Basma Ricaurte, MD

Noninvasive positive pressure ventilation (NIPPV) is any form of positive ventilatory support applied without an endotracheal tube, including continuous positive airway pressure (CPAP).¹ The role of NIPPV in acute care has been discussed in an earlier review in the Cleveland Clinic Journal of Medicine.²

NIPPV is also used at night in outpatients with stable chronic conditions, first used in the 1980s in the treatment of obstructive sleep apnea³ and neuromuscular diseases,⁴ and since then in several other conditions including sleep disorders associated with congestive heart failure (including sleep apnea and the Cheyne-Stokes respiration-central sleep apnea syndrome), chronic obstructive pulmonary disease (COPD), and the obesity-hypoventilation syndrome.

In this review, we discuss the different types of NIPPV, the specific conditions in which they can be used, and the indications, recommendations, and evidence supporting the efficacy of NIPPV in outpatients.

THE TYPES OF NIPPV AND THEIR USES

Although the conditions for which different types of NIPPV can be used overlap significantly, each type has general indications and different goals of treatment. This section begins with types of NIPPV that are predominantly used to treat sleep-disordered breathing, and then proceeds to those predominantly used for conditions associated with hypoventilation and hypercapnia.

Continuous positive airway pressure

CPAP, currently the most widely used form of NIPPV, applies a constant level of positive pressure at the airway opening during spontaneous breathing.

CPAP is commonly used to treat obstructive sleep-disordered breathing, with the goals of improving daytime sleepiness and reducing cardiovascular risk. It has also been used to treat sleep-disordered breathing associated with congestive heart failure.

CPAP’s role in the support of ventilation is limited and indirect. For instance, it has been used in the obesity-hypoventilation syndrome and in the “overlap” syndrome (in which both sleep apnea and COPD coexist). However, its benefits in those conditions are probably derived in large part from correction of underlying obstructive sleep apnea.

The mechanisms of action of CPAP include:

• Preventing intermittent narrowing and collapse of the airway in patients with obstructive sleep apnea-hypopnea syndrome by acting as a pneumatic splint during sleep^3,5,6
• Counteracting auto-positive end-expiratory pressure, thereby reducing respiratory muscle load, reducing the work of breathing, and lowering daytime Paco₂ in patients with coexistent COPD and obstructive sleep apnea-hypopnea syndrome (the overlap syndrome)^7–9
• Improving lung function (particularly the functional residual capacity) and daytime gas exchange in obstructive sleep apnea-hypopnea syndrome ¹⁰
• Improving left ventricular systolic function in patients with heart failure coexisting with obstructive sleep apnea-hypopnea syndrome.^11,12

Auto-CPAP is delivered via a self-titrating CPAP device, which uses algorithms to detect variations in the degree of obstruction and consequently adjusts the pressure level to restore normal breathing. Auto-CPAP therefore compensates for factors that modify the upper airway collapsibility, such as body posture during sleep, stage of sleep, use of alcohol, and drugs that affect upper airway muscle tone.¹³

Although one of the premises of using auto-CPAP is that it improves the patient’s satisfaction and compliance, several studies found it to be no more effective than fixed CPAP for treating obstructive sleep apnea-hypopnea syndrome.^14–16 Current guidelines of the American Academy of Sleep Medicine do not recommend self-titrating CPAP devices to diagnose obstructive sleep apnea or to treat patients with cardiopulmonary disorders or other conditions in which nocturnal desaturation may be unrelated to obstructive events.¹⁷

Adaptive servo-ventilation

Adaptive servo-ventilation was developed for Cheyne-Stokes respiration-central sleep apnea syndrome in patients with congestive heart failure, who may have periods of crescendo-decrescendo change in tidal volume (Cheyne-Stokes respiration) with possible intercalated episodes of central apnea or hypopnea. It is also applied in patients with the complex sleep apnea syndrome.

Adaptive servo-ventilation devices are usually set at an expiratory positive airway pressure (EPAP) level sufficient to control obstructive sleep apnea. The device then automatically adjusts the pressure support for each inspiration, within a prespecified range, to maintain a moving-target ventilation set at 90% of the patient’s recent average ventilation. The aim is to stabilize breathing and reduce respiratory alkalosis, which can trigger apnea reentry cycles.¹⁸

Bilevel positive airway pressure

Bilevel positive airway pressure (bilevel PAP) can be of use in sleep-disordered breathing (including cases associated with congestive heart failure), but it is predominantly applied in conditions associated with hypoventilation.

Bilevel PAP devices deliver a higher pressure during inspiration (inspiratory positive airway pressure, or IPAP) and a lower pressure during expiration (EPAP). The gradient between IPAP and EPAP is of key importance in maintaining alveolar ventilation and reducing Paco₂. The IPAP acts as pressure support to augment the patient’s effort, maintain adequate alveolar ventilation, unload respiratory muscles, decrease the work of breathing, and control obstructive hypopnea, whereas EPAP is set to maintain upper airway patency, control obstructive apnea, improve functional residual capacity, and prevent microatelectasis.

Although there is no evidence that bilevel PAP is better adhered to or more effective than CPAP, current guidelines propose it as an option for patients who require high pressures to control obstructive sleep apnea-hypopnea syndrome or for those who cannot tolerate exhaling against a high fixed CPAP pressure.¹⁹

Other, more-common uses of bilevel PAP are to treat coexisting central sleep apnea or hypoventilation,¹⁹ the obesity-hypoventilation syndrome with residual alveolar hypoventilation despite CPAP and control of concomitant obstructive sleep apnea-hypopnea syndrome,^5,20 severe stable COPD with significant nocturnal hypoventilation and daytime hypercarbia,²¹ and restrictive pulmonary diseases.²¹

Although the patient should be able to maintain spontaneous breathing on bilevel PAP, a backup rate option can be set for those whose ventilation during sleep may be significantly impaired (eg, those with neuromuscular diseases, complex sleep apnea, central apnea in congestive heart failure, or obesity-hypoventilation syndrome) (Table 1, Table 2).^22,23 However, one important paradoxical consideration is that both CPAP and bilevel PAP (with or without a backup rate) promote ventilation and have the potential of dropping the carbon dioxide level below a hypocapnic apneic threshold during sleep, thereby triggering central apnea and the complex sleep apnea syndrome.²⁴

Average volume-assured pressure support

Average volume-assured pressure support is directed mainly at patients with chronic hypoventilation such as those with obesity-hypoventilation syndrome, neuromuscular diseases, and COPD. In this mode, a target tidal volume is set, and the device adjusts the pressure support to reach that set tidal volume. The advantage is that it guarantees a delivered tidal volume despite variability in patient effort, airway resistance, and lung or chest wall compliance. A particular potential benefit is that it may adapt to disease progression, as may occur in patients with progressive neuromuscular disorders.

 

CONDITIONS IN WHICH NOCTURNAL NIPPV IS USED IN OUT PATIENTS

Obstructive sleep apnea-hypopnea syndrome

Obstructive sleep apnea-hypopnea syndrome is estimated to affect 2% of women and 4% of men.²⁵ It is characterized by recurrent episodes of partial (hypopnea) or complete (apnea) upper airway obstruction during sleep despite ongoing inspiratory efforts, with associated episodes of arousal or desaturation or both. Corresponding symptoms include excessive daytime sleepiness, choking and gasping during sleep, recurrent awakenings from sleep, unrefreshing sleep, daytime fatigue, and impaired concentration that is not explained by other factors.²⁶

Current understanding of the pathophysiology of obstructive sleep apnea implicates an impairment in the balance between factors that promote collapsibility of the airway (including obesity and anatomic issues such as the volume of the soft-tissue structures surrounding the upper airway) and the compensatory neuromuscular response.^27,28

Long-standing obstructive sleep apnea-hypopnea syndrome has been linked in prospective studies to the development of hypertension,^29–31 coronary artery disease,^32,33 increased coagulation,^34,35 and stroke or death from any cause.^36,37 It is also associated with a greater rate and severity of motor vehicular accidents,³⁸ greater health care utilization, impaired work performance, and occupational injuries.³⁹

Strong evidence exists that NIPPV (most commonly CPAP) is beneficial in obstructive sleep apnea-hypopnea syndrome, improving sleep quality, sleepiness, cognitive impairment, and quality of life,^40,41 decreasing motor vehicle accidents,⁴² lowering blood pressure, ^43,44 and decreasing the rates of myocardial infarction,³² stroke,³² and death.⁴⁵

The American Academy of Sleep Medicine recommends CPAP as an optional adjunctive therapy to lower blood pressure in patients with obstructive sleep apnea-hypopnea syndrome with concomitant hypertension.¹⁹ This is supported by a recent study that suggested that CPAP may have additional benefits on blood pressure in a subgroup of patients with uncontrolled hypertension while on antihypertensive medications.⁴⁶ Indications with Medicare guidelines for reimbursement of CPAP devices are summarized in Table 2.

Complex sleep apnea syndrome

The complex sleep apnea syndrome is characterized by the emergence of significant central sleep apnea or Cheyne-Stokes respiration after obstructive events have been brought under control with NIPPV in patients who initially appear to have obstructive sleep apnea-hypopnea syndrome. A retrospective study of patients with the complex sleep apnea syndrome who continued their NIPPV use until a subsequent polysomnographic study and NIPPV titration showed that the syndrome may resolve spontaneously, but that 46% of patients had a persistently elevated apnea-hypopnea index with central apnea activity.⁴⁷

Restoration of upper airway patency by CPAP and dysregulation or delayed adaptation of chemosensitive ventilatory control to a changing Paco₂ level may be a key pathophysiologic mechanism of the complex sleep apnea syndrome.⁴⁸ In this mechanism, increased ventilation from restored airway patency and from an increase in the slope of the ventilatory response may intermittently draw the Paco₂ to below the hypocapnic apneic threshold and trigger episodes of central apnea.⁴⁸

The ideal NIPPV device for use in the complex sleep apnea syndrome should be able to provide enough pressure to resolve the obstructive sleep apnea-hypopnea syndrome while maintaining proper ventilatory support during central apnea episodes without fluctuations of Paco₂, which could further worsen the dysregulated ventilatory control. Currently, adaptive servo-ventilation appears to be superior to bilevel PAP and CPAP in the management of the complex sleep apnea syndrome.^49,50

Sleep disturbances associated with cardiac dysfunction

There are specific indications for NIPPV modes in the setting of respiratory sleep disturbances associated with heart failure.

Obstructive sleep apnea in congestive heart failure. The prevalence of obstructive sleep apnea in patients with impaired left ventricular ejection fraction is 11% to 53%.⁵¹ Obstructive sleep apnea-hypopnea syndrome can worsen congestive heart failure by causing a periodic increase in negative intrathoracic pressure from breathing against an occluded airway, by raising arterial blood pressure, and causing tachycardia from sympathetic nervous system stimulation from hypoxia, hypercarbia, and arousals.^52,53 Both heart failure and sleep apnea contribute in an additive manner to the increased sympathetic nervous activity.⁵⁴

Fortunately, treatment with CPAP has been found to reduce systolic blood pressure and improve left ventricular systolic function in medically treated patients with heart failure and coexisting obstructive sleep apnea.^11,12 Furthermore, in a randomized trial in patients with stable congestive heart failure and newly diagnosed obstructive sleep apnea-hypopnea syndrome, a greater improvement in cardiac function was observed in patients on bilevel PAP than in those on CPAP.⁵⁵ The authors speculated that bilevel PAP might provide more unloading of the respiratory muscles, reduce the work of breathing more, and result in less positive intrathoracic pressure than with CPAP, and that the higher intrathoracic pressure with CPAP could reduce the left ventricular ejection fraction in patients with low filling pressures (pulmonary capillary wedge pressure < 12 mm Hg) and low baseline left ventricular ejection fractions (< 30%).⁵⁵

Whether these interventions reduce the mortality rate is uncertain. In a prospective nonrandomized study, 9 (24%) of 37 patients who had heart failure with untreated obstructive sleep apnea died, compared with no deaths in 14 treated patients (P = .07).⁵⁶

Cheyne-Stokes respiration with central sleep apnea in congestive heart failure. A related but different situation is central apnea associated with congestive heart failure.

There are several pathophysiologic mechanisms of Cheyne-Stokes respiration with central sleep apnea. Specifically, the elevation of left ventricular filling pressures, end-diastolic volumes, and pulmonary congestion generate hyperventilation, chronic hypocapnia, and increased chemoreceptor responsiveness, which contribute to the development of central apnea by promoting a decrease in the Paco₂ during sleep to below the hypocapnic apneic threshold.^57,58 Additionally, an increase in circulation time may result in periodicity of breathing and hyperpnea.⁵⁹ Obstructive events can then occur at the end of the central events corresponding with the nadir of the inspiratory drive.^60,61

The Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure (CANPAP) trial, a randomized trial of CPAP in this clinical setting, showed that compared with optimal medical therapy alone, CPAP plus optimal medical therapy improved the ejection fraction, reduced central sleep apnea, improved nocturnal oxygenation, and improved the 6-minute walking distance, but without a survival benefit.⁶² The disappointing survival results from CANPAP have to be interpreted in the context that CPAP may have failed to control the central apnea in some patients, such that the mean apnea-hypopnea index in treated patients (19 events/hour) remained above the entry criterion for recruitment (15 events/hour). In a post hoc analysis of this study, the heart-transplantation-free survival rate was significantly greater in the subgroup of patients in whom CPAP effectively suppressed central sleep apnea (< 15 events/hour).⁶³

Other NIPPV modes such as bilevel PAP with backup rate and adaptive servo-ventilation have been shown in some studies to be superior to CPAP in controlling respiratory events, with adaptive servo-ventilation being the most effective in controlling central, mixed, and complex sleep apnea in this setting. ^49,50 Whether more effective resolution of obstructive and central events with these treatment modes translates into improved mortality rates and transplantation-free survival rates remains to be determined.

