Nocturnal ventilation can serve as a bridge to lung transplantation for cystic fibrosis patients.

Respiratory disease is the leading cause of morbidity and mortality in patients with cystic fibrosis (CF). Advances in antimicrobial therapy and attention to chest physiotherapy, exercise, and nutrition have increased mean survival beyond 20 years of age over the past 3 decades.

Many patients with CF may now reasonably expect to live beyond 30 years. Nevertheless, almost all who have CF will experience distressing dyspnea and disability, followed by death from respiratory failure (unless they are fortunate enough to receive lung transplants). In the course of relentless respiratory failure, patients with CF may experience fatigue, impaired sleep quality, morning headaches, and malnourishment. Malnourishment is common and is, in part, secondary to the increased caloric expenditure necessary to maintain adequate ventilation.

For CF patients, invasive mechanical ventilation is associated with a poor prognosis,1 and it constitutes a relative contraindication for lung transplantation. Noninvasive ventilation, however, may represent a reasonable alternative for the treatment of chronic respiratory failure.

CF Characteristics

CF is an autosomal recessive condition characterized by abnormalities of exocrine and endocrine function that result in hepatic, pancreatic, gastrointestinal, sinus, and pulmonary disease. The estimated prevalence of CF in North America ranges from
1 in 1,000 to 1 in 4,000. The diagnosis is suspected when there is typical organ involvement and is confirmed by an elevated chloride level in perspiration. Recent advances in the identification of the CF transmembrane conductance regulator gene have led to diagnosis through genetic analysis.

Pulmonary disease is often the most prominent feature of CF, and it is usually manifest by the age of 9 years. It is present in almost all patients by the age of 20. Pulmonary involvement is responsible for the majority of morbidity and mortality in adolescents and adult CF patients. It accounts for 75 percent of their hospital admissions, which are usually due to infectious exacerbations. Progressive dyspnea and exercise intolerance occur later, as the degree of airway obstruction increases or hypoxemia develops. Hemoptysis, allergic bronchopulmonary aspergillosis, and pneumothorax are complications that can contribute significantly to pulmonary morbidity and mortality.

Medical treatment for lung involvement in CF (although not for pneumothorax) involves chest physiotherapy and the use of inhaled bronchodilators. Other therapies include antibiotics (inhaled, oral, and intravenous), steroids, and recombinant human DNAse. Attention to nutrition, pancreatic enzyme replacement, and occasional supplemental enteral feeding are also important treatment strategies.

Invasive ventilatory strategies are only useful when a readily reversible event occurs in the presence of sufficient pulmonary reserve. Davis and diSant¬°Agnese1 reported outcomes for 51 episodes of mechanical ventilation or acute respiratory failure in 46 patients with CF. In 48 episodes, the patient had a background of the progressive decline seen in severe chronic obstructive pulmonary disease (COPD). Approximately 70 percent of patients died while receiving mechanical ventilation. Only 20 percent left the hospital; 18 percent died within 6 weeks following discharge and 6 percent survived for more than 1 year. Hypercapnia was found to be associated with a poor prognosis.

The most effective treatment for end-stage CF lung disease at this time is lung transplantation. CF now constitutes the most common indication for double lung transplantation, with approximately 950 procedures performed to date worldwide according to the 1998 Registry of the International Society for Heart and Lung Transplantation.2 Unfortunately, too many patients die while waiting for lung transplants because of organ shortages. Hence, a treatment designed to serve as a bridge to transplantation would be welcome.

Noninvasive Support In Other Diseases

Intermittent nocturnal noninvasive positive pressure ventilation (NPPV) in patients with restrictive lung disorders has led to significant improvements in daytime respiratory gas exchange and a reduction in symptoms attributed to hypoventilation. Benefits have occurred following the application of positive pressure to the mouth and/or nose via mask in patients with COPD or kyphoscoliosis,3-6 neuromuscular weakness, and obesity hypoventilation syndrome. This has been accomplished using modified volume-cycled or pressure-cycled systems. The nocturnal application of such devices has been preferred for long-term use in chronic respiratory failure.

The utility of NPPV has also been studied7-9 in the setting of acute respiratory failure. In patients with COPD who were experiencing acute deterioration in airflow along with alveolar hypoventilation (increasing Paco2), both volume-cycled and pressure-cycled ventilation through a face mask allowed patients to avoid endotracheal intubation with conventional mechanical ventilation and its attendant complications. Significant improvements in Paco2, Pao2, and arterial pH were noted.

