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1.  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
2.  Extracorporeal Lung Support Technologies – Bridge to Recovery and Bridge to Lung Transplantation in Adult Patients 
Executive Summary
For cases of acute respiratory distress syndrome (ARDS) and progressive chronic respiratory failure, the first choice or treatment is mechanical ventilation. For decades, this method has been used to support critically ill patients in respiratory failure. Despite its life-saving potential, however, several experimental and clinical studies have suggested that ventilator-induced lung injury can adversely affect the lungs and patient outcomes. Current opinion is that by reducing the pressure and volume of gas delivered to the lungs during mechanical ventilation, the stress applied to the lungs is eased, enabling them to rest and recover. In addition, mechanical ventilation may fail to provide adequate gas exchange, thus patients may suffer from severe hypoxia and hypercapnea. For these reasons, extracorporeal lung support technologies may play an important role in the clinical management of patients with lung failure, allowing not only the transfer of oxygen and carbon dioxide (CO2) but also buying the lungs the time needed to rest and heal.
Objective
The objective of this analysis was to assess the effectiveness, safety, and cost-effectiveness of extracorporeal lung support technologies in the improvement of pulmonary gas exchange and the survival of adult patients with acute pulmonary failure and those with end-stage chronic progressive lung disease as a bridge to lung transplantation (LTx). The application of these technologies in primary graft dysfunction (PGD) after LTx is beyond the scope of this review and is not discussed.
Clinical Applications of Extracorporeal Lung Support
Extracorporeal lung support technologies [i.e., Interventional Lung Assist (ILA) and extracorporeal membrane oxygenation (ECMO)] have been advocated for use in the treatment of patients with respiratory failure. These techniques do not treat the underlying lung condition; rather, they improve gas exchange while enabling the implantation of a protective ventilation strategy to prevent further damage to the lung tissues imposed by the ventilator. As such, extracorporeal lung support technologies have been used in three major lung failure case types:
As a bridge to recovery in acute lung failure – for patients with injured or diseased lungs to give their lungs time to heal and regain normal physiologic function.
As a bridge to LTx – for patients with irreversible end stage lung disease requiring LTx.
As a bridge to recovery after LTx – used as lung support for patients with PGD or severe hypoxemia.
Ex-Vivo Lung Perfusion and Assessment
Recently, the evaluation and reconditioning of donor lungs ex-vivo has been introduced into clinical practice as a method of improving the rate of donor lung utilization. Generally, about 15% to 20% of donor lungs are suitable for LTx, but these figures may increase with the use of ex-vivo lung perfusion. The ex-vivo evaluation and reconditioning of donor lungs is currently performed at the Toronto General Hospital (TGH) and preliminary results have been encouraging (Personal communication, clinical expert, December 17, 2009). If its effectiveness is confirmed, the use of the technique could lead to further expansion of donor organ pools and improvements in post-LTx outcomes.
Extracorporeal Lung support Technologies
ECMO
The ECMO system consists of a centrifugal pump, a membrane oxygenator, inlet and outlet cannulas, and tubing. The exchange of oxygen and CO2 then takes place in the oxygenator, which delivers the reoxygenated blood back into one of the patient’s veins or arteries. Additional ports may be added for haemodialysis or ultrafiltration.
Two different techniques may be used to introduce ECMO: venoarterial and venovenous. In the venoarterial technique, cannulation is through either the femoral artery and the femoral vein, or through the carotid artery and the internal jugular vein. In the venovenous technique cannulation is through both femoral veins or a femoral vein and internal jugular vein; one cannula acts as inflow or arterial line, and the other as an outflow or venous line. Venovenous ECMO will not provide adequate support if a patient has pulmonary hypertension or right heart failure. Problems associated with cannulation during the procedure include bleeding around the cannulation site and limb ischemia distal to the cannulation site.
ILA
Interventional Lung Assist (ILA) is used to remove excess CO2 from the blood of patients in respiratory failure. The system is characterized by a novel, low-resistance gas exchange device with a diffusion membrane composed of polymethylpentene (PMP) fibres. These fibres are woven into a complex configuration that maximizes the exchange of oxygen and CO2 by simple diffusion. The system is also designed to operate without the help of an external pump, though one can be added if higher blood flow is required. The device is then applied across an arteriovenous shunt between the femoral artery and femoral vein. Depending on the size of the arterial cannula used and the mean systemic arterial pressure, a blood flow of up to 2.5 L/min can be achieved (up to 5.5 L/min with an external pump). The cannulation is performed after intravenous administration of heparin.
Recently, the first commercially available extracorporeal membrane ventilator (NovaLung GmbH, Hechingen, Germany) was approved for clinical use by Health Canada for patients in respiratory failure. The system has been used in more than 2,000 patients with various indications in Europe, and was used for the first time in North America at the Toronto General Hospital in 2006.
Evidence-Based Analysis
The research questions addressed in this report are:
Does ILA/ECMO facilitate gas exchange in the lungs of patients with severe respiratory failure?
Does ILA/ECMO improve the survival rate of patients with respiratory failure caused by a range of underlying conditions including patients awaiting LTx?
What are the possible serious adverse events associated with ILA/ECMO therapy?
To address these questions, a systematic literature search was performed on September 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to September 28, 2008. 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. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Studies in which ILA/ECMO was used as a bridge to recovery or bridge to LTx
Studies containing information relevant to the effectiveness and safety of the procedure
Studies including at least five patients
Exclusion Criteria
Studies reporting the use of ILA/ECMO for inter-hospital transfers of critically ill patients
Studies reporting the use of ILA/ECMO in patients during or after LTx
Animal or laboratory studies
Case reports
Outcomes of Interest
Reduction in partial pressure of CO2
Correction of respiratory acidosis
Improvement in partial pressure of oxygen
Improvement in patient survival
Frequency and severity of adverse events
The search yielded 107 citations in Medline and 107 citations in EMBASE. After reviewing the information provided in the titles and abstracts, eight citations were found to meet the study inclusion criteria. One study was then excluded because of an overlap in the study population with a previous study. Reference checking did not produce any additional studies for inclusion. Seven case series studies, all conducted in Germany, were thus included in this review (see Table 1).
Also included is the recently published CESAR trial, a multicentre RCT in the UK in which ECMO was compared with conventional intensive care management. The results of the CESAR trial were published when this review was initiated. In the absence of any other recent RCT on ECMO, the results of this trial were considered for this assessment and no further searches were conducted. A literature search was then conducted for application of ECMO as bridge to LTx patients (January, 1, 2005 to current). A total of 127 citations on this topic were identified and reviewed but none were found to have examined the use of ECMO as bridge to LTx.
Quality of Evidence
To grade the quality of evidence, the grading system formulated by the GRADE working group and adopted by MAS was applied. The GRADE system classifies the quality of a body of evidence as high, moderate, low, or very low according to four key elements: study design, study quality, consistency across studies, and directness.
Results
Trials on ILA
Of the seven studies identified, six involved patients with ARDS caused by a range of underlying conditions; the seventh included only patients awaiting LTx. All studies reported the rate of gas exchange and respiratory mechanics before ILA and for up to 7 days of ILA therapy. Four studies reported the means and standard deviations of blood gas transfer and arterial blood pH, which were used for meta-analysis.
Fischer et al. reported their first experience on the use of ILA as a bridge to LTx. In their study, 12 patients at high urgency status for LTx, who also had severe ventilation refractory hypercapnea and respiratory acidosis, were connected to ILA prior to LTx. Seven patients had a systemic infection or sepsis prior to ILA insertion. Six hours after initiation of ILA, the partial pressure of CO2 in arterial blood significantly decreased (P < .05) and arterial blood pH significantly improved (P < .05) and remained stable for one week (last time point reported). The partial pressure of oxygen in arterial blood improved from 71 mmHg to 83 mmHg 6 hours after insertion of ILA. The ratio of PaO2/FiO2 improved from 135 at baseline to 168 at 24 hours after insertion of ILA but returned to baseline values in the following week.
Trials on ECMO
The UK-based CESAR trial was conducted to assess the effectiveness and cost of ECMO therapy for severe, acute respiratory failure. The trial protocol were published in 2006 and details of the methods used for the economic evaluation were published in 2008. The study itself was a pragmatic trial (similar to a UK trial of neonatal ECMO), in which best standard practice was compared with an ECMO protocol. The trial involved 180 patients with acute but potentially reversible respiratory failure, with each also having a Murray score of ≥ 3.0 or uncompensated hypercapnea at a pH of < 7.2. Enrolled patients were randomized in a 1:1 ratio to receive either conventional ventilation treatment or ECMO while on ventilator. Conventional management included intermittent positive pressure ventilation, high frequency oscillatory ventilation, or both. As a pragmatic trial, a specific management protocol was not followed; rather the treatment centres were advised to follow a low volume low pressure ventilation strategy. A tidal volume of 4 to 8 mL/kg body weight and a plateau pressure of < 30 cm H2O were recommended.