 

 

Obesity-hypoventilation syndrome

Obesity-hypoventilation syndrome refers to daytime hypercapnia (Paco₂ > 45 mm Hg) in obese people when no other cause of hypoventilation is present.

The prevalence of obesity-hypoventilation syndrome among patients with obstructive sleep apnea-hypopnea syndrome is 20% to 30% and is greater in extremely obese patients (body mass index > 40 kg/m²).⁶⁴ However, about 10% of patients with obesity-hypoventilation syndrome do not have obstructive sleep apnea-hypopnea syndrome.⁶⁴ Additionally, nocturnal hypoxemia and diurnal hypercapnia persist in about 40% of patients with obesity-hypoventilation syndrome after CPAP eliminates their sleep apnea.⁶⁵ Therefore, factors other than sleep apnea contribute to the development of obesity-hypoventilation syndrome, and in a meta-analysis, factors associated with daytime hypercapnia included, in addition to body mass index and the apnea-hypopnea index, mean overnight oxygen saturation and severity of restrictive pulmonary function.⁶⁶ Predictors of success with CPAP include better spirometric findings, a higher apnea-hypopnea index, and adequate oxygenation.^67,68

Bilevel PAP therapy can be tried in patients in whom CPAP by itself fails. In a study of patients with obesity-hypoventilation syndrome in whom initial CPAP treatment failed, average volume-assured pressure support lowered Paco₂ compared to bilevel PAP alone, but did not further improve oxygenation, sleep quality, or quality of life.⁶⁹

Restrictive pulmonary diseases

Neuromuscular diseases and thoracic cage abnormalities. Noninvasive ventilation has been used in patients with progressive neuromuscular disorders or severe thoracic cage abnormalities, with recognized benefits including an improved survival rate and improved quality of life.^70,71 However, NIPPV is used in only 9% of patients with amyotrophic lateral sclerosis when clearly indicated.⁷² The indications and Medicare guidelines for reimbursement of NIPPV (with or without a backup rate) in this setting are shown in Table 2.

Potential contraindications to starting NIPPV in this population include upper airway obstruction, failure to clear secretions despite optimal noninvasive support, inability to achieve a mask fit, and intolerance of the intervention.^73,74

The mechanisms of benefit of NIPPV in these settings include improvements in daytime blood gas levels (including hypercapnia⁷⁵), a reduction in the oxygen cost of breathing,⁷⁶ an increase in the ventilatory response to carbon dioxide,⁷⁵ and improved lung compliance.⁷⁷

Chronic hypercapnic failure due to severe COPD

The use of NIPPV in chronic COPD is less well established than in patients with exacerbations of COPD,⁷⁸ and limitations in its use are reflected in the more stringent Medicare indications for NIPPV in this setting (Table 2).

A particular subset of patients with stable COPD who may benefit from NIPPV includes those with daytime hypercapnia and super-imposed nocturnal hypoventilation.⁷⁸ The potential benefits of NIPPV in these patients include improved daytime and nocturnal gas exchange, increased sleep duration, and improved quality of life.⁷⁸ Additionally, a recent randomized controlled trial of NIPPV plus long-term oxygen therapy compared with oxygen therapy alone in patients with severe COPD and a Paco₂ greater than 46 mm Hg demonstrated a survival benefit in favor of adding NIPPV (hazard ratio 0.6).⁷⁹

However, that study also found no reduction in hospitalization rates, an apparent worsening in general and mental health (as reflected on the 36-Item Short Form Health Survey or SF-36, a quality-of-life questionnaire), as well as increased confusion and bewilderment (reflected on the Profile of Mood States scale).⁷⁹ These potentially deleterious effects may explain why adherence to NIPPV is low in patients with stable COPD: only 37% to 57% of patients continued to use it in several reported studies.^79–81

A level of inspiratory pressure support that is insufficient to reduce hypercapnia may account for the low adherence rate and worsened quality of life in such patients. For instance, in a randomized trial,⁸² compared with low-intensity NIPPV (mean IPAP 14 cm H₂O, backup rate 8 per minute), settings that aimed to maximally reduce Paco₂ (mean IPAP 29 cm H₂O with a backup rate of 17.5 per minute) increased the daily use of NIPPV by 3.6 hours/day and improved exercise-related dyspnea, daytime Paco₂, forced expiratory volume in 1 second (FEV₁), vital capacity, and health-related quality of life.

The overlap syndrome was first described by Flenley in 1985 as a combination of chronic respiratory disease (more generally limited to COPD) and obstructive sleep apnea-hypopnea syndrome.⁸³ Epidemiologic studies do not consistently show a higher incidence of obstructive sleep apnea-hypopnea syndrome in patients with COPD, but the exaggerated oxygen desaturation during sleep in patients with this combination increases the risk of hypoxemia, hypercapnia, and pulmonary hypertension. ⁸⁴ In addition, there was evidence of higher risks of death and of hospitalization for COPD in patients with the overlap syndrome. ⁸⁵ NIPPV is the main treatment for obstructive sleep apnea-hypopnea syndrome with or without COPD.

A recent study by Marin et al⁸⁵ showed that CPAP was associated with improved survival and decreased hospitalization in patients with the overlap syndrome. However, polysomnography or nocturnal oximetry while on NIPPV alone must be done, as additional nocturnal oxygen therapy may be warranted when significant chronic respiratory illness coexists with sleep apnea.
 

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Acknowledgment: The authors gratefully acknowledge the contribution of Scott Marlow, RRT, to Table 2 of this review.

Noninvasive positive pressure ventilation (NIPPV) is any form of positive ventilatory support applied without an endotracheal tube, including continuous positive airway pressure (CPAP).¹ The role of NIPPV in acute care has been discussed in an earlier review in the Cleveland Clinic Journal of Medicine.²

NIPPV is also used at night in outpatients with stable chronic conditions, first used in the 1980s in the treatment of obstructive sleep apnea³ and neuromuscular diseases,⁴ and since then in several other conditions including sleep disorders associated with congestive heart failure (including sleep apnea and the Cheyne-Stokes respiration-central sleep apnea syndrome), chronic obstructive pulmonary disease (COPD), and the obesity-hypoventilation syndrome.

In this review, we discuss the different types of NIPPV, the specific conditions in which they can be used, and the indications, recommendations, and evidence supporting the efficacy of NIPPV in outpatients.

THE TYPES OF NIPPV AND THEIR USES

Although the conditions for which different types of NIPPV can be used overlap significantly, each type has general indications and different goals of treatment. This section begins with types of NIPPV that are predominantly used to treat sleep-disordered breathing, and then proceeds to those predominantly used for conditions associated with hypoventilation and hypercapnia.

Continuous positive airway pressure

CPAP, currently the most widely used form of NIPPV, applies a constant level of positive pressure at the airway opening during spontaneous breathing.

CPAP is commonly used to treat obstructive sleep-disordered breathing, with the goals of improving daytime sleepiness and reducing cardiovascular risk. It has also been used to treat sleep-disordered breathing associated with congestive heart failure.

CPAP’s role in the support of ventilation is limited and indirect. For instance, it has been used in the obesity-hypoventilation syndrome and in the “overlap” syndrome (in which both sleep apnea and COPD coexist). However, its benefits in those conditions are probably derived in large part from correction of underlying obstructive sleep apnea.

The mechanisms of action of CPAP include:

• Preventing intermittent narrowing and collapse of the airway in patients with obstructive sleep apnea-hypopnea syndrome by acting as a pneumatic splint during sleep^3,5,6
• Counteracting auto-positive end-expiratory pressure, thereby reducing respiratory muscle load, reducing the work of breathing, and lowering daytime Paco₂ in patients with coexistent COPD and obstructive sleep apnea-hypopnea syndrome (the overlap syndrome)^7–9
• Improving lung function (particularly the functional residual capacity) and daytime gas exchange in obstructive sleep apnea-hypopnea syndrome ¹⁰
• Improving left ventricular systolic function in patients with heart failure coexisting with obstructive sleep apnea-hypopnea syndrome.^11,12

Auto-CPAP is delivered via a self-titrating CPAP device, which uses algorithms to detect variations in the degree of obstruction and consequently adjusts the pressure level to restore normal breathing. Auto-CPAP therefore compensates for factors that modify the upper airway collapsibility, such as body posture during sleep, stage of sleep, use of alcohol, and drugs that affect upper airway muscle tone.¹³

Although one of the premises of using auto-CPAP is that it improves the patient’s satisfaction and compliance, several studies found it to be no more effective than fixed CPAP for treating obstructive sleep apnea-hypopnea syndrome.^14–16 Current guidelines of the American Academy of Sleep Medicine do not recommend self-titrating CPAP devices to diagnose obstructive sleep apnea or to treat patients with cardiopulmonary disorders or other conditions in which nocturnal desaturation may be unrelated to obstructive events.¹⁷

Adaptive servo-ventilation

Adaptive servo-ventilation was developed for Cheyne-Stokes respiration-central sleep apnea syndrome in patients with congestive heart failure, who may have periods of crescendo-decrescendo change in tidal volume (Cheyne-Stokes respiration) with possible intercalated episodes of central apnea or hypopnea. It is also applied in patients with the complex sleep apnea syndrome.

Adaptive servo-ventilation devices are usually set at an expiratory positive airway pressure (EPAP) level sufficient to control obstructive sleep apnea. The device then automatically adjusts the pressure support for each inspiration, within a prespecified range, to maintain a moving-target ventilation set at 90% of the patient’s recent average ventilation. The aim is to stabilize breathing and reduce respiratory alkalosis, which can trigger apnea reentry cycles.¹⁸

Bilevel positive airway pressure

Bilevel positive airway pressure (bilevel PAP) can be of use in sleep-disordered breathing (including cases associated with congestive heart failure), but it is predominantly applied in conditions associated with hypoventilation.

Bilevel PAP devices deliver a higher pressure during inspiration (inspiratory positive airway pressure, or IPAP) and a lower pressure during expiration (EPAP). The gradient between IPAP and EPAP is of key importance in maintaining alveolar ventilation and reducing Paco₂. The IPAP acts as pressure support to augment the patient’s effort, maintain adequate alveolar ventilation, unload respiratory muscles, decrease the work of breathing, and control obstructive hypopnea, whereas EPAP is set to maintain upper airway patency, control obstructive apnea, improve functional residual capacity, and prevent microatelectasis.

Although there is no evidence that bilevel PAP is better adhered to or more effective than CPAP, current guidelines propose it as an option for patients who require high pressures to control obstructive sleep apnea-hypopnea syndrome or for those who cannot tolerate exhaling against a high fixed CPAP pressure.¹⁹

Other, more-common uses of bilevel PAP are to treat coexisting central sleep apnea or hypoventilation,¹⁹ the obesity-hypoventilation syndrome with residual alveolar hypoventilation despite CPAP and control of concomitant obstructive sleep apnea-hypopnea syndrome,^5,20 severe stable COPD with significant nocturnal hypoventilation and daytime hypercarbia,²¹ and restrictive pulmonary diseases.²¹

Although the patient should be able to maintain spontaneous breathing on bilevel PAP, a backup rate option can be set for those whose ventilation during sleep may be significantly impaired (eg, those with neuromuscular diseases, complex sleep apnea, central apnea in congestive heart failure, or obesity-hypoventilation syndrome) (Table 1, Table 2).^22,23 However, one important paradoxical consideration is that both CPAP and bilevel PAP (with or without a backup rate) promote ventilation and have the potential of dropping the carbon dioxide level below a hypocapnic apneic threshold during sleep, thereby triggering central apnea and the complex sleep apnea syndrome.²⁴

Average volume-assured pressure support

Average volume-assured pressure support is directed mainly at patients with chronic hypoventilation such as those with obesity-hypoventilation syndrome, neuromuscular diseases, and COPD. In this mode, a target tidal volume is set, and the device adjusts the pressure support to reach that set tidal volume. The advantage is that it guarantees a delivered tidal volume despite variability in patient effort, airway resistance, and lung or chest wall compliance. A particular potential benefit is that it may adapt to disease progression, as may occur in patients with progressive neuromuscular disorders.