The use of a bilevel device provides significant advantages. Bilevel units are truly portable, easy to use, and relatively inexpensive; bilevel support is generally well tolerated without significant adverse effects. Initial assessment10 in other patient populations with chronic respiratory failure demonstrates that bilevel support is capable of augmenting ventilation, decreasing respiratory efforts, and reducing hypercapnia.

Potential Benefits Of NPPV In CF

If information for NPPV use in other lung diseases applies to CF, nocturnal NPPV should reduce the work of breathing and improve the hypercapnia and hypoxemia that commonly worsen during sleep in individuals with chronic respiratory failure. Patients with advanced CF lung disease experience a disturbed quality of sleep characterized by increased arousals, decreased sleep time, and proportionately less rapid-eye-movement (REM) sleep.11 Minute ventilation and tidal volume (Vt) are decreased, which may be associated with increasing hypercapnia.12 Arterial oxygen desaturation is more pronounced during REM sleep, presumably because of a decrease in expiratory reserve volume that produces lung regions with diminished ratios of ventilation to perfusion.11-13 Supplemental oxygen, blended at the inspiratory limb of the circuit, is capable of improving arterial desaturation, but it does not affect sleep quality.11 Furthermore, nocturnal oxygen use in CF may lead to worsening hypercapnia.14

A therapeutic modality that improves the quality of sleep might lead to more comfortable daytime functioning. It is possible that lessening respiratory muscle work could lead to improved exercise performance and reduced caloric expenditure. While this effect is hypothetical, decreased caloric requirements due to the assistance provided to the respiratory muscles at night could translate into improved nutritional status. Poor nutritional status has been associated with higher mortality.15 Improvements in respiratory muscle function during the day as a result of nocturnal NPPV may result in more effective coughing and clearing of secretions. As a result of these potential improvements, quality and quantity of life could be enhanced.

Nocturnal NPPV In CF

Perhaps the earliest report of noninvasive mechanical ventilation for progressive chronic respiratory failure in CF was published by Hodson et al16 in 1991. A flow-generated, time-cycled ventilator delivering a preset Vt via nasal mask was prescribed. The Vt was delivered either in response to the initiation of a spontaneous breath or automatically. Four of six patients with progressive respiratory failure survived for 3 to 17 days until a suitable organ became available for transplantation.

Regnis et al17 applied nasal continuous positive airway pressure (CPAP) nocturnally to patients with CF and noted improvements in oxygenation, but no changes in sleep architecture or transcutaneous carbon dioxide levels. Gozal18 examined sleep architecture and nocturnal gas exchange in six patients with CF and severe lung disease. Nocturnal NPPV (with a mean expiratory pressure of 16 cm H2O and a mean inspiratory pressure of 5 cm H2O) and supplemental oxygen at an average flow rate of 2 L/min alone significantly improved night-time oxygen saturation, but did not change sleep architecture. Oxygen therapy, however, was associated with increases in transcutaneous carbon dioxide levels, while the opposite was true for nocturnal NPPV. The author concluded that nocturnal NPPV should be considered a viable, feasible form of therapy for chronic respiratory failure in CF.

Granton and Kesten19 studied eight patients with end-stage lung disease due to CF (mean forced expiratory volume in one second: 24 percent of the predicted value) and evidence of chronic respiratory failure with either hypoxemia or hypercapnia. All patients had lung disease so severe that they were awaiting lung transplantation. NPPV via nasal mask was applied acutely over a 20-minute period at inspiratory pressures of 10 to 12 cm H2O and expiratory pressures of 4 to 6 cm H2O, as tolerated. NPPV resulted in minor improvements in oxygenation and hypercapnia, and Vt increased while respiratory rate decreased. Overall, minute ventilation decreased from 5.3 to 4.6 L/min. Decreased minute ventilation, along with the improvements seen in gas exchange, suggested that there was either a reduction in carbon dioxide production or, more likely, an increase in alveolar ventilation. In two patients, esophageal pressure measurements were recorded. In both cases, there was a significant decrease in esophageal pressure, compatible with decreased respiratory muscle activity and a reduction in work of breathing.

