilator-associated pneumonia and tracheotomies. Both showed a reduction in ventilator-associated pneumonia in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 34.6%, P = 0.07; and 6.4% vs. 37.2%, P < 0.001, respectively). Similarly, both studies showed a reduction in tracheotomies in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 23.1%, P = 0.29; and 6.4% vs. 34.6%; P < 0.001).
GRADE: very low
Other Outcomes
One of the studies followed patients for 12 months. At the end of follow-up, patients in the NPPV group had a significantly lower rate of needing de novo oxygen supplementation at home. In addition, the IMV group experienced significant increases in functional limitations due to COPD, while no increase was seen in the NPPV group. Finally, no significant differences were observed for hospital readmissions, ICU readmissions, and patients with an open tracheotomy, between the NPPV and IMV groups.
NPPV for Weaning COPD Patients From IMV
A total of 80 participants were included in the 2 RCTs; the sample sizes of the studies were 30 and 50 patients. The mean age of the participants ranged from 58 to 69 years of age. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, both studies included patients with very severe COPD. Both studies also included patients with very severe respiratory failure (mean pH of the study populations was less than 7.23). Chronic obstructive pulmonary disease patients receiving IMV were enrolled in the study if they failed a T-piece weaning trial (spontaneous breathing test), so they could not be directly extubated from IMV.
Both studies were conducted in the ICU. Patients in the NPPV group received weaning using either BiPAP or pressure support ventilation NPPV through a face mask, and patients in the IMV weaning group received pressure support ventilation. In both cases, weaning was achieved by tapering the ventilation level.
The individual quality of the studies ranged. Common methodological problems included unclear randomization methods and allocation concealment, lack of blinding, and small sample size.
Mortality
Both studies reported mortality as an outcome. The pooled results showed a significant reduction in ICU mortality in the NPPV group compared with the IMV group (RR, 0.47; 95% CI, 0.23−0.97; P = 0.04).
GRADE: moderate
Intensive Care Unit Length of Stay
Both studies reported ICU LOS as an outcome. The pooled results showed a nonsignificant reduction in ICU LOS in the NPPV group compared with the IMV group (WMD, −5.21 days; 95% CI, −11.60 to 1.18 days).
GRADE: low
Duration of Mechanical Ventilation
Both studies reported duration of mechanical ventilation (including both invasive and noninvasive ventilation) as an outcome. The pooled results showed a nonsignificant reduction in duration of mechanical ventilation (WMD, −3.55 days; 95% CI, −8.55 to 1.44 days).
GRADE: low
Nosocomial Pneumonia
Both studies reported nosocominal pneumonia as an outcome. The pooled results showed a significant reduction in nosocomial pneumonia in the NPPV group compared with the IMV group (RR, 0.14; 95% CI, 0.03−0.71; P = 0.02).
GRADE: moderate
Weaning Failure
One study reported a significant reduction in weaning failure in the NPPV group compared with the IMV group, but the results were not reported in the publication. In this study, 1 of 25 patients in the NPPV group and 2 of 25 patients in the IMV group could not be weaned after 60 days in the ICU.
NPPV After Extubation of COPD Patients From IMV
The literature was reviewed to identify studies examining the effectiveness of NPPV compared with UMC in preventing recurrence of ARF after extubation from IMV or treating acute ARF which has recurred after extubation from IMV. No studies that included only COPD patients or reported results for COPD patients separately were identified for the prevention of ARF postextubation.
One study was identified for the treatment of ARF in COPD patients that recurred within 48 hours of extubation from IMV. This study included 221 patients, of whom 23 had COPD. A post hoc subgroup analysis was conducted examining the rate of reintubation in the COPD patients only. A nonsignificant reduction in the rate of reintubation was observed in the NPPV group compared with the UMC group (7 of 14 patients vs. 6 of 9 patients, P = 0.67). GRADE: low
Conclusions
NPPV Plus UMC Versus UMC Alone for First Line Treatment of ARF due to Acute Exacerbations of COPD
Moderate quality of evidence showed that compared with UMC, NPPV plus UMC significantly reduced the need for endotracheal intubation, inhospital mortality, and the mean length of hospital stay.