Conclusions
ILA
Bridge to recovery
No RCTs or observational studies compared ILA to other treatment modalities.
Case series have shown that ILA therapy results in significant CO2 removal from arterial blood and correction of respiratory acidosis, as well as an improvement in oxygen transfer.
ILA therapy enabled a lowering of respiratory settings to protect the lungs without causing a negative impact on arterial blood CO2 and arterial blood pH.
The impact of ILA on patient long-term survival cannot be determined through the studies reviewed.
In-hospital mortality across studies ranged from 20% to 65%.
Ischemic complications were the most frequent adverse events following ILA therapy.
Leg amputation is a rare but possible outcome of ILA therapy, having occurred in about 0.9% of patients in these case series. New techniques involving the insertion of additional cannula into the femoral artery to perfuse the leg may lower this rate.
Bridge to LTx
The results of one case series (n=12) showed that ILA effectively removes CO2 from arterial blood and corrects respiratory acidosis in patients with ventilation refractory hypercapnea awaiting a LTx
Eight of the 12 patients (67%) awaiting a LTx were successfully transplanted and one-year survival for those transplanted was 80%
Since all studies are case series, the grade of the evidence for these observations is classified as “LOW”.
ECMO
Bridge to recovery
Based on the results of a pragmatic trial and an intention to treat analysis, referral of patient to an ECMO based centre significantly improves patient survival without disability compared to conventional ventilation. The results of CESAR trial showed that:
For patients with information about disability, survival without severe disability was significantly higher in ECMO arm
Assuming that the three patients in the conventional ventilation arm who did not have information about severe disability were all disabled, the results were also significant.
Assuming that none of these patients were disabled, the results were at borderline significance
A greater, though not statistically significant, proportion of patients in ECMO arm survived.
The rate of serious adverse events was higher among patients in ECMO group
The grade of evidence for the above observations is classified as “HIGH”.
Bridge to LTx
No studies fitting the inclusion criteria were identified.
There is no accurate data on the use of ECMO in patients awaiting LTx.
Economic Analysis
The objective of the economic analysis was to determine the costs associated with extracorporeal lung support technologies for bridge to LTx in adults. A literature search was conducted for which the target population was adults eligible for extracorporeal lung support. The primary analytic perspective was that of the Ministry of Health and Long-Term Care (MOHLTC). Articles published in English and fitting the following inclusion criteria were reviewed:
Full economic evaluations including cost-effectiveness analyses (CEA), cost-utility analyses (CUA), cost-benefit analyses (CBA);
Economic evaluations reporting incremental cost-effectiveness ratios (ICER) i.e. cost per quality adjusted life year (QALY), life years gained (LYG), or cost per event avoided; and
Studies in patients eligible for lung support technologies for to lung transplantation.
The search yielded no articles reporting comparative economic analyses.
Resource Use and Costs
Costs associated with both ILA and ECMO (outlined in Table ES-1) were obtained from the University Health Network (UHN) case costing initiative (personal communication, UHN, January 2010). Consultation with a clinical expert in the field was also conducted to verify resource utilization. The consultant was situated at the UHN in Toronto. The UHN has one ECMO machine, which cost approximately $100,000. The system is 18 years old and is used an average of 3 to 4 times a year with 35 procedures being performed over the last 9 years. The disposable cost per patient associated with ECMO is, on average, $2,200. There is a maintenance cost associated with the machine (not reported by the UHN), which is currently absorbed by the hospital’s biomedical engineering department.
The average capital cost of an ILA device is $7,100 per device, per patient, while the average cost of the reusable pump $65,000. The UHN has performed 16 of these procedures over the last 2.5 years. Similarly, there is a maintenance cost not that was reported by UHN but is absorbed by the hospital’s biomedical engineering department.
Resources Associated with Extracorporeal Lung Support Technologies
Hospital costs associated with ILA were based on the average cost incurred by the hospital for 11 cases performed in the FY 07/08 (personal communication, UHN, January 2010). The resources incurred with this hospital procedure included:
Device and disposables
OR transplant
Surgical ICU
Laboratory work
Medical imaging
Pharmacy
Clinical nutrition
Physiotherapy
Occupational therapy
Speech and language pathology
Social work
The average length of stay in hospital was 61 days for ILA (range: 5 to 164 days) and the average direct cost was $186,000 per case (range: $19,000 to $552,000). This procedure has a high staffing requirement to monitor patients in hospital, driving up the average cost per case.
PMCID: PMC3415698  PMID: 23074408
3.  Economics of membrane occupancy and respiro-fermentation 
The authors propose that prokaryotic metabolism is fundamentally constrained by the cytoplasmic membrane surface area available for protein expression, and show that this constraint can explain previously puzzling physiological phenomena, including respiro-fermentation.
We propose that prokaryotic cellular metabolism is fundamentally constrained by the finite cytoplasmic membrane surface area available for protein expression.A metabolic model of Escherichia coli updated to include a cytoplasmic membrane constraint is capable of predicting a variety of puzzling phenomena in this organism, including the respiro-fermentation phenomenon.Because the surface area to volume ratio is directly related to the morphology of the cell, this constraint provides a direct link between prokaryotic morphology and physiology.The potential relevance of this constraint to eukaryotes is discussed.
Many heterotrophs can produce ATP through both respiratory and fermentative pathways, allowing them to survive with or without oxygen. Since the molar ATP yield (molar ATP yield: mole of ATP produced/mole of substrate consumed) from respiration is about 15-fold higher than that from fermentation, ATP production via respiration is more efficient. Surprisingly, at high catabolic rate, many facultative aerobic organisms employ fermentative pathways simultaneously with respiration, even in the presence of abundant oxygen to produce ATP (Pfeiffer et al, 2001; Vemuri et al, 2006; Molenaar et al, 2009). This leads to an observable tradeoff between the ATP yield and the catabolic rate (Pfeiffer et al, 2001; Vemuri et al, 2006). This respiro-fermentation physiology is commonly observed in microorganisms, including Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae (Molenaar et al, 2009), as well as cancer cells (Vander Heiden et al, 2009). Despite extensive research, existing theories (Majewski and Domach, 1990; Varma and Palsson, 1994; Pfeiffer et al, 2001; Vazquez et al, 2008; Molenaar et al, 2009) cannot fully explain the respiro-fermentation phenomenon.
The membrane economics theory
We propose the hypothesis that the prokaryotic metabolism is fundamentally constrained by the finite cytoplasmic surface area available for protein expression—in order to maximize fitness, prokaryotic organisms such as E. coli must economically manage the expression of membrane proteins based on the membrane cost and the fitness benefit of the proteins. This hypothesis is proposed based on theoretical considerations (in this work), numerical analysis (Phillips and Milo, 2009), and experimental observation that the overexpression of non-respiratory membrane protein significantly reduces the oxygen consumption rate and induces aerobic fermentation (Wagner et al, 2007). Such a constraint on transmembrane protein expression may have significant physiological consequences in prokaryotes, such as E. coli, at higher catabolic rates. First, since both substrate transporters and respiratory enzymes are localized on the cytoplasmic membrane in prokaryotes, increased substrate uptake rates necessitates a decrease in the respiratory rate. This decrease in the respiratory rate, forces prokaryotes to process the additional substrate through the fermentative pathways, which are not catalyzed by transmembrane proteins, for continued ATP production. Furthermore, since the membrane requirement of an enzyme is inversely related to its turnover rate (see Materials and methods section in the manuscript), the faster and inefficient respiratory enzymes (such as Cyd-I and Cyd-II in E. coli) might be preferred over the slower and efficient enzymes (such as Cyo in E. coli), leading to an altered respiratory stoichiometry at higher catabolic rates. Finally, the absence of the respiratory enzymes under anaerobic conditions explains why the maximum glucose uptake rate (GUR) of E. coli is much higher.
