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Chronic obstructive pulmonary disease (COPD) is a major global healthcare problem. Studies vary widely in the reported frequency of mechanical ventilation in acute exacerbations of COPD. Invasive intubation and mechanical ventilation may be associated with significant morbidity and mortality. A good understanding of the airway pathophysiology and lung mechanics in COPD is necessary to appropriately manage acute exacerbations and respiratory failure. The basic pathophysiology in COPD exacerbation is the critical expiratory airflow limitation with consequent dynamic hyperinflation. These changes lead to further derangement in ventilatory mechanics, muscle function and gas exchange which may result in respiratory failure. This review discusses the altered respiratory mechanics in COPD, ways to detect these changes in a ventilated patient and formulating ventilatory techniques to optimize management of respiratory failure due to exacerbation of COPD.

Mechanical ventilation is the defining event of intensive care unit (ICU) management. Although it is a life saving intervention in patients with acute respiratory failure and other disease entities, a major goal of critical care clinicians should be to liberate patients from mechanical ventilation as early as possible to avoid the multitude of complications and risks associated with prolonged unnecessary mechanical ventilation, including ventilator induced lung injury, ventilator associated pneumonia, increased length of ICU and hospital stay, and increased cost of care delivery. This review highlights the recent developments in assessing and testing for readiness of liberation from mechanical ventilation, the etiology of weaning failure, the value of weaning protocols, and a simple practical approach for liberation from mechanical ventilation.

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.

Common medical conditions that require mechanical ventilation include chronic obstructive lung disease, acute lung injury, sepsis, heart failure, drug overdose, neuromuscular disorders, and surgery. Although mechanical ventilation can be a life saving measure, prolonged mechanical ventilation can also present clinical problems. Indeed, numerous well-controlled animal studies have demonstrated that prolonged mechanical ventilation results in diaphragmatic weakness due to both atrophy and contractile dysfunction. Importantly, a recent clinical investigation has confirmed that prolonged mechanical ventilation results in atrophy of the human diaphragm. This mechanical ventilation-induced diaphragmatic weakness is important because the most frequent cause of weaning difficulty is respiratory muscle failure due to inspiratory muscle weakness and/or a decline in inspiratory muscle endurance. Therefore, developing methods to protect against mechanical ventilation-induced diaphragmatic weakness is important.

Pulmonary disease changes the physiology of the lungs, which manifests as changes in respiratory mechanics. Therefore, measurement of respiratory mechanics allows a clinician to monitor closely the course of pulmonary disease. Here we review the principles of respiratory mechanics and their clinical applications. These principles include compliance, elastance, resistance, impedance, flow, and work of breathing. We discuss these principles in normal conditions and in disease states. As the severity of pulmonary disease increases, mechanical ventilation can become necessary. We discuss the use of pressure–volume curves in assisting with poorly compliant lungs while on mechanical ventilation. In addition, we discuss physiologic parameters that assist with ventilator weaning as the disease process abates.

Noninvasive ventilation (NIV) is the provision of ventilatory support without the need for an invasive airway, and has revolutionized the management of patients with diverse forms of respiratory failure. The advantages of NIV include improved patient comfort and reduced need for sedation, while avoiding the complications of endotracheal intubation, including upper airway trauma, sinusitis, otitis, and nosocomial pneumonia. In selected patients, NIV has also been shown to improve survival. The role of NIV in acute severe asthma is at best controversial. In this case report, we describe a patient with acute severe asthma who was initially managed and failed with NIV, and was successfully managed with invasive ventilation. We also review the pathophysiological mechanisms of benefit of NIV in acute severe asthma, and the current literature on the use of NIV in acute asthma. In conclusion, a trial of NIV in acute asthma may be justified in carefully selected and monitored patients who do not respond to initial medical therapy. However, as its role is not clear and as the condition of an asthmatic patient may deteriorate abruptly, extreme caution is advisable to recognize failure of NIV as in the case presented here. Facilities for immediate endotracheal intubation and next level of treatment should be readily available.