In a follow-up study,20 nocturnal NPPV was administered for 2 months to 13 patients with end-stage CF lung disease and chronic respiratory failure. A washout period of 1 month followed the 2-month trial. Of the 13 subjects, one underwent transplantation surgery during the trial, one refused to discontinue nocturnal NPPV after 2 months, one could not tolerate NPPV, one developed hemoptysis, and another refused full participation. The remaining eight patients tolerated the application of NPPV, and all requested further therapy with NPPV after the 1-month washout period was discontinued. All nine patients who tolerated NPPV survived until they underwent transplantation procedures.20 The study documented that a large proportion of patients with advanced lung disease and CF can tolerate nasal CPAP and can gain subjective benefits.

Initiating Nocturnal NPPV

Several recommendations can be based on experience with nocturnal NPPV in patients with advanced lung disease from CF. There are no controlled studies describing the optimal way of initiating NPPV in patients with CF. These suggestions apply to patients who are not in acute respiratory failure (Table 1).

It is best to initiate NPPV when the patient is otherwise stable. Bronchodilator therapy should be optimized. The patient should be receiving maximal medical management. The nasal mask should be comfortable and should have been fitted appropriately. The recent introduction of gel and other sealing masks provides additional tools to increase comfort. Humidifier attachments are also available from manufacturers to increase comfort. Reassurance and instruction from an experienced health care professional will be likely to enhance compliance. The selection of the initial pressures is somewhat arbitrary, but pressure levels are essentially titrated to patient comfort. I have found that patients are generally most comfortable with an initial inspiratory pressure of 10 cm H2O and an expiratory pressure of 4 cm H2O. These pressures may be below therapeutic levels, and should be gradually increased over time. Initial trials, held during the day for 30 to 60 minutes, may be useful before introducing a nocturnal study. It is important that the patient not become frustrated and not acquire a negative opinion of the device. To that end, I have instructed patients to use the mask as tolerated for the first few nights. This may represent simply 30 to 60 minutes of treatment while the patient is resting in bed. As the comfort level increases, the patient will become acclimated to the mask and the pressure; he or she will eventually fall asleep, and sleep through the night, wearing the mask. In my experience, the majority of subjects are able to tolerate the device for many hours during the first night.

Pressures can gradually be increased over a period of days or weeks. An expiratory pressure of 4 to 5 cm H2O and an inspiratory pressure of 12 to 16 cm H2O are reasonable targets. Overnight oximetry and transcutaneous or end-tidal carbon dioxide levels (as well as morning arterial blood gas tensions) can be used to document objective improvements. If treatment is successful, the patient will report improved sleep quality, along with the elimination of morning headaches and fatigue (if previously present). Anecdotally, several patients have commented on decreased frequency and severity of cough after the initiation of nocturnal NPPV, for reasons that are unclear.

A potential problem in applying NPPV to patients with CF is the chronic sinusitis that is nearly universal in such patients. In the presence of chronic sinusitis, it is intuitive that positive pressure delivery through the nose would be uncomfortable, or that insufficient pressure would be transmitted to the lower airways. NPPV, however, appears to be well tolerated in a number of cases, according to published clinical investigations.16-19 Nevertheless, there are patients who may experience difficulty due to upper-airway disorders.

Treatments that may improve tolerance include intranasal decongestants, intranasal steroids, or even oral steroids. The role of surgical intervention (such as sinus drainage) is unknown. If the nasal mask cannot be reasonably applied because of sinus difficulties, one could then prescribe a face mask.


CF is the most common cause of chronic respiratory failure among young people. In patients with chronic respiratory failure, nocturnal NPPV can improve oxygenation and ventilation while decreasing the load on the inspiratory muscles. Potential benefits in patients with CF include a reduction in work of breathing, improved sleep quality, and improved nutrition.

Case series16,19 suggest that NPPV has the potential to decrease symptoms and serve as a bridge to lung transplantation. Such ventilatory assistance is generally well tolerated in a cooperative patient. Further studies will define whether the introduction of nocturnal NPPV will lead to improvements in lifespan.

Steven Kesten, MD, FRCPC, FCCP, is Medical Director, Advanced Lung Disease and Lung Transplant Program, at Rush-Presbyterian-St Luke’s Medical Center, in Chicago.


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