Applying membrane economics theory to E. coli
To illustrate that the ‘membrane economics' theory could satisfactorily explain the physiological changes associated with the respiro-fermentation phenomenon in E. coli, we modified the genome-scale metabolic model of E. coli (Feist et al, 2007) to include a cytoplasmic membrane occupancy constraint. Using ‘relative membrane costs' calculated from experimental data, the new modeling framework—FBA with membrane economics (FBAME)—predicted that wild-type E. coli has a GUR of 10.7 mmol/gdw/h, an oxygen uptake rate (OUR) of 15.8 mmol/gdw/h, and a specific growth rate of 0.69 per hour during aerobic growth with excess glucose. FBAME also predicted that under the same growth condition, an E. coli knockout strain with no cytochromes has a GUR of 18 mmol/gdw/h and growth rate of 0.42. These values agree very well with the reported experimental values for E. coli grown in batch cultures (Vemuri et al, 2006; Portnoy et al, 2008), which supports our hypothesis that the higher GUR of E. coli during glucose-excess anaerobiosis than under aerobic conditions is due to the absence of the respiratory enzymes. We also simulated the aerobic growth of E. coli in glucose-limited chemostat using both conventional FBA and FBAME. FBAME successfully predicted the growth rate and yield changes with respect to increasing GUR (Figure 2A and B), as well as the aerobic production of acetate (Figure 2C) and concomitant repression of oxygen uptake (Figure 2D). On the other hand, traditional FBA significantly overestimated the growth rate and yield at higher GURs (this overestimation cannot be explained by varying the growth-associated maintenance (GAM) energy parameter; Figure 2A), and failed to predict the decrease in yield independent of acetate overflow and reduction in oxygen uptake at higher GURs (Figure 2). In addition, FBAME was able to predict the reduction of the TCA cycle activities at higher uptake rates (Figure 3C and D) as well as the selective expression of Cyo and Cyd-II at lower uptake rates (Figure 3A and B), whereas conventional FBA cannot predict the expression of inefficient Cyd-II. These predictions agree with the gene expression data from glucose-limited chemostat (Figure 3). Given the simplicity of the constraint we imposed, our model predictions agree surprisingly well with experimental observations, lending strong credibility to the membrane economics hypothesis.
Concluding remarks
Although it has been long suggested that cellular evolution are governed by non-adjustable mechanistic constraints (Palsson, 2000; Papin et al, 2005; Novak et al, 2006), to date, most metabolic models rely on empirically derived parameters such as glucose and OUR. In this article, we showed that complex phenomena, such as the respiro-fermentation in E. coli, could be satisfactorily explained and accurately predicted by using constraint-based optimization by introducing a simple mechanistic constraint on membrane enzyme occupancy. Given that the cytoplasmic membrane occupancy constraint is directly related to the surface area to volume (S/V) ratio of the cell, it is possible that this constraint resulted in the evolution of mitochondria in eukaryotes as mitochondria allows for a significantly increased S/V ratio. Further efforts to elucidate such fundamental cellular constraints as well as the underlying design principles could significantly improve our understanding of the regulation and evolution of metabolism.
The simultaneous utilization of efficient respiration and inefficient fermentation even in the presence of abundant oxygen is a puzzling phenomenon commonly observed in bacteria, yeasts, and cancer cells. Despite extensive research, the biochemical basis for this phenomenon remains obscure. We hypothesize that the outcome of a competition for membrane space between glucose transporters and respiratory chain (which we refer to as economics of membrane occupancy) proteins influences respiration and fermentation. By incorporating a sole constraint based on this concept in the genome-scale metabolic model of Escherichia coli, we were able to simulate respiro-fermentation. Further analysis of the impact of this constraint revealed differential utilization of the cytochromes and faster glucose uptake under anaerobic conditions than under aerobic conditions. Based on these simulations, we propose that bacterial cells manage the composition of their cytoplasmic membrane to maintain optimal ATP production by switching between oxidative and substrate-level phosphorylation. These results suggest that the membrane occupancy constraint may be a fundamental governing constraint of cellular metabolism and physiology, and establishes a direct link between cell morphology and physiology.
doi:10.1038/msb.2011.34
PMCID: PMC3159977  PMID: 21694717
constraint-based modeling; flux balance analysis; membrane occupancy; overflow metabolism; respiro-fermentation
4.  Relating oxygen partial pressure, saturation and content: the haemoglobin–oxygen dissociation curve 
Breathe  2015;11(3):194-201.
Key Points
In clinical practice, the level of arterial oxygenation can be measured either directly by blood gas sampling to measure partial pressure (PaO2) and percentage saturation (SaO2) or indirectly by pulse oximetry (SpO2).
This review addresses the strengths and weaknesses of each of these tests and gives advice on their clinical use.
The haemoglobin–oxygen dissociation curve describing the relationship between oxygen partial pressure and saturation can be modelled mathematically and routinely obtained clinical data support the accuracy of a historical equation used to describe this relationship.
Educational Aims
To understand how oxygen is delivered to the tissues.
To understand the relationships between oxygen saturation, partial pressure, content and tissue delivery.
The clinical relevance of the haemoglobin–oxygen dissociation curve will be reviewed and we will show how a mathematical model of the curve, derived in the 1960s from limited laboratory data, accurately describes the relationship between oxygen saturation and partial pressure in a large number of routinely obtained clinical samples.
To understand the role of pulse oximetry in clinical practice.
To understand the differences between arterial, capillary and venous blood gas samples and the role of their measurement in clinical practice.
The delivery of oxygen by arterial blood to the tissues of the body has a number of critical determinants including blood oxygen concentration (content), saturation (SO2) and partial pressure, haemoglobin concentration and cardiac output, including its distribution. The haemoglobin–oxygen dissociation curve, a graphical representation of the relationship between oxygen satur­ation and oxygen partial pressure helps us to understand some of the principles underpinning this process. Historically this curve was derived from very limited data based on blood samples from small numbers of healthy subjects which were manipulated in vitro and ultimately determined by equations such as those described by Severinghaus in 1979. In a study of 3524 clinical specimens, we found that this equation estimated the SO2 in blood from patients with normal pH and SO2 >70% with remarkable accuracy and, to our knowledge, this is the first large-scale validation of this equation using clinical samples. Oxygen saturation by pulse oximetry (SpO2) is nowadays the standard clinical method for assessing arterial oxygen saturation, providing a convenient, pain-free means of continuously assessing oxygenation, provided the interpreting clinician is aware of important limitations. The use of pulse oximetry reduces the need for arterial blood gas analysis (SaO2) as many patients who are not at risk of hypercapnic respiratory failure or metabolic acidosis and have acceptable SpO2 do not necessarily require blood gas analysis. While arterial sampling remains the gold-standard method of assessing ventilation and oxygenation, in those patients in whom blood gas analysis is indicated, arterialised capillary samples also have a valuable role in patient care. The clinical role of venous blood gases however remains less well defined.
Understand the role of oximetry in clinical practice and how oxygen delivery, saturation and partial pressure relate http://ow.ly/R05hK
doi:10.1183/20734735.001415
PMCID: PMC4666443  PMID: 26632351
5.  Physiological aspects of the determination of comprehensive arterial inflows in the lower abdomen assessed by Doppler ultrasound 
Non-invasive measurement of splanchnic hemodynamics has been utilized in the clinical setting for diagnosis of gastro-intestinal disease, and for determining reserve blood flow (BF) distribution. However, previous studies that measured BF in a "single vessel with small size volume", such as the superior mesenteric and coeliac arteries, were concerned solely with the target organ in the gastrointestinal area, and therefore evaluation of alterations in these single arterial BFs under various states was sometimes limited to "small blood volumes", even though there was a relatively large change in flow. BF in the lower abdomen (BFAb) is potentially a useful indicator of the influence of comprehensive BF redistribution in cardiovascular and hepato-gastrointestinal disease, in the postprandial period, and in relation to physical exercise. BFAb can be determined theoretically using Doppler ultrasound by subtracting BF in the bilateral proximal femoral arteries (FAs) from BF in the upper abdominal aorta (Ao) above the coeliac trunk. Prior to acceptance of this method of determining a true BFAb value, it is necessary to obtain validated normal physiological data that represent the hemodynamic relationship between the three arteries. In determining BFAb, relative reliability was acceptably high (range in intra-class correlation coefficient: 0.85-0.97) for three arterial hemodynamic parameters (blood velocity, vessel diameter, and BF) in three repeated measurements obtained over three different days. Bland-Altman analysis of the three repeated measurements revealed that day-to-day physiological variation (potentially including measurement error) was within the acceptable minimum range (95% of confidence interval), calculated as the difference in hemodynamics between two measurements. Mean BF (ml/min) was 2951 ± 767 in Ao, 316 ± 97 in left FA, 313 ± 83 in right FA, and 2323 ± 703 in BFAb, which is in agreement with a previous study that measured the sum of BF in the major part of the coeliac, mesenteric, and renal arteries. This review presents the methodological concept that underlies BFAb, and aspects of its day-to-day relative reliability in terms of the hemodynamics of the three target arteries, relationship with body surface area, respiratory effects, and potential clinical usefulness and application, in relation to data previously reported in original dedicated research.
doi:10.1186/1476-7120-10-13
PMCID: PMC3366871  PMID: 22443486
Lower abdominal inflows; splanchnic blood flow; Doppler ultrasound
6.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
7.  A dose escalation study in sheep of the effects of the benzodiazepine CNS 7056 on sedation, the EEG and the respiratory and cardiovascular systems 
British Journal of Pharmacology  2008;155(1):52-61.
Background and purpose:
CNS 7056 is a new, rapidly metabolized benzodiazepine. The effects of escalating doses of CNS 7056 on sedation, and respiratory and cardiovascular function, were examined in conscious, chronically instrumented sheep for the first time.
Experimental approach:
Three sheep were given doses of CNS 7056 (0, 0.037, 0.074, 0.18, 0.37, 0.74, 2.21, 4.41 and 8.82 mg kg−1) as 2 min intravenous infusions in order on consecutive days. A range of physiological variables, including the EEG, were measured.