 

CONDITIONS IN WHICH NOCTURNAL NIPPV IS USED IN OUT PATIENTS

Obstructive sleep apnea-hypopnea syndrome

Obstructive sleep apnea-hypopnea syndrome is estimated to affect 2% of women and 4% of men.²⁵ It is characterized by recurrent episodes of partial (hypopnea) or complete (apnea) upper airway obstruction during sleep despite ongoing inspiratory efforts, with associated episodes of arousal or desaturation or both. Corresponding symptoms include excessive daytime sleepiness, choking and gasping during sleep, recurrent awakenings from sleep, unrefreshing sleep, daytime fatigue, and impaired concentration that is not explained by other factors.²⁶

Current understanding of the pathophysiology of obstructive sleep apnea implicates an impairment in the balance between factors that promote collapsibility of the airway (including obesity and anatomic issues such as the volume of the soft-tissue structures surrounding the upper airway) and the compensatory neuromuscular response.^27,28

Long-standing obstructive sleep apnea-hypopnea syndrome has been linked in prospective studies to the development of hypertension,^29–31 coronary artery disease,^32,33 increased coagulation,^34,35 and stroke or death from any cause.^36,37 It is also associated with a greater rate and severity of motor vehicular accidents,³⁸ greater health care utilization, impaired work performance, and occupational injuries.³⁹

Strong evidence exists that NIPPV (most commonly CPAP) is beneficial in obstructive sleep apnea-hypopnea syndrome, improving sleep quality, sleepiness, cognitive impairment, and quality of life,^40,41 decreasing motor vehicle accidents,⁴² lowering blood pressure, ^43,44 and decreasing the rates of myocardial infarction,³² stroke,³² and death.⁴⁵

The American Academy of Sleep Medicine recommends CPAP as an optional adjunctive therapy to lower blood pressure in patients with obstructive sleep apnea-hypopnea syndrome with concomitant hypertension.¹⁹ This is supported by a recent study that suggested that CPAP may have additional benefits on blood pressure in a subgroup of patients with uncontrolled hypertension while on antihypertensive medications.⁴⁶ Indications with Medicare guidelines for reimbursement of CPAP devices are summarized in Table 2.

Complex sleep apnea syndrome

The complex sleep apnea syndrome is characterized by the emergence of significant central sleep apnea or Cheyne-Stokes respiration after obstructive events have been brought under control with NIPPV in patients who initially appear to have obstructive sleep apnea-hypopnea syndrome. A retrospective study of patients with the complex sleep apnea syndrome who continued their NIPPV use until a subsequent polysomnographic study and NIPPV titration showed that the syndrome may resolve spontaneously, but that 46% of patients had a persistently elevated apnea-hypopnea index with central apnea activity.⁴⁷

Restoration of upper airway patency by CPAP and dysregulation or delayed adaptation of chemosensitive ventilatory control to a changing Paco₂ level may be a key pathophysiologic mechanism of the complex sleep apnea syndrome.⁴⁸ In this mechanism, increased ventilation from restored airway patency and from an increase in the slope of the ventilatory response may intermittently draw the Paco₂ to below the hypocapnic apneic threshold and trigger episodes of central apnea.⁴⁸

The ideal NIPPV device for use in the complex sleep apnea syndrome should be able to provide enough pressure to resolve the obstructive sleep apnea-hypopnea syndrome while maintaining proper ventilatory support during central apnea episodes without fluctuations of Paco₂, which could further worsen the dysregulated ventilatory control. Currently, adaptive servo-ventilation appears to be superior to bilevel PAP and CPAP in the management of the complex sleep apnea syndrome.^49,50

Sleep disturbances associated with cardiac dysfunction

There are specific indications for NIPPV modes in the setting of respiratory sleep disturbances associated with heart failure.

Obstructive sleep apnea in congestive heart failure. The prevalence of obstructive sleep apnea in patients with impaired left ventricular ejection fraction is 11% to 53%.⁵¹ Obstructive sleep apnea-hypopnea syndrome can worsen congestive heart failure by causing a periodic increase in negative intrathoracic pressure from breathing against an occluded airway, by raising arterial blood pressure, and causing tachycardia from sympathetic nervous system stimulation from hypoxia, hypercarbia, and arousals.^52,53 Both heart failure and sleep apnea contribute in an additive manner to the increased sympathetic nervous activity.⁵⁴

Fortunately, treatment with CPAP has been found to reduce systolic blood pressure and improve left ventricular systolic function in medically treated patients with heart failure and coexisting obstructive sleep apnea.^11,12 Furthermore, in a randomized trial in patients with stable congestive heart failure and newly diagnosed obstructive sleep apnea-hypopnea syndrome, a greater improvement in cardiac function was observed in patients on bilevel PAP than in those on CPAP.⁵⁵ The authors speculated that bilevel PAP might provide more unloading of the respiratory muscles, reduce the work of breathing more, and result in less positive intrathoracic pressure than with CPAP, and that the higher intrathoracic pressure with CPAP could reduce the left ventricular ejection fraction in patients with low filling pressures (pulmonary capillary wedge pressure < 12 mm Hg) and low baseline left ventricular ejection fractions (< 30%).⁵⁵

Whether these interventions reduce the mortality rate is uncertain. In a prospective nonrandomized study, 9 (24%) of 37 patients who had heart failure with untreated obstructive sleep apnea died, compared with no deaths in 14 treated patients (P = .07).⁵⁶

Cheyne-Stokes respiration with central sleep apnea in congestive heart failure. A related but different situation is central apnea associated with congestive heart failure.

There are several pathophysiologic mechanisms of Cheyne-Stokes respiration with central sleep apnea. Specifically, the elevation of left ventricular filling pressures, end-diastolic volumes, and pulmonary congestion generate hyperventilation, chronic hypocapnia, and increased chemoreceptor responsiveness, which contribute to the development of central apnea by promoting a decrease in the Paco₂ during sleep to below the hypocapnic apneic threshold.^57,58 Additionally, an increase in circulation time may result in periodicity of breathing and hyperpnea.⁵⁹ Obstructive events can then occur at the end of the central events corresponding with the nadir of the inspiratory drive.^60,61

The Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure (CANPAP) trial, a randomized trial of CPAP in this clinical setting, showed that compared with optimal medical therapy alone, CPAP plus optimal medical therapy improved the ejection fraction, reduced central sleep apnea, improved nocturnal oxygenation, and improved the 6-minute walking distance, but without a survival benefit.⁶² The disappointing survival results from CANPAP have to be interpreted in the context that CPAP may have failed to control the central apnea in some patients, such that the mean apnea-hypopnea index in treated patients (19 events/hour) remained above the entry criterion for recruitment (15 events/hour). In a post hoc analysis of this study, the heart-transplantation-free survival rate was significantly greater in the subgroup of patients in whom CPAP effectively suppressed central sleep apnea (< 15 events/hour).⁶³

Other NIPPV modes such as bilevel PAP with backup rate and adaptive servo-ventilation have been shown in some studies to be superior to CPAP in controlling respiratory events, with adaptive servo-ventilation being the most effective in controlling central, mixed, and complex sleep apnea in this setting. ^49,50 Whether more effective resolution of obstructive and central events with these treatment modes translates into improved mortality rates and transplantation-free survival rates remains to be determined.

 

 

Obesity-hypoventilation syndrome

Obesity-hypoventilation syndrome refers to daytime hypercapnia (Paco₂ > 45 mm Hg) in obese people when no other cause of hypoventilation is present.

The prevalence of obesity-hypoventilation syndrome among patients with obstructive sleep apnea-hypopnea syndrome is 20% to 30% and is greater in extremely obese patients (body mass index > 40 kg/m²).⁶⁴ However, about 10% of patients with obesity-hypoventilation syndrome do not have obstructive sleep apnea-hypopnea syndrome.⁶⁴ Additionally, nocturnal hypoxemia and diurnal hypercapnia persist in about 40% of patients with obesity-hypoventilation syndrome after CPAP eliminates their sleep apnea.⁶⁵ Therefore, factors other than sleep apnea contribute to the development of obesity-hypoventilation syndrome, and in a meta-analysis, factors associated with daytime hypercapnia included, in addition to body mass index and the apnea-hypopnea index, mean overnight oxygen saturation and severity of restrictive pulmonary function.⁶⁶ Predictors of success with CPAP include better spirometric findings, a higher apnea-hypopnea index, and adequate oxygenation.^67,68

Bilevel PAP therapy can be tried in patients in whom CPAP by itself fails. In a study of patients with obesity-hypoventilation syndrome in whom initial CPAP treatment failed, average volume-assured pressure support lowered Paco₂ compared to bilevel PAP alone, but did not further improve oxygenation, sleep quality, or quality of life.⁶⁹

Restrictive pulmonary diseases

Neuromuscular diseases and thoracic cage abnormalities. Noninvasive ventilation has been used in patients with progressive neuromuscular disorders or severe thoracic cage abnormalities, with recognized benefits including an improved survival rate and improved quality of life.^70,71 However, NIPPV is used in only 9% of patients with amyotrophic lateral sclerosis when clearly indicated.⁷² The indications and Medicare guidelines for reimbursement of NIPPV (with or without a backup rate) in this setting are shown in Table 2.

Potential contraindications to starting NIPPV in this population include upper airway obstruction, failure to clear secretions despite optimal noninvasive support, inability to achieve a mask fit, and intolerance of the intervention.^73,74

The mechanisms of benefit of NIPPV in these settings include improvements in daytime blood gas levels (including hypercapnia⁷⁵), a reduction in the oxygen cost of breathing,⁷⁶ an increase in the ventilatory response to carbon dioxide,⁷⁵ and improved lung compliance.⁷⁷

Chronic hypercapnic failure due to severe COPD

The use of NIPPV in chronic COPD is less well established than in patients with exacerbations of COPD,⁷⁸ and limitations in its use are reflected in the more stringent Medicare indications for NIPPV in this setting (Table 2).

A particular subset of patients with stable COPD who may benefit from NIPPV includes those with daytime hypercapnia and super-imposed nocturnal hypoventilation.⁷⁸ The potential benefits of NIPPV in these patients include improved daytime and nocturnal gas exchange, increased sleep duration, and improved quality of life.⁷⁸ Additionally, a recent randomized controlled trial of NIPPV plus long-term oxygen therapy compared with oxygen therapy alone in patients with severe COPD and a Paco₂ greater than 46 mm Hg demonstrated a survival benefit in favor of adding NIPPV (hazard ratio 0.6).⁷⁹

However, that study also found no reduction in hospitalization rates, an apparent worsening in general and mental health (as reflected on the 36-Item Short Form Health Survey or SF-36, a quality-of-life questionnaire), as well as increased confusion and bewilderment (reflected on the Profile of Mood States scale).⁷⁹ These potentially deleterious effects may explain why adherence to NIPPV is low in patients with stable COPD: only 37% to 57% of patients continued to use it in several reported studies.^79–81

A level of inspiratory pressure support that is insufficient to reduce hypercapnia may account for the low adherence rate and worsened quality of life in such patients. For instance, in a randomized trial,⁸² compared with low-intensity NIPPV (mean IPAP 14 cm H₂O, backup rate 8 per minute), settings that aimed to maximally reduce Paco₂ (mean IPAP 29 cm H₂O with a backup rate of 17.5 per minute) increased the daily use of NIPPV by 3.6 hours/day and improved exercise-related dyspnea, daytime Paco₂, forced expiratory volume in 1 second (FEV₁), vital capacity, and health-related quality of life.

The overlap syndrome was first described by Flenley in 1985 as a combination of chronic respiratory disease (more generally limited to COPD) and obstructive sleep apnea-hypopnea syndrome.⁸³ Epidemiologic studies do not consistently show a higher incidence of obstructive sleep apnea-hypopnea syndrome in patients with COPD, but the exaggerated oxygen desaturation during sleep in patients with this combination increases the risk of hypoxemia, hypercapnia, and pulmonary hypertension. ⁸⁴ In addition, there was evidence of higher risks of death and of hospitalization for COPD in patients with the overlap syndrome. ⁸⁵ NIPPV is the main treatment for obstructive sleep apnea-hypopnea syndrome with or without COPD.

A recent study by Marin et al⁸⁵ showed that CPAP was associated with improved survival and decreased hospitalization in patients with the overlap syndrome. However, polysomnography or nocturnal oximetry while on NIPPV alone must be done, as additional nocturnal oxygen therapy may be warranted when significant chronic respiratory illness coexists with sleep apnea.
 

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Acknowledgment: The authors gratefully acknowledge the contribution of Scott Marlow, RRT, to Table 2 of this review.

Noninvasive positive pressure ventilation (NIPPV) is any form of positive ventilatory support applied without an endotracheal tube, including continuous positive airway pressure (CPAP).¹ The role of NIPPV in acute care has been discussed in an earlier review in the Cleveland Clinic Journal of Medicine.²

NIPPV is also used at night in outpatients with stable chronic conditions, first used in the 1980s in the treatment of obstructive sleep apnea³ and neuromuscular diseases,⁴ and since then in several other conditions including sleep disorders associated with congestive heart failure (including sleep apnea and the Cheyne-Stokes respiration-central sleep apnea syndrome), chronic obstructive pulmonary disease (COPD), and the obesity-hypoventilation syndrome.

In this review, we discuss the different types of NIPPV, the specific conditions in which they can be used, and the indications, recommendations, and evidence supporting the efficacy of NIPPV in outpatients.

THE TYPES OF NIPPV AND THEIR USES

Although the conditions for which different types of NIPPV can be used overlap significantly, each type has general indications and different goals of treatment. This section begins with types of NIPPV that are predominantly used to treat sleep-disordered breathing, and then proceeds to those predominantly used for conditions associated with hypoventilation and hypercapnia.

Continuous positive airway pressure

CPAP, currently the most widely used form of NIPPV, applies a constant level of positive pressure at the airway opening during spontaneous breathing.

CPAP is commonly used to treat obstructive sleep-disordered breathing, with the goals of improving daytime sleepiness and reducing cardiovascular risk. It has also been used to treat sleep-disordered breathing associated with congestive heart failure.

CPAP’s role in the support of ventilation is limited and indirect. For instance, it has been used in the obesity-hypoventilation syndrome and in the “overlap” syndrome (in which both sleep apnea and COPD coexist). However, its benefits in those conditions are probably derived in large part from correction of underlying obstructive sleep apnea.