Mechanical ventilation during acute respiratory failure in children is associated with development of ventilator-induced lung injury. Experimental models of mechanical ventilation that limit phasic changes in lung volumes and prevent alveolar overdistension appear to be less damaging to the lung. High-frequency oscillatory ventilation, using very small tidal volumes and relatively high end-expiratory lung volumes, provides a safe and effective means of delivering mechanical ventilatory support with the prospect of reducing the development of ventilator-induced lung injury. Despite theoretical advantages and convincing laboratory data, however, the use of high-frequency oscillatory ventilation in the paediatric population has not yet been associated with significant improvements in clinically significant outcome measures.

In the present issue of Critical Care, Frank and Matthay review the physiologic mechanisms that lead to ventilator-induced lung injury. Our greater understanding of basic physiologic principles has already had a major impact on the treatment of critically ill patients. Novel strategies to limit ventilator-induced lung injury have now been shown to improve survival. However, there has been debate in the literature regarding the safety and efficacy of the Acute Respiratory Distress Syndrome (ARDS) Network study protocol in reducing ventilator-induced lung injury. The issues surrounding the ARDS Network protocol and a recent meta-analysis criticizing its use are presented. As clinicians, we now have the responsibility to ensure that our patients benefit from these recent developments.

Background

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS.

Methods and Findings

We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMed™, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10–15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03).

Conclusions

This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents.

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.

A new valveless ventilator, which uses an air jet to provide the driving force for positive pressure ventilation, was used on 13 newborn babies (10 of very low birthweight) who had severe respiratory disease. The ventilator differs from 'true' jet ventilators in that its driving gas does not take part in gas exchange. Functionally it is a pressure pre-set, time-cycled ventilator, whose performance is characterised by the rapid and precise maintenance of both inspiratory and expiratory airway opening pressure. All the babies had progressively worsening respiratory failure (mean values of arterial pCO2 were 9.46 kPa, with a pH of 7.14, and an inspired oxygen concentration of 92.5%) on conventional mechanical ventilation. On the new ventilator, with the same settings, there was a dramatic and highly significant improvement within 20 to 30 minutes (mean values of arterial pCO2 were 6.45 kPa, pH 7.26, and inspired oxygen concentration 85.7%). This improvement was maintained. The new ventilator represents an important advance in the management of babies with severe respiratory failure.

The management of chronic respiratory insufficiency and/or long-term inability to breathe independently has traditionally been via positive-pressure ventilation through a mechanical ventilator. Although life-sustaining, it is associated with limitations of function, lack of independence, decreased quality of life, sleep disturbance, and increased risk for infections. In addition, its mechanical and electronic complexity requires full understanding of the possible malfunctions by patients and caregivers. Ventilator-associated pneumonia, tracheal injury, and equipment malfunction account for common complications of prolonged ventilation, and respiratory infections are the most common cause of death in spinal cord–injured patients. The development of functional electric stimulation (FES) as an alternative to mechanical ventilation has been motivated by a goal to improve the quality of life of affected individuals. In this article, we will review the physiology, types, characteristics, risks and benefits, surgical techniques, and complications of the 2 commercially available FES strategies – phrenic nerve pacing (PNP) and diaphragm motor point pacing (DMPP).

Background

Chronic obstructive pulmonary disease (COPD) is a condition in which there is limited airflow during expiration (exhaling, or breathing out) that is not fully reversible and usually worsens over time. The disease is estimated to kill more than 100,000 Americans each year, and costs related to care of patients with COPD are significant. Physiologically, COPD represents a disruption in ventilation and in the exchange of gases in the lungs. Laboratory tests indicate elevated CO2 levels, gradual reduction of the levels of oxygen and pH in arterial blood, and a consequent rise in the dead space fraction (DSF) of the lungs.

Objective

Patients with COPD exacerbation represent a large portion of those artificially ventilated. In an attempt to develop a prognostic tool for length of treatment, we compared the proportion of DSF to the length of mechanical ventilation (MV).