Key results:
Sheep became transiently drowsy for the lowest (0.037 and 0.074 mg kg−1) doses of CNS 7056, whereas the highest (8.82 mg kg−1) dose produced profound loss of consciousness (LOC) for over 30 min. The EEG alpha power correlated well (r=0.91) with duration of LOC and had a high signal-to-noise ratio. CNS 7056 reduced respiratory rate (maximum 33%) and dose-dependently increased arterial carbon dioxide tension (maximum 12%). There was a transient, dose-related reduction in arterial oxygen tension (maximum 34%), but haemoglobin desaturation was minimal (maximum 4%). CNS 7056 produced a dose-related transient drop in mean arterial blood pressure (maximum 12%) but cardiac output was unchanged.
Conclusions and implications:
Doses of 0.37–2.21 mg kg−1 of CNS 7056 produced sedation for 9–25 min without excessive respiratory or cardiovascular depression, and would be suitable for pharmacokinetic studies. The power in the alpha band of the EEG can be used as a continuous measure of the sedative effects of CNS 7056.
doi:10.1038/bjp.2008.228
PMCID: PMC2527850  PMID: 18552878
CNS 7056; sheep; sedation; cardiovascular effects; respiratory effects
8.  Sleep hypoxia in myotonic dystrophy and its correlation with awake respiratory function. 
Thorax  1994;49(1):66-70.
BACKGROUND--Tiredness and daytime respiratory failure occur frequently in myotonic dystrophy. Sleep hypoxaemia was studied in 12 patients with myotonic dystrophy and correlations were sought with their daytime lung and respiratory muscle function. METHODS--All patients underwent overnight sleep studies, clinical assessment, measurement of flow-volume loops and carbon monoxide transfer factor, arterial blood gas analysis, and physiological assessment of both thoracic muscle function and upper airways obstruction. RESULTS--The mean nadir of oxygen saturation during sleep was 75% (95% confidence interval 69% to 81%). A mean of 3.4% of total sleep duration was spent at an oxygen saturation level below 85%. Five of the 12 patients had an apnoea index of > 5, the group mean apnoea/hypopnoea index being 15.8 events/sleep hour. The mean awake arterial oxygen tension (PaO2) was 10.7 kPa. There was a trend to hypercapnoea with a mean awake arterial carbon dioxide tension of 6.1 kPa; carbon dioxide retention worsened during sleep. Respiratory muscle dysfunction was mainly evident as a low maximum expiratory mouth pressure. Upper airway obstruction assessed by physiological criteria was found in four of the 12 patients. The proportion of total sleep duration with oxygen saturation levels below 85% was directly related to body mass index (weight/height2) and inversely related to the awake PaO2. Body mass index was inversely related to the overnight nadir of oxygen saturation. CONCLUSIONS--Patients with myotonic dystrophy are often hypoxic during sleep and the subgroup that are obese, or have symptoms of sleep apnoea, or both, are particularly at risk. Sleep studies should be considered in this subgroup of patients with myotonic dystrophy.
PMCID: PMC474096  PMID: 8153943
9.  High incidence of adverse events during intra-hospital transport of critically ill patients and new related risk factors: a prospective, multicenter study in China 
Critical Care  2016;20:12.
Background
The aim of the present study was to investigate the incidence of adverse events (AEs) during intra-hospital transport (IHT) of critically ill patients and evaluate the risk factors associated with these events.
Methods
This prospective multicenter observational study was performed in 34 intensive care units in China during 20 consecutive days from 5 November to 25 November 2012. All consecutive patients who required IHT for diagnostic testing or therapeutic procedures during the study period were included. All AEs that occurred during IHT were recorded. The incidence of AEs was defined as the rate of transports with at least one AE. The statistical analysis included a description of demographic and clinical characteristics of the cohort as well as identification of risk factors for AEs during IHT by univariate and multivariate logistic regression analyses.
Results
In total, 441 IHTs of 369 critically ill patients were analyzed. The overall incidence of AEs was 79.8 % (352 IHTs). The proportion of equipment- and staff-related adverse events was 7.9 % (35 IHTs). The rate of patient-related adverse events (P-AEs) was 79.4 % (349 IHTs). The rates of vital sign–related P-AEs and arterial blood gas analysis–related P-AEs were 57.1 % (252 IHTs) and 46.9 % (207 IHTs), respectively. The incidence of critical P-AEs was 33.1 % (146 IHTs). The rates of vital sign–related critical P-AEs and arterial blood gas analysis–related critical P-AEs were 22.9 % (101 IHTs) and 15.0 % (66 IHTs), respectively. All data collected in our study were considered potential risk factors. In the multivariate analysis, predictive factors for P-AEs were pH, partial pressure of carbon dioxide in arterial blood, lactate level, glucose level, and heart rate before IHT. Furthermore, the Acute Physiology and Chronic Health Evaluation II score, partial pressure of oxygen in arterial blood, lactate level, glucose level, heart rate, respiratory rate, pulse oximetry, and sedation before transport were independent influential factors for critical P-AEs during IHT.
Conclusions
The incidence of P-AEs during IHT of critically ill patients was high. Risk factors for P-AEs during IHT were identified. Strategies are needed to reduce their frequency.
Trial registration
Chinese Clinical Trial Register identifier ChiCTR-OCS-12002661. Registered 5 November 2012.
doi:10.1186/s13054-016-1183-y
PMCID: PMC4717618  PMID: 26781179
10.  Carotid artery stiffness, high-density lipoprotein cholesterol and inflammation in men with pre-hypertension 
Journal of human hypertension  2009;23(9):590-596.
Low circulating levels of high density lipoprotein cholesterol (HDL-C) are associated with increased risk for cardiovascular events. HDL-C has a variety of poorly understood atheroprotective effects, including altering lipid metabolism and reducing inflammation. Increased arterial stiffness is an important predictor of subsequent cardiovascular risk. Therefore, in the current study, we sought to determine whether HDL-C levels are associated with carotid arterial stiffness. In addition we examined potential correlates of this association such as inflammatory factors, cardio-respiratory fitness and body fat percentage.
Methods
Carotid artery β stiffness was measured by ultrasound in 47 (23 yrs old) healthy pre-hypertensive men. Low HDL-C was defined as <1.0 mmol/L. Body fat was measured by air displacement plethysmograpy. Cardio-respiratory fitness was measured using a maximal exercise test with metabolic gas analysis and inflammatory markers consisted of C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count.
Results
Men with low HDL-C had significantly higher carotid artery stiffness, CRP, WBC count, neutrophil count, body fat, fasting glucose and lower cardio-respiratory fitness (p<0.05). Co-varying for cardio-respiratory fitness, % body fat, and glucose had no effect on group differences in carotid artery stiffness. Co-varying for inflammatory markers resulted in groups having similar carotid artery stiffness.
Conclusion
Pre-hypertensive men with low HDL-C have higher carotid artery stiffness when compared with those with higher HDL-C. The detrimental effects of low HDL-C on large artery stiffness in pre-hypertensive men may be mediated by inflammation and not by cardio-respiratory fitness or body fat levels.
doi:10.1038/jhh.2009.7
PMCID: PMC2914456  PMID: 19225528
arterial stiffness; C-reactive protein; maximal oxygen consumption; body fat
11.  Impact of chemically-modified tetracycline 3 on intertwined physiological, biochemical, and inflammatory networks in porcine sepsis/ARDS 
Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO2/FiO2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered by pleiotropic interruption of inflammation by CMT-3.
PMCID: PMC4448085  PMID: 26064799
Sepsis; shock; MODS; ARDS; CMT-3; data-driven; model; networks; porcine
12.  Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care 
Critical Care  2000;4(5):302-308.
The respiratory effects of dexmedetomidine were retrospectively examined in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit (ICU). Morphine requirements were reduced by over 50% in patients receiving dexmedetomidine. There were no differences in respiratory rates, oxygen saturations, arterial pH and arterial partial carbon dioxide tension (PaCO2) between the groups. Interestingly the arterial partial oxygen tension (PaO2) : fractional inspired oxygen (FIO2) ratios were statistically significantly higher in the dexmedetomidine group. Dexmedetomidine provides important postsurgical analgesia and appears to have no clinically important adverse effects on respiration in the surgical patient who requires intensive care.
Introduction:
The α2-agonist dexmedetomidine is a new class of sedative drug that is being investigated for use in ICU settings. It is an effective agent for the management of sedation and analgesia after cardiac, general, orthopaedic, head and neck, oncological and vascular surgery in the ICU [1]. Cardiovascular stability was demonstrated, with significant reductions in rate-pressure product during sedation and over the extubation period.