The mechanisms of action of CPAP include:

• Preventing intermittent narrowing and collapse of the airway in patients with obstructive sleep apnea-hypopnea syndrome by acting as a pneumatic splint during sleep^3,5,6
• Counteracting auto-positive end-expiratory pressure, thereby reducing respiratory muscle load, reducing the work of breathing, and lowering daytime Paco₂ in patients with coexistent COPD and obstructive sleep apnea-hypopnea syndrome (the overlap syndrome)^7–9
• Improving lung function (particularly the functional residual capacity) and daytime gas exchange in obstructive sleep apnea-hypopnea syndrome ¹⁰
• Improving left ventricular systolic function in patients with heart failure coexisting with obstructive sleep apnea-hypopnea syndrome.^11,12

Auto-CPAP is delivered via a self-titrating CPAP device, which uses algorithms to detect variations in the degree of obstruction and consequently adjusts the pressure level to restore normal breathing. Auto-CPAP therefore compensates for factors that modify the upper airway collapsibility, such as body posture during sleep, stage of sleep, use of alcohol, and drugs that affect upper airway muscle tone.¹³

Although one of the premises of using auto-CPAP is that it improves the patient’s satisfaction and compliance, several studies found it to be no more effective than fixed CPAP for treating obstructive sleep apnea-hypopnea syndrome.^14–16 Current guidelines of the American Academy of Sleep Medicine do not recommend self-titrating CPAP devices to diagnose obstructive sleep apnea or to treat patients with cardiopulmonary disorders or other conditions in which nocturnal desaturation may be unrelated to obstructive events.¹⁷

Adaptive servo-ventilation

Adaptive servo-ventilation was developed for Cheyne-Stokes respiration-central sleep apnea syndrome in patients with congestive heart failure, who may have periods of crescendo-decrescendo change in tidal volume (Cheyne-Stokes respiration) with possible intercalated episodes of central apnea or hypopnea. It is also applied in patients with the complex sleep apnea syndrome.

Adaptive servo-ventilation devices are usually set at an expiratory positive airway pressure (EPAP) level sufficient to control obstructive sleep apnea. The device then automatically adjusts the pressure support for each inspiration, within a prespecified range, to maintain a moving-target ventilation set at 90% of the patient’s recent average ventilation. The aim is to stabilize breathing and reduce respiratory alkalosis, which can trigger apnea reentry cycles.¹⁸

Bilevel positive airway pressure

Bilevel positive airway pressure (bilevel PAP) can be of use in sleep-disordered breathing (including cases associated with congestive heart failure), but it is predominantly applied in conditions associated with hypoventilation.

Bilevel PAP devices deliver a higher pressure during inspiration (inspiratory positive airway pressure, or IPAP) and a lower pressure during expiration (EPAP). The gradient between IPAP and EPAP is of key importance in maintaining alveolar ventilation and reducing Paco₂. The IPAP acts as pressure support to augment the patient’s effort, maintain adequate alveolar ventilation, unload respiratory muscles, decrease the work of breathing, and control obstructive hypopnea, whereas EPAP is set to maintain upper airway patency, control obstructive apnea, improve functional residual capacity, and prevent microatelectasis.

Although there is no evidence that bilevel PAP is better adhered to or more effective than CPAP, current guidelines propose it as an option for patients who require high pressures to control obstructive sleep apnea-hypopnea syndrome or for those who cannot tolerate exhaling against a high fixed CPAP pressure.¹⁹

Other, more-common uses of bilevel PAP are to treat coexisting central sleep apnea or hypoventilation,¹⁹ the obesity-hypoventilation syndrome with residual alveolar hypoventilation despite CPAP and control of concomitant obstructive sleep apnea-hypopnea syndrome,^5,20 severe stable COPD with significant nocturnal hypoventilation and daytime hypercarbia,²¹ and restrictive pulmonary diseases.²¹

Although the patient should be able to maintain spontaneous breathing on bilevel PAP, a backup rate option can be set for those whose ventilation during sleep may be significantly impaired (eg, those with neuromuscular diseases, complex sleep apnea, central apnea in congestive heart failure, or obesity-hypoventilation syndrome) (Table 1, Table 2).^22,23 However, one important paradoxical consideration is that both CPAP and bilevel PAP (with or without a backup rate) promote ventilation and have the potential of dropping the carbon dioxide level below a hypocapnic apneic threshold during sleep, thereby triggering central apnea and the complex sleep apnea syndrome.²⁴

Average volume-assured pressure support

Average volume-assured pressure support is directed mainly at patients with chronic hypoventilation such as those with obesity-hypoventilation syndrome, neuromuscular diseases, and COPD. In this mode, a target tidal volume is set, and the device adjusts the pressure support to reach that set tidal volume. The advantage is that it guarantees a delivered tidal volume despite variability in patient effort, airway resistance, and lung or chest wall compliance. A particular potential benefit is that it may adapt to disease progression, as may occur in patients with progressive neuromuscular disorders.

 

CONDITIONS IN WHICH NOCTURNAL NIPPV IS USED IN OUT PATIENTS

Obstructive sleep apnea-hypopnea syndrome

Obstructive sleep apnea-hypopnea syndrome is estimated to affect 2% of women and 4% of men.²⁵ It is characterized by recurrent episodes of partial (hypopnea) or complete (apnea) upper airway obstruction during sleep despite ongoing inspiratory efforts, with associated episodes of arousal or desaturation or both. Corresponding symptoms include excessive daytime sleepiness, choking and gasping during sleep, recurrent awakenings from sleep, unrefreshing sleep, daytime fatigue, and impaired concentration that is not explained by other factors.²⁶

Current understanding of the pathophysiology of obstructive sleep apnea implicates an impairment in the balance between factors that promote collapsibility of the airway (including obesity and anatomic issues such as the volume of the soft-tissue structures surrounding the upper airway) and the compensatory neuromuscular response.^27,28

Long-standing obstructive sleep apnea-hypopnea syndrome has been linked in prospective studies to the development of hypertension,^29–31 coronary artery disease,^32,33 increased coagulation,^34,35 and stroke or death from any cause.^36,37 It is also associated with a greater rate and severity of motor vehicular accidents,³⁸ greater health care utilization, impaired work performance, and occupational injuries.³⁹

Strong evidence exists that NIPPV (most commonly CPAP) is beneficial in obstructive sleep apnea-hypopnea syndrome, improving sleep quality, sleepiness, cognitive impairment, and quality of life,^40,41 decreasing motor vehicle accidents,⁴² lowering blood pressure, ^43,44 and decreasing the rates of myocardial infarction,³² stroke,³² and death.⁴⁵

The American Academy of Sleep Medicine recommends CPAP as an optional adjunctive therapy to lower blood pressure in patients with obstructive sleep apnea-hypopnea syndrome with concomitant hypertension.¹⁹ This is supported by a recent study that suggested that CPAP may have additional benefits on blood pressure in a subgroup of patients with uncontrolled hypertension while on antihypertensive medications.⁴⁶ Indications with Medicare guidelines for reimbursement of CPAP devices are summarized in Table 2.

Complex sleep apnea syndrome

The complex sleep apnea syndrome is characterized by the emergence of significant central sleep apnea or Cheyne-Stokes respiration after obstructive events have been brought under control with NIPPV in patients who initially appear to have obstructive sleep apnea-hypopnea syndrome. A retrospective study of patients with the complex sleep apnea syndrome who continued their NIPPV use until a subsequent polysomnographic study and NIPPV titration showed that the syndrome may resolve spontaneously, but that 46% of patients had a persistently elevated apnea-hypopnea index with central apnea activity.⁴⁷

Restoration of upper airway patency by CPAP and dysregulation or delayed adaptation of chemosensitive ventilatory control to a changing Paco₂ level may be a key pathophysiologic mechanism of the complex sleep apnea syndrome.⁴⁸ In this mechanism, increased ventilation from restored airway patency and from an increase in the slope of the ventilatory response may intermittently draw the Paco₂ to below the hypocapnic apneic threshold and trigger episodes of central apnea.⁴⁸

The ideal NIPPV device for use in the complex sleep apnea syndrome should be able to provide enough pressure to resolve the obstructive sleep apnea-hypopnea syndrome while maintaining proper ventilatory support during central apnea episodes without fluctuations of Paco₂, which could further worsen the dysregulated ventilatory control. Currently, adaptive servo-ventilation appears to be superior to bilevel PAP and CPAP in the management of the complex sleep apnea syndrome.^49,50

Sleep disturbances associated with cardiac dysfunction

There are specific indications for NIPPV modes in the setting of respiratory sleep disturbances associated with heart failure.

Obstructive sleep apnea in congestive heart failure. The prevalence of obstructive sleep apnea in patients with impaired left ventricular ejection fraction is 11% to 53%.⁵¹ Obstructive sleep apnea-hypopnea syndrome can worsen congestive heart failure by causing a periodic increase in negative intrathoracic pressure from breathing against an occluded airway, by raising arterial blood pressure, and causing tachycardia from sympathetic nervous system stimulation from hypoxia, hypercarbia, and arousals.^52,53 Both heart failure and sleep apnea contribute in an additive manner to the increased sympathetic nervous activity.⁵⁴

Fortunately, treatment with CPAP has been found to reduce systolic blood pressure and improve left ventricular systolic function in medically treated patients with heart failure and coexisting obstructive sleep apnea.^11,12 Furthermore, in a randomized trial in patients with stable congestive heart failure and newly diagnosed obstructive sleep apnea-hypopnea syndrome, a greater improvement in cardiac function was observed in patients on bilevel PAP than in those on CPAP.⁵⁵ The authors speculated that bilevel PAP might provide more unloading of the respiratory muscles, reduce the work of breathing more, and result in less positive intrathoracic pressure than with CPAP, and that the higher intrathoracic pressure with CPAP could reduce the left ventricular ejection fraction in patients with low filling pressures (pulmonary capillary wedge pressure < 12 mm Hg) and low baseline left ventricular ejection fractions (< 30%).⁵⁵

Whether these interventions reduce the mortality rate is uncertain. In a prospective nonrandomized study, 9 (24%) of 37 patients who had heart failure with untreated obstructive sleep apnea died, compared with no deaths in 14 treated patients (P = .07).⁵⁶

Cheyne-Stokes respiration with central sleep apnea in congestive heart failure. A related but different situation is central apnea associated with congestive heart failure.

There are several pathophysiologic mechanisms of Cheyne-Stokes respiration with central sleep apnea. Specifically, the elevation of left ventricular filling pressures, end-diastolic volumes, and pulmonary congestion generate hyperventilation, chronic hypocapnia, and increased chemoreceptor responsiveness, which contribute to the development of central apnea by promoting a decrease in the Paco₂ during sleep to below the hypocapnic apneic threshold.^57,58 Additionally, an increase in circulation time may result in periodicity of breathing and hyperpnea.⁵⁹ Obstructive events can then occur at the end of the central events corresponding with the nadir of the inspiratory drive.^60,61

The Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure (CANPAP) trial, a randomized trial of CPAP in this clinical setting, showed that compared with optimal medical therapy alone, CPAP plus optimal medical therapy improved the ejection fraction, reduced central sleep apnea, improved nocturnal oxygenation, and improved the 6-minute walking distance, but without a survival benefit.⁶² The disappointing survival results from CANPAP have to be interpreted in the context that CPAP may have failed to control the central apnea in some patients, such that the mean apnea-hypopnea index in treated patients (19 events/hour) remained above the entry criterion for recruitment (15 events/hour). In a post hoc analysis of this study, the heart-transplantation-free survival rate was significantly greater in the subgroup of patients in whom CPAP effectively suppressed central sleep apnea (< 15 events/hour).⁶³

Other NIPPV modes such as bilevel PAP with backup rate and adaptive servo-ventilation have been shown in some studies to be superior to CPAP in controlling respiratory events, with adaptive servo-ventilation being the most effective in controlling central, mixed, and complex sleep apnea in this setting. ^49,50 Whether more effective resolution of obstructive and central events with these treatment modes translates into improved mortality rates and transplantation-free survival rates remains to be determined.

 

 

Obesity-hypoventilation syndrome

Obesity-hypoventilation syndrome refers to daytime hypercapnia (Paco₂ > 45 mm Hg) in obese people when no other cause of hypoventilation is present.

The prevalence of obesity-hypoventilation syndrome among patients with obstructive sleep apnea-hypopnea syndrome is 20% to 30% and is greater in extremely obese patients (body mass index > 40 kg/m²).⁶⁴ However, about 10% of patients with obesity-hypoventilation syndrome do not have obstructive sleep apnea-hypopnea syndrome.⁶⁴ Additionally, nocturnal hypoxemia and diurnal hypercapnia persist in about 40% of patients with obesity-hypoventilation syndrome after CPAP eliminates their sleep apnea.⁶⁵ Therefore, factors other than sleep apnea contribute to the development of obesity-hypoventilation syndrome, and in a meta-analysis, factors associated with daytime hypercapnia included, in addition to body mass index and the apnea-hypopnea index, mean overnight oxygen saturation and severity of restrictive pulmonary function.⁶⁶ Predictors of success with CPAP include better spirometric findings, a higher apnea-hypopnea index, and adequate oxygenation.^67,68

Bilevel PAP therapy can be tried in patients in whom CPAP by itself fails. In a study of patients with obesity-hypoventilation syndrome in whom initial CPAP treatment failed, average volume-assured pressure support lowered Paco₂ compared to bilevel PAP alone, but did not further improve oxygenation, sleep quality, or quality of life.⁶⁹

Restrictive pulmonary diseases

Neuromuscular diseases and thoracic cage abnormalities. Noninvasive ventilation has been used in patients with progressive neuromuscular disorders or severe thoracic cage abnormalities, with recognized benefits including an improved survival rate and improved quality of life.^70,71 However, NIPPV is used in only 9% of patients with amyotrophic lateral sclerosis when clearly indicated.⁷² The indications and Medicare guidelines for reimbursement of NIPPV (with or without a backup rate) in this setting are shown in Table 2.