Methods

This study included 73 patients admitted to the intensive care unit (ICU) where they received MV due to exacerbation of COPD. Each patient’s arterial blood gases (ABG) were measured upon admission. PeCO2 was tested using a Datex S/5 instrument. Subsequently, DSF was calculated using the Bohr equation. Statistical data was analyzed using SPSS software.

Results

Patients included in the study were ventilated from 6 to 160 hours (average 40 ± 47). In addition to ABG measurements, PeCO2 (expired CO2) levels were measured and DSF calculated for each patient. DSF values varied from 0.21 to 0.76 (average 0.119 ± 0.489). No correlation was found between DSF and length of artificial ventilation.

Conclusion

Evaluation of DSF does not provide a factor in estimating the length of treatment for patients with acute respiratory failure due to COPD exacerbation.

In obstructive lung diseases such as asthma and COPD dyspnea is a common respiratory symptom with different characteristics given the different pathogenic mechanisms: in COPD initially it can occur during exertion but then it increases progressively along with the airflow obstruction, whereas in asthma it occurs episodically and is caused by transient bronchoconstriction.

The language of dyspnea includes a large range of clinical descriptors which have been evaluated for their correlation (of one or several descriptors) with underlying physiologic/physiopathologic mechanisms. These studies were done in asthma rather than in COPD, and dyspnea descriptors were found to be useful in identifying patients with life-threatening asthma. However further studies are needed to further explore such descriptors and their clinical utility.

This review discusses dyspnea mechanisms in various obstructive lung disease subsets as well as the descriptors of dyspnea and their utility in clinical practice.

Although diffuse alveolar hemorrhage complicating warfarin therapy is rare, it generally has a worsening clinical course and can be a life threatening condition. A 56-year-old male who had undergone a pulmonary lobectomy for lung cancer 2 years before had received warfarin for about 5 months due to pulmonary vein thrombosis. The patient presented with severe dyspnea and had prolonged anticoagulation values. Chest X-ray and computed tomography revealed diffuse pulmonary consolidations, and bronchoalveolar lavage demonstrated diffuse alveolar hemorrhage. The reversal of anticoagulation was initiated, and extracorporeal membrane oxygenation was performed for refractory respiratory failure that did not improve despite maximal mechanical ventilatory support. The diffuse alveolar infiltrations resolved after 5 days, and we successfully weaned off both extracorporeal membrane oxygenation and mechanical ventilation. Herein we report the detailed course of a case that was successfully treated with extracorporeal membrane oxygenation as a bridge-to-recovery for warfarin- exacerbated diffuse alveolar hemorrhage.

Background. There are modes of mechanical ventilation that can select ventilator settings with computer controlled algorithms (targeting schemes). Two examples are adaptive support ventilation (ASV) and mid-frequency ventilation (MFV). We studied how different clinician-chosen ventilator settings are from these computer algorithms under different scenarios. Methods. A survey of critical care clinicians provided reference ventilator settings for a 70 kg paralyzed patient in five clinical/physiological scenarios. The survey-derived values for minute ventilation and minute alveolar ventilation were used as goals for ASV and MFV, respectively. A lung simulator programmed with each scenario's respiratory system characteristics was ventilated using the clinician, ASV, and MFV settings. Results. Tidal volumes ranged from 6.1 to 8.3 mL/kg for the clinician, 6.7 to 11.9 mL/kg for ASV, and 3.5 to 9.9 mL/kg for MFV. Inspiratory pressures were lower for ASV and MFV. Clinician-selected tidal volumes were similar to the ASV settings for all scenarios except for asthma, in which the tidal volumes were larger for ASV and MFV. MFV delivered the same alveolar minute ventilation with higher end expiratory and lower end inspiratory volumes. Conclusions. There are differences and similarities among initial ventilator settings selected by humans and computers for various clinical scenarios. The ventilation outcomes are the result of the lung physiological characteristics and their interaction with the targeting scheme.