Dexmedetomidine possesses several properties that may additionally benefit those critically ill patients who require sedation. In spontaneously breathing volunteers, intravenous dexmedetomidine caused marked sedation with only mild reductions in resting ventilation at higher doses [2]. Dexmedetomidine reduces the haemodynamic response to intubation and extubation [3,4,5] and attenuates the stress response to surgery [6], as a result of the α2-mediated reduction in sympathetic tone. Therefore, it should be possible to continue sedation with dexmedetomidine over the stressful extubation period without concerns over respiratory depression, while ensuring that haemodynamic stability is preserved.
The present study is a retrospective analysis of the respiratory response to dexmedetomidine in 33 postsurgical patients (who were involved in a randomized, double-blind, placebo-controlled trial [1]) after extubation in the ICU.
Methods:
Patients who participated in the present study were admitted after surgery to our general or cardiothoracic ICUs, and were expected to receive at least 6 h of postsurgical sedation and artificial ventilation.
On arrival in the ICU after surgery, patients were randomized to receive either dexmedetomidine or placebo (normal saline) with rescue sedation and analgesia being provided, only if clinically needed, with midazolam and morphine boluses, respectively. Sedation was titrated to maintain a Ramsay Sedation Score [7] of 3 or greater while the patients were intubated, and infusions of study drug were continued for a maximum of 6 h after extubation to achieve a Ramsay Sedation Score of 2 or greater.
The patients were intubated and ventilated with oxygen-enriched air to attain acceptable arterial blood gases, and extubation occurred when clinically indicated. All patients received supplemental oxygen after extubation, which was delivered by a fixed performance device. Assessment of pain was by direct communication with the patient.
Results are expressed as mean ± standard deviation unless otherwise stated. Patient characteristics, operative details and morphine usage were analyzed using the Mann-Whitney U-test. Statistical differences for respiratory measurements between the two groups were determined using analysis of variance for repeated measures, with the Bonferroni test for post hoc comparisons.
Results:
Of the 40 patients who participated in the study, seven patients could not be included in the analysis of respiratory function because they did not receive a study drug infusion after extubation. Consequently, data from 33 patients are used in the analysis of respiratory function; 16 received dexmedetomidine and 17 placebo. Inadequate arterial blood gas analysis was available in five patients (two from the dexmedetomidine group, and three from the placebo group). There were no significant differences in patient characteristics and operative details between the groups.
Requirements for morphine were reduced by more than 50% in patients receiving dexmedetomidine when compared with placebo after extubation (0.003 ± 0.004 vs 0.008 ± 0.006 mg/kg per h; P= 0.040).
There were no statistically significant differences between placebo and dexmedetomidine for oxygen saturations measured by pulse oximetry (P= 0.26), respiratory rate (P= 0.16; Fig. 1), arterial pH (P= 0.77) and PaCO2 (P= 0.75; Fig. 2) for the 6 h after extubation.
The dexmedetomidine group showed significantly higher PaO2: FIO2 ratios throughout the 6-h intubation (P= 0.036) and extubation (P= 0.037) periods (Fig. 3). There were no adverse respiratory events seen in either the dexmedetomidine or placebo group.
Respiratory rate for the 6-h periods before and after extubation. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaCO2 (PCO2) for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaO2 : FIO2 ratio for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
Discussion:
Lack of respiratory depression in patients sedated with α2-adrenoceptor agonists was first reported by Maxwell [8] in a study investigating the respiratory effects of clonidine. However, more recent data suggests that clonidine may cause mild respiratory depression in humans [9], and α2-adrenoceptor agonists are well known to produce profound intraoperative hypoxaemia in sheep [10,11]. The effects of dexmedetomidine on other ventilation parameters also appear to be species specific [12].
Belleville et al [2] investigated the ventilatory effects of a 2-min intravenous infusion of dexmedetomidine on human volunteers. According to those investigators, minute ventilation and arterial PaCO2 were mildly decreased and increased, respectively. There was a rightward shift and depression of the hypercapnic response with infusions of 1.0 and 2.0 μg/kg.
Previous studies that investigated the respiratory effects of dexmedetomidine have only been performed in healthy human volunteers, who have received either single intramuscular injections or short (= 10 min) intravenous infusions of dexmedetomidine. It is therefore reassuring that no deleterious clinical effects on respiration and gas exchange were seen in the patients we studied, who were receiving long-term infusions. However, there are important limitations to the present results. No dose/response curve for dexmedetomidine can be formulated from the data, and further investigation is probably ethically difficult to achieve in the spontaneously ventilating intensive care patient. We also have no data on the ventilatory responses to hypercapnia and hypoxia, which would also be difficult to examine practically and ethically. The placebo group received more than twice as much morphine as patients receiving dexmedetomidine infusions after extubation, but there were no differences in respiratory rate or PaCO2 between the groups. We can not therefore determine from this study whether dexmedetomidine has any benefits over morphine from a respiratory perspective.
There were no differences in oxygen saturations between the groups because the administered oxygen concentration was adjusted to maintain satisfactory gas exchange. Interestingly, however, there were statistically significant higher PaO2 : FIO2 ratios in the dexmedetomidine group. This ratio allows for the variation in administered oxygen to patients during the study period, and gives some clinical indication of alveolar gas exchange. However, this variable was not a primary outcome variable for the present study, and may represent a type 1 error, although post hoc analysis reveals that the data have 80% power to detect a significant difference (α value 0.05). Further studies are obviously required.
Sedation continued over the extubation period, has been shown to reduce haemodynamic disturbances and myocardial ischaemia [13]. We have previously shown [1] that dexmedetomidine provides cardiovascular stability, with a reduction in rate-pressure product over the extubation period. A sedative agent that has analgesic properties, minimal effects on respiration and offers ischaemia protection would have enormous potential in the ICU. Dexmedetomidine may fulfill all of these roles, but at present we can only conclude that dexmedetomidine has no deleterious clinical effects on respiration when used in doses that are sufficient to provide adequate sedation and effective analgesia in the surgical population requiring intensive care.
PMCID: PMC29047  PMID: 11056756
α2-Adrenoceptor agonist; analgesia; dexmedetomidine; intensive care; postoperative; respiratory; sedation
13.  Lack of agreement between tonometric and gastric juice partial carbon dioxide tension 
Critical Care  2000;4(4):249-254.
Our goal was to compare measurement of tonometered saline and gastric juice partial carbon dioxide tension (PCO2). In this prospective observational study, 112 pairs of measurements were simultaneously obtained under various hemodynamic conditions, in 15 critical care patients. Linear regression analysis showed a significant correlation between the two methods of measuring PCO2 (r 2 = 0.43; P < 0.0001). However, gastric juice PCO2 was systematically higher (mean difference 51 mmHg). The 95% limits of agreement were 315 mmHg and the dispersion increased as the values of PCO2 increased. Tonometric and gastric juice PCO2 cannot be used interchangeably. Gastric juice PCO2 measurement should be interpreted with caution.
Introduction:
In recent years there has been growing interest in tonometric estimation of gastric intramucosal pH (pHi). More recently, attention has focused on the gradient between intraluminal and arterial PCO2. pHi appears to be a useful diagnostic and prognostic tool in critically ill patients, and may also be used as a therapeutic guide. However, intraluminal PCO2 is the parameter measured to calculate pHi, and it is assumed as equivalent to the PCO2 of the upper layers of the gastric mucosa.
Direct measurement of PCO2 in gastric juice might offer advantages over tonometry. Tonometer costs could be saved, and equilibration time would no longer be necessary. Additionally, preanalytic factors that account for poor reproducibility, such as inadequate volume of saline in the tonometer, errors in the dwell time of the sample or in the technique used to aspirate saline, mixing of the sample with tonometer dead space and delay in analysis, could be prevented. Nevertheless, to our knowledge few experimental or clinical studies have examined PCO2 in gastric juice. Moreover, no comparison with simultaneous tonometric samples has been performed. Our goal was to compare simultaneous measurement of PCO2 in gastric juice and in saline samples from a tonometer. Data from the present study show that gastric juice PCO2 is systematically higher. Furthermore, differences widen at high PCO2 values, and data dispersion becomes even more striking. Therefore, tonometric PCO2 and gastric juice PCO2 are not interchangeable.
Patients and methods:
The present study was approved by the local ethics committee, and informed consent was obtained from the next of kin of each patient.
We studied 15 consecutive mechanically ventilated patients from a medical/surgical intensive care unit, in whom tonometric monitoring was indicated by attending physicians. All patients were receiving 50 mg intravenous ranitidine every 8 h. Gastric tonometers were filled with saline, which was extracted after 90 min of equilibration time. At the same time, gastric juice was anaerobically extracted from the aspiration port of the tonometer. The initial 20 ml was discarded. PCO2 in both samples was measured using a blood gas analyzer (AVL 945; AVL List GMBH, Gratz, Austria). These measurements were taken at various time points in each patient, and under various haemodynamic and oxygen transport conditions, All measurements were performed with the patient fasted. Correlation between the two measurements was examined using the Bland-Altman technique.