Potential contraindications to starting NIPPV in this population include upper airway obstruction, failure to clear secretions despite optimal noninvasive support, inability to achieve a mask fit, and intolerance of the intervention.^73,74

The mechanisms of benefit of NIPPV in these settings include improvements in daytime blood gas levels (including hypercapnia⁷⁵), a reduction in the oxygen cost of breathing,⁷⁶ an increase in the ventilatory response to carbon dioxide,⁷⁵ and improved lung compliance.⁷⁷

Chronic hypercapnic failure due to severe COPD

The use of NIPPV in chronic COPD is less well established than in patients with exacerbations of COPD,⁷⁸ and limitations in its use are reflected in the more stringent Medicare indications for NIPPV in this setting (Table 2).

A particular subset of patients with stable COPD who may benefit from NIPPV includes those with daytime hypercapnia and super-imposed nocturnal hypoventilation.⁷⁸ The potential benefits of NIPPV in these patients include improved daytime and nocturnal gas exchange, increased sleep duration, and improved quality of life.⁷⁸ Additionally, a recent randomized controlled trial of NIPPV plus long-term oxygen therapy compared with oxygen therapy alone in patients with severe COPD and a Paco₂ greater than 46 mm Hg demonstrated a survival benefit in favor of adding NIPPV (hazard ratio 0.6).⁷⁹

However, that study also found no reduction in hospitalization rates, an apparent worsening in general and mental health (as reflected on the 36-Item Short Form Health Survey or SF-36, a quality-of-life questionnaire), as well as increased confusion and bewilderment (reflected on the Profile of Mood States scale).⁷⁹ These potentially deleterious effects may explain why adherence to NIPPV is low in patients with stable COPD: only 37% to 57% of patients continued to use it in several reported studies.^79–81

A level of inspiratory pressure support that is insufficient to reduce hypercapnia may account for the low adherence rate and worsened quality of life in such patients. For instance, in a randomized trial,⁸² compared with low-intensity NIPPV (mean IPAP 14 cm H₂O, backup rate 8 per minute), settings that aimed to maximally reduce Paco₂ (mean IPAP 29 cm H₂O with a backup rate of 17.5 per minute) increased the daily use of NIPPV by 3.6 hours/day and improved exercise-related dyspnea, daytime Paco₂, forced expiratory volume in 1 second (FEV₁), vital capacity, and health-related quality of life.

The overlap syndrome was first described by Flenley in 1985 as a combination of chronic respiratory disease (more generally limited to COPD) and obstructive sleep apnea-hypopnea syndrome.⁸³ Epidemiologic studies do not consistently show a higher incidence of obstructive sleep apnea-hypopnea syndrome in patients with COPD, but the exaggerated oxygen desaturation during sleep in patients with this combination increases the risk of hypoxemia, hypercapnia, and pulmonary hypertension. ⁸⁴ In addition, there was evidence of higher risks of death and of hospitalization for COPD in patients with the overlap syndrome. ⁸⁵ NIPPV is the main treatment for obstructive sleep apnea-hypopnea syndrome with or without COPD.

A recent study by Marin et al⁸⁵ showed that CPAP was associated with improved survival and decreased hospitalization in patients with the overlap syndrome. However, polysomnography or nocturnal oximetry while on NIPPV alone must be done, as additional nocturnal oxygen therapy may be warranted when significant chronic respiratory illness coexists with sleep apnea.
 

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Acknowledgment: The authors gratefully acknowledge the contribution of Scott Marlow, RRT, to Table 2 of this review.

Noninvasive positive pressure ventilation (NIPPV)—delivered via a tight-fitting mask rather than via an endotracheal tube or tracheostomy—is one of the most important advances in the management of acute respiratory failure to emerge in the past 2 decades. It is now recommended as the first choice for ventilatory support in selected patients, such as those with exacerbations of chronic obstructive pulmonary disease (COPD) or with cardiogenic pulmonary edema.^1–3 In fact, some authors suggest that using NIPPV in more than 20% of COPD patients is a characteristic of respiratory care departments that are “avid for change”⁴—change being a good thing.

However, NIPPV has not been universally accepted, with wide variations in its utilization. In a 2006 survey, it was being used in only 33% of patients with COPD or congestive heart failure, for which it might be indicated. ⁵ Some potential reasons for the low rate are that physicians do not know about it, respiratory therapists are not sufficiently trained in it, and hospitals lack the equipment to do it.⁵

Our goal in this review is to familiarize the reader with how NIPPV has evolved and with its indications and contraindications in specific acute care conditions.

FROM A VACUUM CLEANER TO THE INTENSIVE CARE UNIT

NIPPV appears to have been first tried in 1870 by Chaussier, who used a bag and face mask to resuscitate neonates.⁶

In 1936, Poulton and Oxon⁷ described their “pulmonary plus pressure machine,” which used a vacuum cleaner blower and a mask to increase the alveolar pressure and thus counteract the increased intrapulmonary pressure in patients with heart failure, pulmonary edema, Cheyne-Stokes breathing, and asthma.

In the 1940s, intermittent positive pressure breathing devices were developed for use in high-altitude aviation. Motley, Werko, and Cournand^8,9 subsequently used these devices to treat acute respiratory failure in pneumonia, pulmonary edema, near-drowning, Guillain-Barré syndrome, and acute severe asthma.

Although NIPPV was shown to be effective for acute conditions, invasive ventilation became preferred, particularly as blood gas analysis and ventilator technologies simultaneously matured, spurred at least in part by the polio epidemics of the 1950s.¹⁰

NIPPV reemerged in the 1980s for use in chronic conditions. First, continuous positive airway pressure (CPAP) came into use for obstructive sleep apnea,¹¹ followed by noninvasive positive-pressure volume ventilation in neuromuscular diseases.¹² Bilevel positive pressure devices (ie, with separate inspiratory and expiratory pressures) soon followed, again initially for obstructive sleep apnea¹³ and then for diverse neuromuscular diseases.¹⁴

NIPPV is now a mainstream therapy for diverse conditions in acute and chronic care.³ One reason we now use it in acute conditions is to avoid the complications associated with intubation.

Some clinicians initially resisted using NIPPV, concerned that it demanded too much of the nurses’ time¹⁵ and was costly.¹⁶ However, in a 1997 study in patients with COPD and acute respiratory failure, Nava et al¹⁷ found that NIPPV was no more expensive and no more demanding of staff resources than invasive mechanical ventilation in the first 48 hours of ventilation. Further, after the first few days of ventilation, NIPPV put fewer time demands on physicians and nurses than did invasive mechanical ventilation.

THREE MODES: CPAP, PRESSURE-LIMITED, VOLUME-LIMITED

The term “noninvasive ventilation” generally encompasses various forms of positive pressure ventilation. However, negative pressure ventilation, in the form of diaphragm pacing, may regain a foothold in the devices used for respiratory support.¹⁸ We therefore favor the term “NIPPV” in this review.

The different modes of NIPPV—ie, CPAP, pressure-limited, and volume-limited—are compared in Table 1. Of these, the pressure-limited mode is most commonly used.^2,19–21 Though there are several NIPPV-only devices, machines for invasive ventilation can also provide NIPPV.

NIPPV IN ACUTE RESPIRATORY FAILURE

The main reasons to use NIPPV instead of invasive ventilation in acute care are to avoid the complications of invasive ventilation, to improve outcomes (eg, reduce mortality rates, decrease hospital length of stay), and to decrease the cost of care.

The decision whether to initiate noninvasive support and where to provide it (ie, in a regular hospital ward, intensive care unit, or respiratory care unit) is best made by following the indications for and contraindications to NIPPV (Table 2), considering the specific disease, the strength of the recommendation (Table 3), and the expertise and skill of the staff.^1,2,19 In general, NIPPV is more likely to fail in patients with more severe disease and lower arterial pH.³ It should not be applied indiscriminately, as it may simply delay a necessary intubation and raise the concomitant risks of such a delay, including death.²²

NIPPV is the standard of care for acute exacerbations of COPD

NIPPV is currently considered the standard of care for patients who have acute exacerbations of COPD.^23–26

In a meta-analysis of eight randomized controlled trials,²⁴ the specific advantages of NIPPV compared with usual care in acute exacerbations of COPD included:

• A lower risk of treatment failure, defined as death, need for intubation, or inability to tolerate the treatment (relative risk [RR] 0.51, number needed to treat [NNT] to prevent one treatment failure = 5)
• A lower risk of intubation (RR 0.43, NNT = 5)
• A lower mortality rate (RR 0.41, NNT = 8)
• A lower risk of complications (RR 0.32, NNT = 3)
• A shorter hospital length of stay (by about 3 days).

Mechanisms by which NIPPV may impart these benefits include reducing the work of breathing, unloading the respiratory muscles, lessening diaphragmatic pressure swings, reducing the respiratory rate, eliminating diaphragmatic work, and counteracting the threshold loading effects of auto-positive end-expiratory pressure (auto-PEEP).^24–26

Also, if a patient with COPD is intubated, NIPPV seems to help after the tube is removed, preventing postextubation respiratory failure and facilitating weaning from invasive ventilation.²⁷ These topics are discussed below.

A Cochrane systematic review²⁴ concluded that NIPPV should be tried early in the course of respiratory failure, before severe acidosis develops. The patients in the studies in this review all had partial pressure of arterial carbon dioxide (Paco₂) levels greater than 45 mm Hg.

In patients with severe respiratory acidosis (pH < 7.25), NIPPV failure rates are greater than 50%. However, trying NIPPV may still be justified, even in the presence of hypercapnic encephalopathy, as long as no other indications for invasive support and facilities for prompt endotracheal intubation are available. ¹

However, in another systematic review,²⁶ in patients with mild COPD exacerbations (pH > 7.35), NIPPV was no more effective than standard medical therapy in preventing acute respiratory failure, preventing death, or reducing length of hospitalization. Moreover, nearly 50% of the patients could not tolerate NIPPV.

 

 

Rapid improvement in cardiogenic pulmonary edema, but possibly no lower mortality rate

The Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial,²⁸ with 1,156 patients, was the largest randomized trial to compare NIPPV and standard oxygen therapy for acute pulmonary edema. It found that NIPPV (either CPAP or noninvasive intermittent positive pressure ventilation) was significantly better than standard oxygen therapy (through a variable-delivery oxygen mask with a reservoir) in the first hour of treatment in terms of the dyspnea score, heart rate, acidosis, and hypercapnia. However, there were no significant differences between groups in the 7- or 30-day mortality rates, the rates of intubation, rates of admission to the critical care unit, or in the mean length of hospital stay.

In contrast, several smaller randomized trials and meta-analyses showed lower intubation and mortality rates with NIPPV.^29,30 Factors that may account for those differences include a much lower intubation rate in the 3CPO trial (2.9% overall, compared with 20% with conventional therapy in other trials), a higher mortality rate in the 3CPO trial, and methodologic differences (eg, patients for whom standard therapy failed in the 3CPO trial received rescue NIPPV).

If NIPPV is beneficial in cardiogenic pulmonary edema, the mechanisms are probably its favorable hemodynamic effects and its positive end-expiratory pressure (PEEP) effect on flooded alveoli. Specifically, positive intrathoracic pressure can be expected to reduce both preload and afterload, with improvement in the cardiac index and reduced work of breathing. ^31,32

Notwithstanding the possible lack of impact of NIPPV on death or intubation rates in this setting, the intervention rapidly improves dyspnea and respiratory and metabolic abnormalities and should be considered for treatment of cardiogenic pulmonary edema associated with severe respiratory distress. A subgroup in which the NIPPV may reduce intubation rates is those with hypercapnia.³³ A concern that NIPPV may increase the rate of myocardial infarction³⁴ was not confirmed in the 3CPO trial.²⁸ Interestingly, there were no differences in outcomes between CPAP and noninvasive intermittent positive pressure ventilation in this setting.^28,34,35

Immunocompromised patients with acute respiratory failure

A particular challenge of NIPPV in immunocompromised patients, particularly compared with its use in COPD exacerbation or cardiogenic pulmonary edema, is that the underlying pathophysiology of respiratory dysfunction in immunocompromised patients may not be readily reversible. Therefore, its application in this group may need to follow clearly defined indications.

In one trial,²⁰ inclusion criteria were:

• Immune suppression (due to neutropenia after chemotherapy or bone marrow transplantation, immunosuppressive drugs for organ transplantation, corticosteroids, cytotoxic therapy for nonmalignant conditions, or the acquired immunodeficiency syndrome)
• Persistent pulmonary infiltrates
• Fever (temperature > 38.3°C; 100.9°F)
• A respiratory rate greater than 30 breaths per minute
• Severe dyspnea at rest
• Early hypoxemic acute respiratory failure, defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao₂/Fio₂ ratio) less than 200 while on oxygen.