Low quality of evidence showed a lower rate of complications in the NPPV plus UMC group compared with the UMC group.
NPPV Versus IMV for the Treatment of ARF in Patients Who Have Failed UMC
Due to inconsistent and low to very low quality of evidence, there was insufficient evidence to draw conclusions on the comparison of NPPV versus IMV for patients who failed UMC.
NPPV for Weaning COPD Patients From IMV
Moderate quality of evidence showed that weaning COPD patients from IMV using NPPV results in significant reductions in mortality, nosocomial pneumonia, and weaning failure compared with weaning with IMV.
Low quality of evidence showed a nonsignificant reduction in the mean LOS and mean duration of mechanical ventilation in the NPPV group compared with the IMV group.
NPPV for the Treatment of ARF in COPD Patients After Extubation From IMV
Low quality of evidence showed a nonsignificant reduction in the rate of reintubation in the NPPV group compared with the UMC group; however, there was inadequate evidence to draw conclusions on the effectiveness of NPPV for the treatment of ARF in COPD patients after extubation from IMV
PMCID: PMC3384377  PMID: 23074436
22.  3D-modelling of transient left bronchial obstruction following bidirectional superior cavopulmonary shunt 
Extrinsic compression of airways is one the most important causes of respiratory insufficiency in the perioperative period in children with congenital heart disease. This is especially true of pathologies that involve surgery of the aortic arch or conduit replacement of the right ventricular outflow tract. However bronchial obstruction is uncommon in the setting of bidirectional cavopulmonary shunt alone.
We report the case of an infant with a functionally univentricular heart who had a bidirectional superior cavopulmonary shunt and disconnection of the main pulmonary artery from the ventricular mass with oversewing of pulmonary valve. Post-operatively the patient desaturated due to compression of left main bronchus by the left pulmonary artery anteriorly and the descending aorta posteriorly. This was clearly defined by CT based on 3D-modelling of the airways and great vessels. The child was managed conservatively by ventilator support, selective bronchial suctioning and systemic steroids with a successful outcome.
doi:10.5339/gcsp.2014.22
PMCID: PMC4220431  PMID: 25405175
bronchial compression; left pulmonary artery; descending aorta; CT angiography; 3D-modelling
23.  Blood-Induced Interference of Glucose Sensor Function in Vitro: Implications for in Vivo Sensor Function 
Background
Although tissue hemorrhages, with resulting blood clots, are associated with glucose sensor implantation, virtually nothing known is about the impact of red blood cells and red blood cell clots on sensor function in vitro or in vivo. In these studies, we tested the hypothesis that blood can directly interfere with glucose sensor function in vitro.
Methods
To test this hypothesis, heparinized human whole blood (HWB) and nonheparinized human whole blood (WB) were obtained from normal individuals. Aliquots of HWB and WB samples were also fractionated into plasma, serum, and total leukocyte (TL) components. Resulting HWB, WB, and WB components were incubated in vitro with an amperometric glucose sensor for 24 hours at 37°C. During incubation, blood glucose levels were determined periodically using a glucose monitor, and glucose sensor function (GSF) was monitored continuously as nanoampere output.
Results
Heparinized human whole blood had no significant effect on GSF in vitro, nor did TL, serum, or plasmaderived clots from WB. Sensors incubated with WB displayed a rapid signal loss associated with clot formation at 37°C. The half-life was 0.8 ± 0.2 hours (n = 16) for sensors incubated with WB compared to 3.2 ± 0.5 (n = 12) for sensors incubated with HWB with a blood glucose level of approximately 100 mg/dl.