We also performed an in vitro study to quantify the precision and bias for the AVL 945. For this purpose, a stable PCO2 in saline solution was achieved by bubbling 5% carbon dioxide calibration gas.
Results:
We performed 112 pairs of measurements in 15 patients. Table 1 shows clinical data and the first values of arterial, tonometered and gastric juice PCO2 for each patient. Regression analysis demonstrated a significant correlation between both methods of measuring PCO2 (r 2 =0.43; gastric juice PCO2 = -28.79 + [2.55 × tonometric PCO2]; P < 0.0001; Fig. 1). However, the bias calculated as the mean difference of gastric juice and tonometric PCO2 was 51 mmHg. The 95% limits of agreement were 315 mmHg (Fig. 2). For mean PCO2 values lesser than 100 mmHg, the bias and the 95% limits of agreement were 19 and 102 mmHg, respectively. As mean PCO2 increased, the scattering of differences widened (r 2 =0.71; P < 0.0001).
In an effort to prevent the bias related to multiple measurements per patient, we performed Bland-Altman analysis with the first measurement of each patient. After this the results remained similar (bias 55 mmHg, 95% limits of agreement 216 mmHg).
The AVL 945 blood gas analyzer showed a negative bias of 0.97 mmHg and a precision of 2.13 mmHg. This bias was considered negligible, so no further correction was made to saline tonometric values.
Discussion:
The results of the present study show that tonometric PCO2 and gastric juice PCO2 are not interchangeable. Gastric juice PCO2 is systematically higher. At high PCO2 values the differences widen, and data dispersion becomes even more marked.
There is no clear cause for these observations. A possible explanation might be that tonometric PCO2 is generated over a time interval, whereas gastric juice PCO2 might reflect rapid changes in mucosal metabolism. Different equilibrium time could also account for data dispersion, but not for the positive bias for gastric juice. Rapid changes should occur in both directions.
Another potential confounding factor is the ability of blood gas analyzers to measure PCO2 in gastric juice. Measurement of PCO2 in 0.9% saline is an important source of error in the estimation of pHi. Variation in PCO2 values may occur with different PCO2 equilibration solutions. For example, bias is -66.5% when the Nova Stat Profile 7 blood gas analyzer (Nova Biomedical, Waltham, MA, USA) measures concentration of 1.95% of CO2 equilibrated in normal saline. However, bias changes to +45.4% when 1.95% CO2 is equilibrated in human albumin solution 4.5%.
It would not be surprising if gastric juice components such as proteins, mucopolisaccharides and others interfere with CO2 solubility and its subsequent measurement by blood gas analyzers. In this way, intersubject and intrasubject variation in gastric juice composition could also account for data dispersion. Fiddian-Green et al [1] measured PCO2 in gastric contents of anaesthetized dogs. They isolated the stomach from the oesophagus and the duodenum with ligatures, and washed it through a catheter with saline. Then, they instilled 250 ml 0.9% saline and took samples to measure PCO2 and to estimate pHi. Simultaneously, mucosa pH was recorded with a microglass probe. They found a statistically significant correlation between both methods. However, data dispersion in the graph was considerable.
We were able to exclude analyzer underestimation of PCO2 in saline as the cause for the present results. In vitro performance of the AVL 945 in blood was good. It showed a negative bias less than 1 mmHg and a precision of about 2 mmHg.
We cannot infer from the present data the technique that should be the gold standard for measuring PCO2 in gastric mucosa. However, the studies that have established the normal values for pHi, prognostic changes and its uses as a therapeutic index have been performed with tonometry. Hence, more data are needed for the routine measurement of PCO2 in gastric juice.
Correlation between gastric juice and tonometric PCO2. We performed 112 pairs of measurements of gastric juice and tonometric PCO2 in 15 critical care patients under different haemodynamic and oxygen transport conditions. The linear regression coefficient is significant. However, the slope value indicates systematic overestimation of gastric juice PCO2 in relation to saline PCO2.
Bland-Altman analysis of the differences between gastric juice and tonometric PCO2. The bias calculated as the mean difference of gastric juice and tonometric PCO2 was 51 mmHg. The 95% limits of agreement were 315 mmHg. The bias and the scattering of differences widened as PCO2 increased.
Clinical characteristics and first value of arterial, tonometer and gastric juice PCO2
ARDS, acute respiratory distress syndrome.
PMCID: PMC29045  PMID: 11056754
gastric tonometry; intramucosal partial carbon dioxide tension; intramucosal pH
14.  Overexpressing Superoxide Dismutase 2 Induces a Supernormal Cardiac Function by Enhancing Redox-dependent Mitochondrial Function and Metabolic Dilation* 
During heightened cardiac work, O2 consumption by the heart benefits energy production via mitochondria. However, some electrons leak from the respiratory chain and yield superoxide, which is rapidly metabolized into H2O2 by SOD2. To understand the systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac-specific SOD2 overexpression (SOD2-tg), which increases the H2O2 produced by cardiac mitochondria. Contrast echocardiography was employed to evaluate cardiac function, indicating that SOD2-tg had a significantly greater ejection fraction and a lower mean arterial pressure (MAP) that was partially normalized by intravenous injection of catalase. Norepinephrine-mediated myocardial blood flow (MBF) was significantly enhanced in SOD2-tg mice. Coupling of MBF to the double product (Heart Rate × MAP) was increased in SOD2-tg mice, indicating that the metabolic dilator, “spilled” over, inducing systemic vasodilation. The hypothesis that SOD2 overexpression effectively enhances mitochondrial function was further evaluated. Mitochondria of SOD2-tg mice had a decreased state 3 oxygen consumption rate, but maintained the same ATP production flux under the basal and L-NAME treatment conditions, indicating a higher bioenergetic efficiency. SOD2-tg mitochondria produced less superoxide, and had lower redox activity in converting cyclic hydroxylamine to stable nitroxide, and a lower GSSG concentration. EPR analysis of the isolated mitochondria showed a significant decrease in semiquinones at the SOD2-tg Qi site. These results support a more reductive physiological setting in the SOD2-tg murine heart. Cardiac mitochondria exhibited no significant differences in the respiratory control index between WT and SOD2-tg. We conclude that SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to a phenotype of supernormal cardiac function.
doi:10.1016/j.yjmcc.2015.09.001
PMCID: PMC4641048  PMID: 26374996
superoxide dismutase 2 (SOD2); mitochondria; redox regulation; metabolic dilation; cardiac function; bioenergetics; transgenic mice
15.  Idiopathic scoliosis. Gas exchange and the age dependence of arterial blood gases. 
Journal of Clinical Investigation  1976;58(4):825-833.
The aims were to examine the gas exchange and arterial blood gas abnormalities among patients with scoliosis, and the correlation of these abnormalities with age and severity of deformity. Means among 51 patients were as follows: age 25.4 +/- 17.5 yr, angle of scoliosis 80.2 +/- 29.9 (SD), vital capacity 1.94 +/- 0.91 (SD) (i.e. 60.6 +/- 19.2% of predicted), PaO2 85.8 +/- 12.0 (SD), PaCO2 42.4 +/- 8.0, physiological dead space to tidal volume ratio 0.438 +/- 0.074 (SD), and alveolar-arterial oxygen difference breathing air 14.9 +/- 8.9 (SD). Statistically significant correlations were as follows: the PaCO2 and physiological dead space to tidal volume ratio increased with age, and the PaO2 and alveolar ventilation decreased with age. The PaO2, alveolar ventilation, and tidal volume were inversely related to the angle of scoliosis and directly related to the vital capacity, precent predicted vital capacity, and the compliance of the respiratory system. The physiological dead space to tidal volume ratio and the alveolar-arterial oxygen difference were inversely related to the vital capacity, percent predicted vital capacity, and the compliance of the respiratory system. PaCO2 was directly related to the elastance of the respiratory system. We conclude that ventilation-blood flow maldistribution as a result of deformity of the rib cage was the primary abnormality in gas exchange, and that with age there was progressive deterioration in gas exchange. The age-dependent increase in PaCO2 and decrease in alveolar ventilation were due to the increasing physiological dead space to tidal volume ratio and failure of a compensatory increase in ventilation.
PMCID: PMC333245  PMID: 965490
16.  Acid–base balance, serum electrolytes and need for non-invasive ventilation in patients with hypercapnic acute exacerbation of chronic obstructive pulmonary disease admitted to an internal medicine ward 
Background
Hypoventilation produces or worsens respiratory acidosis in patients with hypercapnia due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In these patients acid–base and hydroelectrolite balance are closely related. Aim of the present study was to evaluate acid–base and hydroelectrolite alterations in these subjects and the effect of non-invasive ventilation and pharmacological treatment.