Noninvasive positive-pressure ventilation is a type of mechanical ventilation that does not require an artificial airway. Studies published in the 1990s that evaluated the efficacy of this technique for the treatment of diseases as chronic obstructive pulmonary disease, congestive heart failure and acute respiratory failure have generalized its use in recent years. Important issues include the selection of the ventilation interface and the type of ventilator. Currently available interfaces include nasal, oronasal and facial masks, mouthpieces and helmets. Comparisons of the available interfaces have not shown one to be clearly superior. Both critical care ventilators and portable ventilators can be used for noninvasive positive-pressure ventilation; however, the choice of ventilator type depends on the patient's condition and therapeutic requirements and on the expertise of the attending staff and the location of care. The best results (decreased need for intubation and decreased mortality) have been reported among patients with exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary edema.

Mechanical ventilation is the cornerstone of therapy for patients with acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation can exacerbate lung damage – a phenomenon known as ventilator-induced lung injury. While new ventilation strategies have reduced the mortality rate in patients with ARDS, this mortality rate still remains high. High-frequency oscillatory ventilation (HFOV) is an unconventional form of ventilation that may improve oxygenation in patients with ARDS, while limiting further lung injury associated with high ventilatory pressures and volumes delivered during conventional ventilation. HFOV has been used for almost two decades in the neonatal population, but there is more limited experience with HFOV in the adult population. In adults, the majority of the published literature is in the form of small observational studies in which HFOV was used as 'rescue' therapy for patients with very severe ARDS who were failing conventional ventilation. Two prospective randomized controlled trials, however, while showing no mortality benefit, have suggested that HFOV, compared with conventional ventilation, is a safe and effective ventilation strategy for adults with ARDS. Several studies suggest that HFOV may improve outcomes if used early in the course of ARDS, or if used in certain populations. This review will summarize the evidence supporting the use of HFOV in adults with ARDS.

Human metapneumovirus (HMPV) is a common virus that can cause respiratory problems ranging from mild upper respiratory tract disease to respiratory failure requiring mechanical support. Here, we report a case of a 32-month-old male with a previous history of asthma, who developed respiratory failure two weeks after onset of cough and rhinorrhea and required extracorporeal membrane oxygenation (ECMO) for 9 days after failing high-frequency oscillatory ventilation (HFOV). To our knowledge, this is the oldest reported pediatric patient with respiratory failure secondary to human metapneumovirus that did not respond to mechanical ventilation. This case highlights three critical points: the potentially fatal causative role of HMPV in respiratory failure in an older pediatric age group of immunocompetent hosts, the importance of early recognition of impending respiratory failure, and the timely utilization of ECMO.

Background

Diaphragmatic paralysis in newborns is related to brachial plexus palsy. It can cause respiratory failure necessitating prolonged mechanical ventilation and subsequent extubation failure.

Case Presentation

We present a two-hour-old male newborn with a birth weight of 4500 grams who had a right-sided brachial plexus palsy and right diaphragmatic paralysis due to shoulder dystocia. He developed respiratory distress due to isolated paralysis of the right hemi diaphragm. The clinical course was progressive, his condition worsening despite oxygen application. Physical examination, chest X-rays and M-mode ultrasonography of the diaphragm confirmed the diagnosis diaphragmatic paralysis. Surgical plication of diaphragm was done earlier than the usual time because of recurrent extubation failure. Diaphragmatic plication led to rapid improvement of pulmonary function and allowed discontinuation of mechanical ventilation in less than 3 days.

Conclusion

Early diaphragmatic plication enhances weaning process and may prevent or minimize the morbidity associated with long-term mechanical ventilation in a neonate with diaphragmatic paralysis.

Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy it is possible to render the respiratory muscles almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury appears to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where it is possible to undertake meaningful controlled trials and thus it is not possible to render concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and also excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow.