Compared with patients who received conventional treatment, fewer of those randomized to additional intermittent noninvasive ventilation had to be intubated (46% vs 77%, P = .03), suffered serious complications (50% vs 81%, P = .02), or died in the intensive care unit (38% vs 69%, P = .03) or in the hospital (50% vs 81%, P = .02).

Similarly, in a randomized trial in 40 patients with acute respiratory failure after solid organ transplantation, more patients in the NIPPV group than in the control group had an improvement in the Pao₂/Fio₂ ratio within the first hour (70% vs 25%, P = .004) or a sustained improvement in the Pao₂/Fio₂ ratio (60% vs 25%, P = .03); fewer of them needed endotracheal intubation (20% vs 70%, P = .002); fewer of them died of complications (20% vs 50%, P = .05); they had a shorter length of stay in the intensive care unit (mean 5.5 vs 9 days, P = .03); and fewer of them died in the intensive care unit (20% vs 50%, P = .05). There was, however, no difference in the overall hospital mortality rate.³⁶

MAY NOT HELP AFTER EXTUBATION, EXCEPT IN SPECIFIC CASES

NIPPV has been used to treat respiratory failure after extubation,^22,37 to prevent acute respiratory failure after failure of weaning,^38–41 and to support breathing in patients who failed a trial of spontaneous breathing.^42–45

Unfortunately, the evidence for using NIPPV in respiratory failure after extubation, including unplanned extubation, appears to be unfavorable, except possibly in patients with chronic pulmonary disease (particularly COPD and possibly obesity) and hypercapnia. An international consensus report stated that NIPPV should be considered in patients with hypercapnic respiratory insufficiency, especially those with COPD, to shorten the duration of intubation, but that it should not be routinely used in extubation respiratory failure.⁴⁶

Treatment of respiratory failure after extubation

Two recent randomized controlled trials compared NIPPV and standard care in patients who met the criteria for readiness for extubation but who developed respiratory failure after mechanical ventilation was discontinued. ^22,37 Those two studies showed a longer time to reintubation for patients randomized to NIPPV but no differences in the rate of reintubation between the two groups and no difference in the lengths of stay in the intensive care unit.

Of greater concern, one study showed a higher rate of death in the intensive care unit in the NIPPV group than in the standard therapy group (25% vs 14%, respectively).²² This finding suggests that NIPPV delayed necessary reintubation in patients developing respiratory failure after extubation, with a consequent risk of fatal complications.

 

 

Prevention of respiratory failure after extubation

Other studies used NIPPV to prevent respiratory failure after extubation rather than wait to apply it after respiratory failure developed.^38–41

Nava et al,⁴⁰ in a trial in patients successfully weaned but considered to be at risk of reintubation, found that fewer of those randomized to NIPPV had to be reintubated than those who received standard care (8% vs 24%), and 10% fewer of them died in the intensive care unit. Risk factors for reintubation (and therefore eligibility criteria for this trial) included a Paco₂ higher than 45 mm Hg, more than one consecutive failure of weaning, chronic heart failure, other comorbidity, weak cough, or stridor.

Extubated patients are a heterogeneous group, so if some subgroups benefit from a transition to NIPPV after extubation, it will be important to identify them. For instance, a subgroup analysis of a study by Ferrer et al³⁸ indicated the survival benefit of NIPPV after extubation was limited to patients with chronic respiratory disorders and hypercapnia during a trial of spontaneous breathing.

In a subsequent successful test of this hypothesis, a randomized trial showed that the early use of noninvasive ventilation in patients with hypercapnia after a trial of spontaneous breathing and with chronic respiratory disorders (COPD, chronic bronchitis, bronchiectasis, obesity-hypoventilation, sequelae of tuberculosis, chest wall deformity, or chronic persistent asthma) reduced the risk of respiratory failure after extubation and the risk of death within the first 90 days.³⁹

Others in which this approach may be helpful are obese patients who have high Paco₂ levels. Compared with historical controls, 62 patients with a body mass index greater than 35 kg/m² who received NIPPV in the 48 hours after extubation had a lower rate of respiratory failure, shorter lengths of stay in the intensive care unit and hospital, and, in the subgroup with hypercapnia, a lower hospital mortality rate.⁴¹

NIPPV to facilitate weaning

In several studies, mechanically ventilated patients who had failed a trial of spontaneous breathing were randomized to undergo either accelerated weaning, extubation, and NIPPV or conventional weaning with pressure support via mechanical ventilation.^42–46 Most patients developed hypercapnia during the spontaneous breathing trials, and most of the patients had COPD.

A meta-analysis⁴⁷ of the randomized trials of this approach concluded that, compared with continued invasive ventilation, NIPPV decreased the risk of death (relative risk 0.41) and of ventilator-associated pneumonia (relative risk 0.28) and reduced the total duration of mechanical ventilation by a weighted mean difference of 7.33 days. The benefits appeared to be most significant in patients with COPD.

NIPPV IN ASTHMA AND STATUS ASTHMATICUS

Noninvasive ventilation is an attractive alternative to intubation for patients with status asthmaticus, given the challenges and conflicting demands of maintaining ventilation despite severe airway obstruction.

In a 1996 prospective study of 17 episodes of asthma associated with acute respiratory failure, Meduri et al⁴⁸ showed that NIPPV could progressively improve the pH and the Paco₂ over 12 to 24 hours and reduce the respiratory rate.

In a subsequent controlled trial, Soroksky et al⁴⁹ randomized 30 patients presenting to an emergency room with a severe asthma attack to NIPPV with conventional therapy vs conventional therapy only. The study group had a significantly greater increase in the forced expiratory volume in 1 second compared with the control group (54% vs 29%, respectively) and a lower hospitalization rate (18% vs 63%).

Another randomized trial of NIPPV, in patients with status asthmaticus presenting to an emergency room, was prematurely terminated due to a physician treatment bias that favored NIPPV.⁵⁰ The preliminary results of that study showed a 7.3% higher intubation rate in the control group than in the NIPPV group, along with trends toward a lower intubation rate, a shorter length of hospital stay, and lower hospital charges in the NIPPV group.

Despite these initial favorable results, a Cochrane review concluded that the use of NIPPV in patients with status asthmaticus is controversial.⁵¹ NIPPV can be tried in selected patients such as those with mild to moderate respiratory distress (respiratory rate greater than 25 breaths per minute, use of accessory muscles to breathe, difficulty speaking), an arterial pH of 7.25 to 7.35, and a Paco₂ of 45 to 55 mm Hg.⁵² Patients with impending respiratory failure or the inability to protect the airway should probably not be considered for NIPPV.⁵²

IN ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME

The most challenging application of NIPPV may be in patients with acute lung injury and the acute respiratory distress syndrome.

Initial trials of NIPPV in this setting have been disappointing, and a meta-analysis of the topic concluded that NIPPV was unlikely to have any significant benefit.⁵³ An earlier study that used CPAP in patients with acute respiratory failure predominantly due to acute lung injury showed early physiologic improvements but no reduction in the need for intubation, no improvement in outcomes, and a higher rate of adverse events, including cardiac arrest, in those randomized to CPAP.⁵⁴

A subsequent observational cohort specifically identified shock, metabolic acidosis, and severe hypoxemia as predictors of NIPPV failure.⁵⁵

A more recent prospective study demonstrated that NIPPV improved gas exchange and obviated intubation in 54% of patients, with a consequent reduction in ventilator-associated pneumonia and a lower rate of death in the intensive care unit.⁵⁶ A Simplified Acute Physiology Score (SAPS) II greater than 34 and a Pao₂/Fio₂ ratio less than 175 after 1 hour of NIPPV were identified as predicting that NIPPV would fail.⁵⁶

 

MISCELLANEOUS APPLICATIONS

The more widespread use of NIPPV has encouraged its use in other acute situations, including during procedures such as percutaneous endoscopic gastrostomy (PEG)^57,58 or bronchoscopy,^59,60 for palliative use in patients listed as “do-not-intubate,”^61–63 and for oxygenation before intubation.⁶⁴

NIPPV during PEG tube insertion

NIPPV during PEG tube placement is particularly useful for patients with neuromuscular diseases who are at a combined risk of aspiration, poor oral intake, and respiratory failure during procedures. The experience with patients with amyotrophic lateral sclerosis⁵⁸ and Duchenne muscular dystrophy⁵⁷ indicates that even patients at high risk of respiratory failure during procedures can be successfully managed with NIPPV. The most recent practice parameters for patients with amyotrophic lateral sclerosis propose that patients with dysphagia may be exposed to less risk if the PEG procedure is performed when the forced vital capacity is greater than 50% of predicted.⁶⁵

In randomized trials of CPAP⁵⁹ or pressure-support NIPPV⁶⁰ in high-risk hypoxemic patients who needed diagnostic bronchoscopy, patients in the intervention groups fared better than those who received oxygen alone, with better oxygenation during and after the procedure and a lower risk of postprocedure respiratory failure. Improved hemodynamics with a lower mean heart rate and a stable mean arterial pressure were also reported in one of those studies.⁶⁰

Palliative use in ‘do-not-intubate’ patients

In patients who decline intubation, NIPPV appears to be most effective in reversing acute respiratory failure and improving mortality rates in those with COPD or with cardiogenic pulmonary edema.^61,62 Controversy surrounding the use of NIPPV in “do-not-intubate” patients, particularly as a potentially uncomfortable life support technique, has been addressed by a task force of the Society of Critical Care Medicine, which recommends that it be applied only after careful discussion of goals of care and parameters of treatment with patients and their families.⁶³

Oxygenation before intubation

In a prospective randomized study of oxygenation before rapid-sequence intubation via either a nonrebreather bag-valve mask or NIPPV, the NIPPV group had a higher oxygen saturation rate before, during, and after the intubation procedure.⁶⁴
 

---

Acknowledgment: The authors wish to thank Jodith Janes of the Cleveland Clinic Alumni Library for her help with reference citations and with locating articles.

Noninvasive positive pressure ventilation (NIPPV)—delivered via a tight-fitting mask rather than via an endotracheal tube or tracheostomy—is one of the most important advances in the management of acute respiratory failure to emerge in the past 2 decades. It is now recommended as the first choice for ventilatory support in selected patients, such as those with exacerbations of chronic obstructive pulmonary disease (COPD) or with cardiogenic pulmonary edema.^1–3 In fact, some authors suggest that using NIPPV in more than 20% of COPD patients is a characteristic of respiratory care departments that are “avid for change”⁴—change being a good thing.

However, NIPPV has not been universally accepted, with wide variations in its utilization. In a 2006 survey, it was being used in only 33% of patients with COPD or congestive heart failure, for which it might be indicated. ⁵ Some potential reasons for the low rate are that physicians do not know about it, respiratory therapists are not sufficiently trained in it, and hospitals lack the equipment to do it.⁵

Our goal in this review is to familiarize the reader with how NIPPV has evolved and with its indications and contraindications in specific acute care conditions.

FROM A VACUUM CLEANER TO THE INTENSIVE CARE UNIT

NIPPV appears to have been first tried in 1870 by Chaussier, who used a bag and face mask to resuscitate neonates.⁶

In 1936, Poulton and Oxon⁷ described their “pulmonary plus pressure machine,” which used a vacuum cleaner blower and a mask to increase the alveolar pressure and thus counteract the increased intrapulmonary pressure in patients with heart failure, pulmonary edema, Cheyne-Stokes breathing, and asthma.

In the 1940s, intermittent positive pressure breathing devices were developed for use in high-altitude aviation. Motley, Werko, and Cournand^8,9 subsequently used these devices to treat acute respiratory failure in pneumonia, pulmonary edema, near-drowning, Guillain-Barré syndrome, and acute severe asthma.

Although NIPPV was shown to be effective for acute conditions, invasive ventilation became preferred, particularly as blood gas analysis and ventilator technologies simultaneously matured, spurred at least in part by the polio epidemics of the 1950s.¹⁰

NIPPV reemerged in the 1980s for use in chronic conditions. First, continuous positive airway pressure (CPAP) came into use for obstructive sleep apnea,¹¹ followed by noninvasive positive-pressure volume ventilation in neuromuscular diseases.¹² Bilevel positive pressure devices (ie, with separate inspiratory and expiratory pressures) soon followed, again initially for obstructive sleep apnea¹³ and then for diverse neuromuscular diseases.¹⁴

NIPPV is now a mainstream therapy for diverse conditions in acute and chronic care.³ One reason we now use it in acute conditions is to avoid the complications associated with intubation.

Some clinicians initially resisted using NIPPV, concerned that it demanded too much of the nurses’ time¹⁵ and was costly.¹⁶ However, in a 1997 study in patients with COPD and acute respiratory failure, Nava et al¹⁷ found that NIPPV was no more expensive and no more demanding of staff resources than invasive mechanical ventilation in the first 48 hours of ventilation. Further, after the first few days of ventilation, NIPPV put fewer time demands on physicians and nurses than did invasive mechanical ventilation.

THREE MODES: CPAP, PRESSURE-LIMITED, VOLUME-LIMITED

The term “noninvasive ventilation” generally encompasses various forms of positive pressure ventilation. However, negative pressure ventilation, in the form of diaphragm pacing, may regain a foothold in the devices used for respiratory support.¹⁸ We therefore favor the term “NIPPV” in this review.