Methods
We retrospectively analysed 110 patients consecutively admitted to the Internal Medicine ward of Cava de’ Tirreni Hospital for acute exacerbation of hypercapnic chronic obstructive pulmonary disease. On admission all patients received oxygen with a Venturi mask to maintain arterial oxygen saturation at least >90 %, and received appropriate pharmacological treatment. Non-Invasive Ventilation (NIV) was started when, despite optimal therapy, patients had severe dyspnea, increased work of breathing and respiratory acidosis. Based on Arterial Blood Gas (ABG) data, we divided the 110 patients in 3 groups: A = 51 patients with compensated respiratory acidosis; B = 36 patients with respiratory acidosis + metabolic alkalosis; and C = 23 patients with respiratory acidosis + metabolic acidosis. 55 patients received only conventional therapy and 55 had conventional therapy plus NIV.
Results
The use of NIV support was lower in the patients belonging to group B than in those belonging to group A and C (25 %, vs 47 % and 96 % respectively; p < 0.01). A statistically significant association was found between pCO2 values and serum chloride concentrations both in the entire cohort and in the three separate groups.
Conclusions
Our study shows that in hypercapnic respiratory acidosis due to AECOPD, differently from previous studies, the metabolic alkalosis is not a negative prognostic factor neither determines greater NIV support need, whereas the metabolic acidosis in addition to respiratory acidosis is an unfavourable element, since it determines an increased need of NIV and invasive mechanical ventilation support.
doi:10.1186/s40248-016-0063-2
PMCID: PMC4879756  PMID: 27226896
COPD; Acid–base balance; Hypercapnia; NIV
17.  Effects of acute hemorrhage on intrapulmonary shunt in a pig model of acute respiratory distress-like syndrome 
Background
In acute respiratory distress syndrome (ARDS), gas exchange and respiratory system mechanics (compliance) are severely impaired. Besides ventilatory parameters, the degree of respiratory abnormality can be influenced by the circulatory state. This study investigated the influence of acute hypovolemia on the respiratory system.
Methods
We performed a secondary analysis of a previous study including 8 pigs with ARDS-like syndrome induced by lung lavage and surfactant depletion method (ARDS group) and 10 mechanically ventilated pigs with no intervention (CTRL group). Animals of both groups were subjected to hemorrhage and retransfusion successively. We reanalyzed the effect of acute blood volume variations on intrapulmonary shunt (shunt), arterial oxygenation (PaO2:FiO2), global oxygen delivery (DO2) and respiratory system compliance (Crs).
Results
In the ARDS group, after hemorrhage, shunt decreased (−28 +/− 3.5 % (p < 0.001)), respiratory system compliance (Crs) increased (+5.1 +/− 1.0 ml/cm H2O (p < 0.001)) moreover, there was a concurrent increase in PaO2:FiO2 (+113 +/− 19.1 mmHg; p < 0.001) but this did not prevent a reduction in DO2 (−317 +/− 49.8 ml/min; p < 0.001). Following retransfusion, shunt and Crs return towards pre-hemorrhage values. Similar changes, but of smaller magnitude were observed in the CTRL group, except that no significant changes in oxygenation occurred.
Conclusions
The present analysis suggests that an acute decrease in blood volume results in a decrease in shunt with a parallel improvement in arterial oxygenation and an increase in Crs during ARDS-like syndrome. Our results strengthen the importance to integrate the circulatory condition in the analysis of the state of the respiratory system. However, the translation of this physiological model in a clinical perspective is not straightforward because our model of acute and severe hemorrhage is not strictly equivalent to a progressive hypovolemia, as could be obtained in ICU by diuretic. Furthermore, the present model does not consider the impact of blood loss induced decrease of DO2 on other vital organs function.
Trial registration
‘Not applicable’.
doi:10.1186/s12890-016-0221-5
PMCID: PMC4845492  PMID: 27113037
Transpulmonary blood flow; Lung compliance; Admission
18.  Effect of Lactate Accumulation during Exercise-induced Muscle Fatigue on the Sensorimotor Cortex 
Journal of Physical Therapy Science  2014;25(12):1637-1642.
[Purpose] During exercise, skeletal muscle motor units are recruited based on afferent sensory input following peripheral metabolic by-product accumulation. The purpose of this study was to investigate whether lactate plays a role in conveying fatigue-related information to the brain. [Subjects] Eleven healthy adults participated in this study. [Methods] Subjects performed handgrip exercises at 10%, 30%, and 50% maximal voluntary contraction for 120 s. They were monitored for brachial artery blood pressure, respiratory quotient, muscle fatigue (integrated electromyogram, median power frequency), blood lactate levels, muscle blood flow, and brain activity. [Results] The handgrip exercise protocol caused significant muscle fatigue based on 28% and 37% reductions in median power frequency detected at 30% and 50% maximal voluntary contraction, respectively. Subjects exhibited intensity-dependent increases in blood pressure, respiratory quotient, muscle blood flow, and circulating lactate concentrations. Furthermore, brain activity increased at 30% and 50% maximal voluntary contraction. Multiple regression analysis identified muscle blood flow at 30% maximal voluntary contraction and lactate at 50% maximal voluntary contraction with standardized partial regression coefficients of −0.64 and 0.75, respectively. [Conclusion] These data suggest that blood lactate concentration and muscle blood flow, which reflect muscle metabolism, may convey load intensity information to the brain during muscle fatigue.
doi:10.1589/jpts.25.1637
PMCID: PMC3885857  PMID: 24409038
Lactate; Fatigue; Brain blood flow
19.  Internal carotid artery blood flow in healthy awake subjects is reduced by simulated hypovolemia and noninvasive mechanical ventilation 
Physiological Reports  2016;4(19):e12969.
Abstract
Intact cerebral blood flow (CBF) is essential for cerebral metabolism and function, whereas hypoperfusion in relation to hypovolemia and hypocapnia can lead to severe cerebral damage. This study was designed to assess internal carotid artery blood flow (ICA‐BF) during simulated hypovolemia and noninvasive positive pressure ventilation (PPV) in young healthy humans. Beat‐by‐beat blood velocity (ICA and aorta) were measured by Doppler ultrasound during normovolemia and simulated hypovolemia (lower body negative pressure), with or without PPV in 15 awake subjects. Heart rate, plethysmographic finger arterial pressure, respiratory frequency, and end‐tidal CO 2 (ETCO 2) were also recorded. Cardiac index (CI) and ICA‐BF were calculated beat‐by‐beat. Medians and 95% confidence intervals and Wilcoxon signed rank test for paired samples were used to test the difference between conditions. Effects on ICA‐BF were modeled by linear mixed‐effects regression analysis. During spontaneous breathing, ICA‐BF was reduced from normovolemia (247, 202–284 mL/min) to hypovolemia (218, 194–271 mL/min). During combined PPV and hypovolemia, ICA‐BF decreased by 15% (200, 152–231 mL/min, P = 0.001). Regression analysis attributed this fall to concurrent reductions in CI (β: 43.2, SE: 17.1, P = 0.013) and ETCO 2 (β: 32.8, SE: 9.3, P = 0.001). Mean arterial pressure was maintained and did not contribute to ICA‐BF variance. In healthy awake subjects, ICA‐BF was significantly reduced during simulated hypovolemia combined with noninvasive PPV. Reductions in CI and ETCO 2 had additive effects on ICA‐BF reduction. In hypovolemic patients, even low‐pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure.
doi:10.14814/phy2.12969
PMCID: PMC5064133  PMID: 27702883
Cerebral blood flow; cerebrovascular circulation; hypovolemia; internal carotid artery blood flow; noninvasive ventilation
20.  Respiratory Changes During Spinal Anaesthesia for Gynaecological Laparoscopic Surgery 
Background:
It is currently presumed that spinal anaesthesia can compromise respiratory muscle function during carbon dioxide (CO2) pneumoperitoneum. This observational study was designed to delineate the respiratory effects of CO2 pneumoperitoneum under spinal anaesthesia.
Patients & Methods:
Forty one patients undergoing elective gynecological laparoscopy were administered spinal anaesthesia with 15 mg heavy bupivacaine and 50 mcg of fentanyl. Heart rare, blood pressure, tidal volume, respiratory rate and end tidal CO2 were serially recorded before, during and after the pneumoperitoneum. Arterial blood gas analysis was done before and 20 min after initiation of pneumoperitoneum.
Results:
The mean heart rate and blood pressure decreased by less than 20% of the preoperative value. The mean tidal volume decreased from 353 ± 81(Standard Deviation) to 299±95 ml, p = 0.032, over the first 9 min after the pneumoperitoneum with a complete recovery towards the base line, 340 ± 72 ml, within 30 min during the surgery. The maximal inspiratory capacity declined from 1308±324 ml to 1067±296 ml at 20 min and recovered to 1187±267 ml, 5min after decompression. There was no observed change in the respiratory rate. Similarly, increase in the end tidal CO2 from 31.68±4.13 to 37.62±4.21 mmHg, p = 0.000, reached a plateau around 15 min and declined after decompression. Arterial carbon dioxide showed a corresponding increase at 20 min without change in arterial to end tidal CO2 difference. All observed changes were within the physiological limits.