Noninvasive positive pressure ventilation (NPPV) refers to the delivery of mechanical respiratory support without the use of endotracheal intubation (ETI). The present review focused on the effectiveness of NPPV in children > 1 month of age with acute respiratory failure (ARF) due to different conditions. ARF is the most common cause of cardiac arrest in children. Therefore, prompt recognition and treatment of pediatric patients with pending respiratory failure can be lifesaving. Mechanical respiratory support is a critical intervention in many cases of ARF. In recent years, NPPV has been proposed as a valuable alternative to invasive mechanical ventilation (IMV) in this acute setting. Recent physiological studies have demonstrated beneficial effects of NPPV in children with ARF. Several pediatric clinical studies, the majority of which were noncontrolled or case series and of small size, have suggested the effectiveness of NPPV in the treatment of ARF due to acute airway (upper or lower) obstruction or certain primary parenchymal lung disease, and in specific circumstances, such as postoperative or postextubation ARF, immunocompromised patients with ARF, or as a means to facilitate extubation. NPPV was well tolerated with rare major complications and was associated with improved gas exchange, decreased work of breathing, and ETI avoidance in 22-100% of patients. High FiO2 needs or high PaCO2 level on admission or within the first hours after starting NPPV appeared to be the best independent predictive factors for the NPPV failure in children with ARF. However, many important issues, such as the identification of the patient, the right time for NPPV application, and the appropriate setting, are still lacking. Further randomized, controlled trials that address these issues in children with ARF are recommended.

Acute respiratory distress syndrome (ARDS) and acute lung injury are among the most frequent reasons for intensive care unit admission, accounting for approximately one-third of admissions. Mortality from ARDS has been estimated as high as 70% in some studies. Until recently, however, no targeted therapy had been found to improve patient outcome, including mortality. With the completion of the National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network low tidal volume study, clinicians now have convincing evidence that ventilation with tidal volumes lower than those conventionally used in this patient population reduces the relative risk of mortality by 21%. These data confirm the long-held suspicion that the role of mechanical ventilation for acute hypoxemic respiratory failure is more than supportive, in that mechanical ventilation can also actively contribute to lung injury. The mechanisms of the protective effects of low tidal volume ventilation in conjunction with positive end expiratory pressure are incompletely understood and are the focus of ongoing studies. The objective of the present article is to review the potential cellular mechanisms of lung injury attributable to mechanical ventilation in patients with ARDS and acute lung injury.

Prediction of ventilation weaning outcome in children is important, as unsuccessful extubation increases both morbidity and mortality. Adult weaning criteria are poor predictors of weaning outcome in children for several possible reasons: the length of mechanical ventilation is generally much shorter, and the weaning failure rate is lower in children (thus larger patient numbers are required); integrated weaning indices, such as the rapid shallow breathing index, do not account for normal developmental changes in respiratory function; and the heterogeneity of mechanically ventilated children is greater than in adults. The challenge remains to find universal weaning outcome predictors in children.

Asthma is a common chronic inflammatory disorder of the airways associated with hyperresponsiveness, reversible airflow limitation and respiratory symptoms.1 All patients with asthma are at risk for exacerbations that may range from mild to life threatening. Different triggers cause asthma exacerbation by inducing airway inflammation and/or provoking bronchospasm. Allergen-induced bronchospasm results from IgE-dependent release of mediators including histamine, prostaglandins and leukotrienes.2 Opiates are commonly used to treat chronic pain.3 Although hypersensitivity to opiates or accumulation of opiates can cause respiratory depression, opiates are also used in the management of cough and dyspnoea associated with advanced COPD and heart failure.4,5 Here, a report is presented on a patient who developed persistent exacerbation of underlying stable asthma after initiating fentanyl transdermal therapy for chronic low back pain. He underwent extensive investigations and a detailed reassessment of history, especially medication history, led to the possible causative factor; once recognised, removal of the offending agent (fenatnyl) resulted in complete improvement in his symptoms within 72 h.