The different modes of NIPPV—ie, CPAP, pressure-limited, and volume-limited—are compared in Table 1. Of these, the pressure-limited mode is most commonly used.^2,19–21 Though there are several NIPPV-only devices, machines for invasive ventilation can also provide NIPPV.

NIPPV IN ACUTE RESPIRATORY FAILURE

The main reasons to use NIPPV instead of invasive ventilation in acute care are to avoid the complications of invasive ventilation, to improve outcomes (eg, reduce mortality rates, decrease hospital length of stay), and to decrease the cost of care.

The decision whether to initiate noninvasive support and where to provide it (ie, in a regular hospital ward, intensive care unit, or respiratory care unit) is best made by following the indications for and contraindications to NIPPV (Table 2), considering the specific disease, the strength of the recommendation (Table 3), and the expertise and skill of the staff.^1,2,19 In general, NIPPV is more likely to fail in patients with more severe disease and lower arterial pH.³ It should not be applied indiscriminately, as it may simply delay a necessary intubation and raise the concomitant risks of such a delay, including death.²²

NIPPV is the standard of care for acute exacerbations of COPD

NIPPV is currently considered the standard of care for patients who have acute exacerbations of COPD.^23–26

In a meta-analysis of eight randomized controlled trials,²⁴ the specific advantages of NIPPV compared with usual care in acute exacerbations of COPD included:

• A lower risk of treatment failure, defined as death, need for intubation, or inability to tolerate the treatment (relative risk [RR] 0.51, number needed to treat [NNT] to prevent one treatment failure = 5)
• A lower risk of intubation (RR 0.43, NNT = 5)
• A lower mortality rate (RR 0.41, NNT = 8)
• A lower risk of complications (RR 0.32, NNT = 3)
• A shorter hospital length of stay (by about 3 days).

Mechanisms by which NIPPV may impart these benefits include reducing the work of breathing, unloading the respiratory muscles, lessening diaphragmatic pressure swings, reducing the respiratory rate, eliminating diaphragmatic work, and counteracting the threshold loading effects of auto-positive end-expiratory pressure (auto-PEEP).^24–26

Also, if a patient with COPD is intubated, NIPPV seems to help after the tube is removed, preventing postextubation respiratory failure and facilitating weaning from invasive ventilation.²⁷ These topics are discussed below.

A Cochrane systematic review²⁴ concluded that NIPPV should be tried early in the course of respiratory failure, before severe acidosis develops. The patients in the studies in this review all had partial pressure of arterial carbon dioxide (Paco₂) levels greater than 45 mm Hg.

In patients with severe respiratory acidosis (pH < 7.25), NIPPV failure rates are greater than 50%. However, trying NIPPV may still be justified, even in the presence of hypercapnic encephalopathy, as long as no other indications for invasive support and facilities for prompt endotracheal intubation are available. ¹

However, in another systematic review,²⁶ in patients with mild COPD exacerbations (pH > 7.35), NIPPV was no more effective than standard medical therapy in preventing acute respiratory failure, preventing death, or reducing length of hospitalization. Moreover, nearly 50% of the patients could not tolerate NIPPV.

 

 

Rapid improvement in cardiogenic pulmonary edema, but possibly no lower mortality rate

The Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial,²⁸ with 1,156 patients, was the largest randomized trial to compare NIPPV and standard oxygen therapy for acute pulmonary edema. It found that NIPPV (either CPAP or noninvasive intermittent positive pressure ventilation) was significantly better than standard oxygen therapy (through a variable-delivery oxygen mask with a reservoir) in the first hour of treatment in terms of the dyspnea score, heart rate, acidosis, and hypercapnia. However, there were no significant differences between groups in the 7- or 30-day mortality rates, the rates of intubation, rates of admission to the critical care unit, or in the mean length of hospital stay.

In contrast, several smaller randomized trials and meta-analyses showed lower intubation and mortality rates with NIPPV.^29,30 Factors that may account for those differences include a much lower intubation rate in the 3CPO trial (2.9% overall, compared with 20% with conventional therapy in other trials), a higher mortality rate in the 3CPO trial, and methodologic differences (eg, patients for whom standard therapy failed in the 3CPO trial received rescue NIPPV).

If NIPPV is beneficial in cardiogenic pulmonary edema, the mechanisms are probably its favorable hemodynamic effects and its positive end-expiratory pressure (PEEP) effect on flooded alveoli. Specifically, positive intrathoracic pressure can be expected to reduce both preload and afterload, with improvement in the cardiac index and reduced work of breathing. ^31,32

Notwithstanding the possible lack of impact of NIPPV on death or intubation rates in this setting, the intervention rapidly improves dyspnea and respiratory and metabolic abnormalities and should be considered for treatment of cardiogenic pulmonary edema associated with severe respiratory distress. A subgroup in which the NIPPV may reduce intubation rates is those with hypercapnia.³³ A concern that NIPPV may increase the rate of myocardial infarction³⁴ was not confirmed in the 3CPO trial.²⁸ Interestingly, there were no differences in outcomes between CPAP and noninvasive intermittent positive pressure ventilation in this setting.^28,34,35

Immunocompromised patients with acute respiratory failure

A particular challenge of NIPPV in immunocompromised patients, particularly compared with its use in COPD exacerbation or cardiogenic pulmonary edema, is that the underlying pathophysiology of respiratory dysfunction in immunocompromised patients may not be readily reversible. Therefore, its application in this group may need to follow clearly defined indications.

In one trial,²⁰ inclusion criteria were:

• Immune suppression (due to neutropenia after chemotherapy or bone marrow transplantation, immunosuppressive drugs for organ transplantation, corticosteroids, cytotoxic therapy for nonmalignant conditions, or the acquired immunodeficiency syndrome)
• Persistent pulmonary infiltrates
• Fever (temperature > 38.3°C; 100.9°F)
• A respiratory rate greater than 30 breaths per minute
• Severe dyspnea at rest
• Early hypoxemic acute respiratory failure, defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao₂/Fio₂ ratio) less than 200 while on oxygen.

Compared with patients who received conventional treatment, fewer of those randomized to additional intermittent noninvasive ventilation had to be intubated (46% vs 77%, P = .03), suffered serious complications (50% vs 81%, P = .02), or died in the intensive care unit (38% vs 69%, P = .03) or in the hospital (50% vs 81%, P = .02).

Similarly, in a randomized trial in 40 patients with acute respiratory failure after solid organ transplantation, more patients in the NIPPV group than in the control group had an improvement in the Pao₂/Fio₂ ratio within the first hour (70% vs 25%, P = .004) or a sustained improvement in the Pao₂/Fio₂ ratio (60% vs 25%, P = .03); fewer of them needed endotracheal intubation (20% vs 70%, P = .002); fewer of them died of complications (20% vs 50%, P = .05); they had a shorter length of stay in the intensive care unit (mean 5.5 vs 9 days, P = .03); and fewer of them died in the intensive care unit (20% vs 50%, P = .05). There was, however, no difference in the overall hospital mortality rate.³⁶

MAY NOT HELP AFTER EXTUBATION, EXCEPT IN SPECIFIC CASES

NIPPV has been used to treat respiratory failure after extubation,^22,37 to prevent acute respiratory failure after failure of weaning,^38–41 and to support breathing in patients who failed a trial of spontaneous breathing.^42–45

Unfortunately, the evidence for using NIPPV in respiratory failure after extubation, including unplanned extubation, appears to be unfavorable, except possibly in patients with chronic pulmonary disease (particularly COPD and possibly obesity) and hypercapnia. An international consensus report stated that NIPPV should be considered in patients with hypercapnic respiratory insufficiency, especially those with COPD, to shorten the duration of intubation, but that it should not be routinely used in extubation respiratory failure.⁴⁶

Treatment of respiratory failure after extubation

Two recent randomized controlled trials compared NIPPV and standard care in patients who met the criteria for readiness for extubation but who developed respiratory failure after mechanical ventilation was discontinued. ^22,37 Those two studies showed a longer time to reintubation for patients randomized to NIPPV but no differences in the rate of reintubation between the two groups and no difference in the lengths of stay in the intensive care unit.

Of greater concern, one study showed a higher rate of death in the intensive care unit in the NIPPV group than in the standard therapy group (25% vs 14%, respectively).²² This finding suggests that NIPPV delayed necessary reintubation in patients developing respiratory failure after extubation, with a consequent risk of fatal complications.

 

 

Prevention of respiratory failure after extubation

Other studies used NIPPV to prevent respiratory failure after extubation rather than wait to apply it after respiratory failure developed.^38–41

Nava et al,⁴⁰ in a trial in patients successfully weaned but considered to be at risk of reintubation, found that fewer of those randomized to NIPPV had to be reintubated than those who received standard care (8% vs 24%), and 10% fewer of them died in the intensive care unit. Risk factors for reintubation (and therefore eligibility criteria for this trial) included a Paco₂ higher than 45 mm Hg, more than one consecutive failure of weaning, chronic heart failure, other comorbidity, weak cough, or stridor.

Extubated patients are a heterogeneous group, so if some subgroups benefit from a transition to NIPPV after extubation, it will be important to identify them. For instance, a subgroup analysis of a study by Ferrer et al³⁸ indicated the survival benefit of NIPPV after extubation was limited to patients with chronic respiratory disorders and hypercapnia during a trial of spontaneous breathing.

In a subsequent successful test of this hypothesis, a randomized trial showed that the early use of noninvasive ventilation in patients with hypercapnia after a trial of spontaneous breathing and with chronic respiratory disorders (COPD, chronic bronchitis, bronchiectasis, obesity-hypoventilation, sequelae of tuberculosis, chest wall deformity, or chronic persistent asthma) reduced the risk of respiratory failure after extubation and the risk of death within the first 90 days.³⁹

Others in which this approach may be helpful are obese patients who have high Paco₂ levels. Compared with historical controls, 62 patients with a body mass index greater than 35 kg/m² who received NIPPV in the 48 hours after extubation had a lower rate of respiratory failure, shorter lengths of stay in the intensive care unit and hospital, and, in the subgroup with hypercapnia, a lower hospital mortality rate.⁴¹

NIPPV to facilitate weaning

In several studies, mechanically ventilated patients who had failed a trial of spontaneous breathing were randomized to undergo either accelerated weaning, extubation, and NIPPV or conventional weaning with pressure support via mechanical ventilation.^42–46 Most patients developed hypercapnia during the spontaneous breathing trials, and most of the patients had COPD.

A meta-analysis⁴⁷ of the randomized trials of this approach concluded that, compared with continued invasive ventilation, NIPPV decreased the risk of death (relative risk 0.41) and of ventilator-associated pneumonia (relative risk 0.28) and reduced the total duration of mechanical ventilation by a weighted mean difference of 7.33 days. The benefits appeared to be most significant in patients with COPD.

NIPPV IN ASTHMA AND STATUS ASTHMATICUS

Noninvasive ventilation is an attractive alternative to intubation for patients with status asthmaticus, given the challenges and conflicting demands of maintaining ventilation despite severe airway obstruction.

In a 1996 prospective study of 17 episodes of asthma associated with acute respiratory failure, Meduri et al⁴⁸ showed that NIPPV could progressively improve the pH and the Paco₂ over 12 to 24 hours and reduce the respiratory rate.

In a subsequent controlled trial, Soroksky et al⁴⁹ randomized 30 patients presenting to an emergency room with a severe asthma attack to NIPPV with conventional therapy vs conventional therapy only. The study group had a significantly greater increase in the forced expiratory volume in 1 second compared with the control group (54% vs 29%, respectively) and a lower hospitalization rate (18% vs 63%).

Another randomized trial of NIPPV, in patients with status asthmaticus presenting to an emergency room, was prematurely terminated due to a physician treatment bias that favored NIPPV.⁵⁰ The preliminary results of that study showed a 7.3% higher intubation rate in the control group than in the NIPPV group, along with trends toward a lower intubation rate, a shorter length of hospital stay, and lower hospital charges in the NIPPV group.

Despite these initial favorable results, a Cochrane review concluded that the use of NIPPV in patients with status asthmaticus is controversial.⁵¹ NIPPV can be tried in selected patients such as those with mild to moderate respiratory distress (respiratory rate greater than 25 breaths per minute, use of accessory muscles to breathe, difficulty speaking), an arterial pH of 7.25 to 7.35, and a Paco₂ of 45 to 55 mm Hg.⁵² Patients with impending respiratory failure or the inability to protect the airway should probably not be considered for NIPPV.⁵²

IN ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME

The most challenging application of NIPPV may be in patients with acute lung injury and the acute respiratory distress syndrome.