Conclusions
These studies demonstrated that human whole blood interfered with GSF in vitro. These studies further demonstrated that this interference was related to blood clot formation, as HWB, serum, plasma-derived clots, or TL did not interfere with GSF in vitro in the same way that WB did. These in vitro studies supported the concept that the formation of blood clots at sites of glucose sensor implantation could have a negative impact on GSF in vivo.
PMCID: PMC2769689  PMID: 19885155
blood; blood clots; diabetes; implantable glucose sensor; red blood cells; sensor function in vitro; tissue hemorrhages
24.  Comparison the Effects of Shallow and Deep Endotracheal Tube Suctioning on Respiratory Rate, Arterial Blood Oxygen Saturation and Number of Suctioning in Patients Hospitalized in the Intensive Care Unit: A Randomized Controlled Trial 
Journal of Caring Sciences  2014;3(3):157-164.
Introduction: Endotracheal tube suctioning is essential for improve oxygenation in the patients undergoing mechanical ventilation. There are two types of shallow and deep endotracheal tube suctioning. This study aimed to evaluate the effect of shallow and deep suctioning methods on respiratory rate (RR), arterial blood oxygen saturation (SpO2) and number of suctioning in patients hospitalized in the intensive care units of Al-Zahra Hospital, Isfahan, Iran. Methods: In this randomized controlled trial, 74 patients who hospitalized in the intensive care units of Isfahan Al-Zahra Hospital were randomly allocated to the shallow and deep suctioning groups. RR and SpO2 were measured immediately before, immediately after, 1 and 3 minute after each suctioning. Number of suctioning was also noted in each groups. Data were analyzed using repeated measures analysis of variance (RMANOVA), chi-square and independent t-tests. Results: RR was significantly increased and SpO2 was significantly decreased after each suctioning in the both groups. However, these changes were not significant between the two groups. The numbers of suctioning was significantly higher in the shallow suctioning group than in the deep suctioning group. Conclusion: Shallow and deep suctioning had a similar effect on RR and SpO2. However, shallow suctioning caused further manipulation of patient's trachea than deep suctioning method. Therefore, it seems that deep endotracheal tube suctioning method can be used to clean the airway with lesser manipulation of the trachea.
doi:10.5681/jcs.2014.017
PMCID: PMC4171817  PMID: 25276759
Airway management; Suction; Respiratory system; Intensive care unit; Nursing
25.  FLUID MECHANICS OF ARTIFICIAL HEART VALVES 
SUMMARY
1. Artificial heart valves have been in use for over five decades to replace diseased heart valves. Since the first heart valve replacement performed with a caged-ball valve, more than 50 valve designs have been developed, differing principally in valve geometry, number of leaflets and material. To date, all artificial heart valves are plagued with complications associated with haemolysis, coagulation for mechanical heart valves and leaflet tearing for tissue-based valve prosthesis. For mechanical heart valves, these complications are believed to be associated with non-physiological blood flow patterns.
2. In the present review, we provide a bird’s-eye view of fluid mechanics for the major artificial heart valve types and highlight how the engineering approach has shaped this rapidly diversifying area of research.
3. Mechanical heart valve designs have evolved significantly, with the most recent designs providing relatively superior haemodynamics with very low aerodynamic resistance. However, high shearing of blood cells and platelets still pose significant design challenges and patients must undergo life-long anticoagulation therapy. Bioprosthetic or tissue valves do not require anticoagulants due to their distinct similarity to the native valve geometry and haemodynamics, but many of these valves fail structurally within the first 10–15 years of implantation.
4. These shortcomings have directed present and future research in three main directions in attempts to design superior artificial valves: (i) engineering living tissue heart valves; (ii) development of advanced computational tools; and (iii) blood experiments to establish the link between flow and blood damage.
doi:10.1111/j.1440-1681.2008.05099.x
PMCID: PMC2752693  PMID: 19220329
aortic; bileaflet; circulation; haemodynamics; heart valve; mechanical; mitral; prosthesis; trileaflet

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