Conclusion:
In a conscious patient undergoing laparoscopy with pneumoperitoneum, under spinal anaesthesia, the preserved inspiratory diaphragmatic activity maintains ventilation and, the gas exchange within physiological limits. Hence it is a safe alternative to general anaesthesia.
PMCID: PMC3087263  PMID: 21547173
Spinal; Pneumoperitonium; Respiratory changes
21.  CLINICAL AND EXPERIMENTAL OBSERVATIONS UPON CHEYNE-STOKES RESPIRATION 
In addition to the results brought out in the separate sections I wish to direct especial attention to the following conclusions: (1) In ten cases of Cheyne-Stokes respiration observed clinically, the alternate periods of respiratory activity and apnœa were associated with Traube-Hering waves of blood pressure. These cases may be separated into two groups characterized by the relation of the respiratory changes to the changes of blood pressure. In one group the period of respiratory activity was associated with a rise of blood pressure, the period of apnœa with a fall; in the other group, the reverse relations existed. The former group included two cases of Cheyne-Stokes respiration occurring with increased intracranial tension; the latter contained eight cases with cardiac and arterial disease. (2) By means of cerebral compression, periodic respirations may be produced experimentally, and the relation of the blood pressure changes to the respiratory variations are the same as in the clinical cases with increased intracranial tension, namely, a rise of pressure with each group of respirations and a fall with each period of apnœa. In the experiments, during each respiratory group, the blood pressure rises above the line of intracranial tension and with each period of apnœa it falls below this line. With the disappearance of this relation, the periodicity of the respirations likewise disappears. It is probable that the same relation between the blood pressure and intracranial pressure exists when Cheyne-Stokes respiration occurs clinically in association with increased intracranial tension. (3) Disappearance of the periodic respiratory activity in the clinical cases of both groups is accompanied by disappearance of the waves of blood pressure. (4) The waves of blood pressure cannot be regarded as a mechanical effect of the periodic respiratory activity; on the contrary the latter must be due to the changes of blood pressure, or both phenomena may be referable to a common cause. (5) Cheyne-Stokes respiration in states of increased intracranial tension, with blood pressure waves rising and falling above and below the line of intracranial tension, is due to periodic activity of the respiratory, vasomotor, and cardio-inhibitory centres, the underlying cause of which is an alternate anæmia and blood supply to the medullary centres. The vasomotor centre, as the result of periodic increase and decrease of the stimulus, shows periodic variations in its activity. It is stimulated to greater activity during the periods of anæmia, and partially relaxes with each period of blood supply. During the periods of anæmia, the respiratory centre loses its irritability for the acting stimulus, and is therefore apnœic. It is finally stimulated to activity, either as a result of an increase in its irritability from a preceding rise of blood pressure, or from a great increase in the respiratory stimulus. The cardio-inhibitory centre is stimulated by the periods of anæmia. This stimulation causes slowing of the pulse, which passes off to a considerable extent with the following period of blood supply. (6) Cheyne-Stokes respiration has heretofore been regarded as always the manifestation of the same conditions and capable of the same explanation; the results of this work, on the contrary, show that two distinct groups of cases may be recognized, depending upon the relation of the blood pressure changes to the periodic respiratory activity.19 (7) The medullary centres show great differences in their susceptibility to anæmia. The respiratory centre is very susceptible to a much reduced blood supply; its irritability is rapidly reduced or lost upon the occurrence of marked or complete anæmia, and is rapidly regained when the blood supply is renewed if the anæmia has not been maintained too long. The effect of a considerable anæmia upon this centre is entirely different from that of a normal or somewhat reduced supply of blood which is more venous than normal, that is, contains more carbon dioxide and less oxygen, such as occurs with ordinary asphyxia. The vasomotor and cardio-inhibitory centres are not nearly so susceptible to anæmia. The former centre may, and frequently does, respond when in a condition of complete anæmia. (8) I am able to confirm, as a result of my experiments upon cerebral compression, in all essential details the conclusions of Cushing, and the general law formulated by him, namely that "an increase of intracranial tension occasions a rise of blood pressure which tends to find a level slightly above that of the pressure exerted against the medulla."
PMCID: PMC2124640  PMID: 19867060
22.  Increased mean carotid intima media thickness in type 2 diabetes mellitus patients with non-blood pressure component metabolic syndrome: A preliminary report 
AIMS:
Patients with type-2 diabetes mellitus have greater carotid intima media thickness and they are at risk for generalized atherosclerosis. This study aimed to compare the thickness of carotid artery intima media in type-2 diabetes mellitus patients with and without nonblood pressure component metabolic syndrome.
SETTINGS AND DESIGN:
This was a comparative observational study conducted in the Departments of Pharmacology and Physiology in the College of Medicine, Al-Mustansiriyia University in cooperation with Baghdad Teaching Hospital.
MATERIALS AND METHODS:
Forty-six diabetic patients of both sexes with systolic blood pressure < 130 mm Hg and diastolic blood pressure < 85 mm Hg were subjected to high resolution B-mode ultrasonography of the common and internal carotid arteries. Patients were grouped into those without metabolic syndrome (Group I) and with nonblood pressure component metabolic syndrome (Group II).
STATISTICAL ANALYSIS:
The two-tailed unpaired Student's t-test was used in this study.
RESULTS:
Significantly high mean thickness was observed in the common carotid intima media (0.824 ± 0.155 mm) but not in the internal carotid arteries in group II patients compared to group I patients (0.708 ± 0.113 mm). Group II also had a significant number of patients with increased lesion intima media thickness (≥ 1.1 mm).
Conclusion:
The greater carotid intima media thickness observed in type 2 diabetes mellitus patients is related to the metabolic syndrome even in the absence of the blood pressure component.
doi:10.4103/0973-3930.50710
PMCID: PMC2802360  PMID: 20062559
Intima media thickness; metabolic syndrome; type 2 diabetes mellitus
23.  Raising the sauropod neck: it costs more to get less 
Biology Letters  2009;5(3):317-319.
The long necks of gigantic sauropod dinosaurs are commonly assumed to have been used for high browsing to obtain enough food. However, this analysis questions whether such a posture was reasonable from the standpoint of energetics. The energy cost of circulating the blood can be estimated accurately from two physiological axioms that relate metabolic rate, blood flow rate and arterial blood pressure: (i) metabolic rate is proportional to blood flow rate and (ii) cardiac work rate is proportional to the product of blood flow rate and blood pressure. The analysis shows that it would have required the animal to expend approximately half of its energy intake just to circulate the blood, primarily because a vertical neck would have required a high systemic arterial blood pressure. It is therefore energetically more feasible to have used a more or less horizontal neck to enable wide browsing while keeping blood pressure low.
doi:10.1098/rsbl.2009.0096
PMCID: PMC2679936  PMID: 19364714
dinosaur; sauropod; blood pressure; circulation; neck; feeding height
24.  Perfusion/ventilation mismatch during exercise in chronic heart failure: an investigation of circulatory determinants. 
British Heart Journal  1995;74(1):27-33.
BACKGROUND--The ventilatory cost of carbon dioxide (CO2) elimination on exercise (VE/VCO2) is increased in chronic heart failure (CHF). This reflects increased physiological dead space ventilation secondary to mismatching between perfusion and ventilation during exercise. The objectives of this study were to investigate the relation of this increased VE/VCO2 slope to the syndrome of CHF or to limitation of the exercise related increase of pulmonary blood flow, or both. PATIENTS AND METHODS--Maximal treadmill exercise tests with respiratory gas analysis were performed in 45 patients with CHF (defined as resting left ventricular ejection fraction < 40% on radionuclide scan); 15 normal controls; 23 patients with coronary artery disease and normal resting left ventricular function; and 13 pacemaker dependent patients (six with and seven without CHF) directly comparing exercise responses in rate responsive and fixed rate mode. RESULTS--Patients with CHF had a steeper VE/VCO2 slope than normal controls: this was related inversely to peak VO2 below 20 mol/min/kg. In patients with coronary artery disease in whom peak VO2 (at respiratory exchange ratio > 1) was as limited as in the patients with CHF but resting left ventricular function was normal, the VE/VCO2 slope was normal. In pacemaker dependent patients fixed rate pacing resulted in lower exercise capacity and peak VO2 than rate responsive pacing; the VE/VCO2 slope was normal in patients without CHF but steeper than normal in patients with CHF; the VE/VCO2 slope was steeper during fixed rate than during rate responsive pacing in these patients with CHF. CONCLUSIONS--These findings suggest that the perfusion/ventilation mismatch during exercise in CHF is related to the chronic consequences of the syndrome and not directly to limitation of exercise related pulmonary flow. Only when the syndrome of CHF is present can matching between perfusion and ventilation be acutely influenced by changes in pulmonary flow.
PMCID: PMC483942  PMID: 7662449
25.  Influenza and Pneumococcal Vaccinations for 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 analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
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 Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431

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