Initial trials of NIPPV in this setting have been disappointing, and a meta-analysis of the topic concluded that NIPPV was unlikely to have any significant benefit.⁵³ An earlier study that used CPAP in patients with acute respiratory failure predominantly due to acute lung injury showed early physiologic improvements but no reduction in the need for intubation, no improvement in outcomes, and a higher rate of adverse events, including cardiac arrest, in those randomized to CPAP.⁵⁴

A subsequent observational cohort specifically identified shock, metabolic acidosis, and severe hypoxemia as predictors of NIPPV failure.⁵⁵

A more recent prospective study demonstrated that NIPPV improved gas exchange and obviated intubation in 54% of patients, with a consequent reduction in ventilator-associated pneumonia and a lower rate of death in the intensive care unit.⁵⁶ A Simplified Acute Physiology Score (SAPS) II greater than 34 and a Pao₂/Fio₂ ratio less than 175 after 1 hour of NIPPV were identified as predicting that NIPPV would fail.⁵⁶

 

MISCELLANEOUS APPLICATIONS

The more widespread use of NIPPV has encouraged its use in other acute situations, including during procedures such as percutaneous endoscopic gastrostomy (PEG)^57,58 or bronchoscopy,^59,60 for palliative use in patients listed as “do-not-intubate,”^61–63 and for oxygenation before intubation.⁶⁴

NIPPV during PEG tube insertion

NIPPV during PEG tube placement is particularly useful for patients with neuromuscular diseases who are at a combined risk of aspiration, poor oral intake, and respiratory failure during procedures. The experience with patients with amyotrophic lateral sclerosis⁵⁸ and Duchenne muscular dystrophy⁵⁷ indicates that even patients at high risk of respiratory failure during procedures can be successfully managed with NIPPV. The most recent practice parameters for patients with amyotrophic lateral sclerosis propose that patients with dysphagia may be exposed to less risk if the PEG procedure is performed when the forced vital capacity is greater than 50% of predicted.⁶⁵

In randomized trials of CPAP⁵⁹ or pressure-support NIPPV⁶⁰ in high-risk hypoxemic patients who needed diagnostic bronchoscopy, patients in the intervention groups fared better than those who received oxygen alone, with better oxygenation during and after the procedure and a lower risk of postprocedure respiratory failure. Improved hemodynamics with a lower mean heart rate and a stable mean arterial pressure were also reported in one of those studies.⁶⁰

Palliative use in ‘do-not-intubate’ patients

In patients who decline intubation, NIPPV appears to be most effective in reversing acute respiratory failure and improving mortality rates in those with COPD or with cardiogenic pulmonary edema.^61,62 Controversy surrounding the use of NIPPV in “do-not-intubate” patients, particularly as a potentially uncomfortable life support technique, has been addressed by a task force of the Society of Critical Care Medicine, which recommends that it be applied only after careful discussion of goals of care and parameters of treatment with patients and their families.⁶³

Oxygenation before intubation

In a prospective randomized study of oxygenation before rapid-sequence intubation via either a nonrebreather bag-valve mask or NIPPV, the NIPPV group had a higher oxygen saturation rate before, during, and after the intubation procedure.⁶⁴
 

---

Acknowledgment: The authors wish to thank Jodith Janes of the Cleveland Clinic Alumni Library for her help with reference citations and with locating articles.

Noninvasive positive pressure ventilation (NIPPV)—delivered via a tight-fitting mask rather than via an endotracheal tube or tracheostomy—is one of the most important advances in the management of acute respiratory failure to emerge in the past 2 decades. It is now recommended as the first choice for ventilatory support in selected patients, such as those with exacerbations of chronic obstructive pulmonary disease (COPD) or with cardiogenic pulmonary edema.^1–3 In fact, some authors suggest that using NIPPV in more than 20% of COPD patients is a characteristic of respiratory care departments that are “avid for change”⁴—change being a good thing.

However, NIPPV has not been universally accepted, with wide variations in its utilization. In a 2006 survey, it was being used in only 33% of patients with COPD or congestive heart failure, for which it might be indicated. ⁵ Some potential reasons for the low rate are that physicians do not know about it, respiratory therapists are not sufficiently trained in it, and hospitals lack the equipment to do it.⁵

Our goal in this review is to familiarize the reader with how NIPPV has evolved and with its indications and contraindications in specific acute care conditions.

FROM A VACUUM CLEANER TO THE INTENSIVE CARE UNIT

NIPPV appears to have been first tried in 1870 by Chaussier, who used a bag and face mask to resuscitate neonates.⁶

In 1936, Poulton and Oxon⁷ described their “pulmonary plus pressure machine,” which used a vacuum cleaner blower and a mask to increase the alveolar pressure and thus counteract the increased intrapulmonary pressure in patients with heart failure, pulmonary edema, Cheyne-Stokes breathing, and asthma.

In the 1940s, intermittent positive pressure breathing devices were developed for use in high-altitude aviation. Motley, Werko, and Cournand^8,9 subsequently used these devices to treat acute respiratory failure in pneumonia, pulmonary edema, near-drowning, Guillain-Barré syndrome, and acute severe asthma.

Although NIPPV was shown to be effective for acute conditions, invasive ventilation became preferred, particularly as blood gas analysis and ventilator technologies simultaneously matured, spurred at least in part by the polio epidemics of the 1950s.¹⁰

NIPPV reemerged in the 1980s for use in chronic conditions. First, continuous positive airway pressure (CPAP) came into use for obstructive sleep apnea,¹¹ followed by noninvasive positive-pressure volume ventilation in neuromuscular diseases.¹² Bilevel positive pressure devices (ie, with separate inspiratory and expiratory pressures) soon followed, again initially for obstructive sleep apnea¹³ and then for diverse neuromuscular diseases.¹⁴

NIPPV is now a mainstream therapy for diverse conditions in acute and chronic care.³ One reason we now use it in acute conditions is to avoid the complications associated with intubation.

Some clinicians initially resisted using NIPPV, concerned that it demanded too much of the nurses’ time¹⁵ and was costly.¹⁶ However, in a 1997 study in patients with COPD and acute respiratory failure, Nava et al¹⁷ found that NIPPV was no more expensive and no more demanding of staff resources than invasive mechanical ventilation in the first 48 hours of ventilation. Further, after the first few days of ventilation, NIPPV put fewer time demands on physicians and nurses than did invasive mechanical ventilation.

THREE MODES: CPAP, PRESSURE-LIMITED, VOLUME-LIMITED

The term “noninvasive ventilation” generally encompasses various forms of positive pressure ventilation. However, negative pressure ventilation, in the form of diaphragm pacing, may regain a foothold in the devices used for respiratory support.¹⁸ We therefore favor the term “NIPPV” in this review.

The different modes of NIPPV—ie, CPAP, pressure-limited, and volume-limited—are compared in Table 1. Of these, the pressure-limited mode is most commonly used.^2,19–21 Though there are several NIPPV-only devices, machines for invasive ventilation can also provide NIPPV.

NIPPV IN ACUTE RESPIRATORY FAILURE

The main reasons to use NIPPV instead of invasive ventilation in acute care are to avoid the complications of invasive ventilation, to improve outcomes (eg, reduce mortality rates, decrease hospital length of stay), and to decrease the cost of care.

The decision whether to initiate noninvasive support and where to provide it (ie, in a regular hospital ward, intensive care unit, or respiratory care unit) is best made by following the indications for and contraindications to NIPPV (Table 2), considering the specific disease, the strength of the recommendation (Table 3), and the expertise and skill of the staff.^1,2,19 In general, NIPPV is more likely to fail in patients with more severe disease and lower arterial pH.³ It should not be applied indiscriminately, as it may simply delay a necessary intubation and raise the concomitant risks of such a delay, including death.²²

NIPPV is the standard of care for acute exacerbations of COPD

NIPPV is currently considered the standard of care for patients who have acute exacerbations of COPD.^23–26

In a meta-analysis of eight randomized controlled trials,²⁴ the specific advantages of NIPPV compared with usual care in acute exacerbations of COPD included:

• A lower risk of treatment failure, defined as death, need for intubation, or inability to tolerate the treatment (relative risk [RR] 0.51, number needed to treat [NNT] to prevent one treatment failure = 5)
• A lower risk of intubation (RR 0.43, NNT = 5)
• A lower mortality rate (RR 0.41, NNT = 8)
• A lower risk of complications (RR 0.32, NNT = 3)
• A shorter hospital length of stay (by about 3 days).

Mechanisms by which NIPPV may impart these benefits include reducing the work of breathing, unloading the respiratory muscles, lessening diaphragmatic pressure swings, reducing the respiratory rate, eliminating diaphragmatic work, and counteracting the threshold loading effects of auto-positive end-expiratory pressure (auto-PEEP).^24–26

Also, if a patient with COPD is intubated, NIPPV seems to help after the tube is removed, preventing postextubation respiratory failure and facilitating weaning from invasive ventilation.²⁷ These topics are discussed below.

A Cochrane systematic review²⁴ concluded that NIPPV should be tried early in the course of respiratory failure, before severe acidosis develops. The patients in the studies in this review all had partial pressure of arterial carbon dioxide (Paco₂) levels greater than 45 mm Hg.

In patients with severe respiratory acidosis (pH < 7.25), NIPPV failure rates are greater than 50%. However, trying NIPPV may still be justified, even in the presence of hypercapnic encephalopathy, as long as no other indications for invasive support and facilities for prompt endotracheal intubation are available. ¹

However, in another systematic review,²⁶ in patients with mild COPD exacerbations (pH > 7.35), NIPPV was no more effective than standard medical therapy in preventing acute respiratory failure, preventing death, or reducing length of hospitalization. Moreover, nearly 50% of the patients could not tolerate NIPPV.

 

 

Rapid improvement in cardiogenic pulmonary edema, but possibly no lower mortality rate

The Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial,²⁸ with 1,156 patients, was the largest randomized trial to compare NIPPV and standard oxygen therapy for acute pulmonary edema. It found that NIPPV (either CPAP or noninvasive intermittent positive pressure ventilation) was significantly better than standard oxygen therapy (through a variable-delivery oxygen mask with a reservoir) in the first hour of treatment in terms of the dyspnea score, heart rate, acidosis, and hypercapnia. However, there were no significant differences between groups in the 7- or 30-day mortality rates, the rates of intubation, rates of admission to the critical care unit, or in the mean length of hospital stay.

In contrast, several smaller randomized trials and meta-analyses showed lower intubation and mortality rates with NIPPV.^29,30 Factors that may account for those differences include a much lower intubation rate in the 3CPO trial (2.9% overall, compared with 20% with conventional therapy in other trials), a higher mortality rate in the 3CPO trial, and methodologic differences (eg, patients for whom standard therapy failed in the 3CPO trial received rescue NIPPV).

If NIPPV is beneficial in cardiogenic pulmonary edema, the mechanisms are probably its favorable hemodynamic effects and its positive end-expiratory pressure (PEEP) effect on flooded alveoli. Specifically, positive intrathoracic pressure can be expected to reduce both preload and afterload, with improvement in the cardiac index and reduced work of breathing. ^31,32

Notwithstanding the possible lack of impact of NIPPV on death or intubation rates in this setting, the intervention rapidly improves dyspnea and respiratory and metabolic abnormalities and should be considered for treatment of cardiogenic pulmonary edema associated with severe respiratory distress. A subgroup in which the NIPPV may reduce intubation rates is those with hypercapnia.³³ A concern that NIPPV may increase the rate of myocardial infarction³⁴ was not confirmed in the 3CPO trial.²⁸ Interestingly, there were no differences in outcomes between CPAP and noninvasive intermittent positive pressure ventilation in this setting.^28,34,35

Immunocompromised patients with acute respiratory failure

A particular challenge of NIPPV in immunocompromised patients, particularly compared with its use in COPD exacerbation or cardiogenic pulmonary edema, is that the underlying pathophysiology of respiratory dysfunction in immunocompromised patients may not be readily reversible. Therefore, its application in this group may need to follow clearly defined indications.

In one trial,²⁰ inclusion criteria were:

• Immune suppression (due to neutropenia after chemotherapy or bone marrow transplantation, immunosuppressive drugs for organ transplantation, corticosteroids, cytotoxic therapy for nonmalignant conditions, or the acquired immunodeficiency syndrome)
• Persistent pulmonary infiltrates
• Fever (temperature > 38.3°C; 100.9°F)
• A respiratory rate greater than 30 breaths per minute
• Severe dyspnea at rest
• Early hypoxemic acute respiratory failure, defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao₂/Fio₂ ratio) less than 200 while on oxygen.

Compared with patients who received conventional treatment, fewer of those randomized to additional intermittent noninvasive ventilation had to be intubated (46% vs 77%, P = .03), suffered serious complications (50% vs 81%, P = .02), or died in the intensive care unit (38% vs 69%, P = .03) or in the hospital (50% vs 81%, P = .02).

Similarly, in a randomized trial in 40 patients with acute respiratory failure after solid organ transplantation, more patients in the NIPPV group than in the control group had an improvement in the Pao₂/Fio₂ ratio within the first hour (70% vs 25%, P = .004) or a sustained improvement in the Pao₂/Fio₂ ratio (60% vs 25%, P = .03); fewer of them needed endotracheal intubation (20% vs 70%, P = .002); fewer of them died of complications (20% vs 50%, P = .05); they had a shorter length of stay in the intensive care unit (mean 5.5 vs 9 days, P = .03); and fewer of them died in the intensive care unit (20% vs 50%, P = .05). There was, however, no difference in the overall hospital mortality rate.³⁶

MAY NOT HELP AFTER EXTUBATION, EXCEPT IN SPECIFIC CASES

NIPPV has been used to treat respiratory failure after extubation,^22,37 to prevent acute respiratory failure after failure of weaning,^38–41 and to support breathing in patients who failed a trial of spontaneous breathing.^42–45

Unfortunately, the evidence for using NIPPV in respiratory failure after extubation, including unplanned extubation, appears to be unfavorable, except possibly in patients with chronic pulmonary disease (particularly COPD and possibly obesity) and hypercapnia. An international consensus report stated that NIPPV should be considered in patients with hypercapnic respiratory insufficiency, especially those with COPD, to shorten the duration of intubation, but that it should not be routinely used in extubation respiratory failure.⁴⁶

Treatment of respiratory failure after extubation

Two recent randomized controlled trials compared NIPPV and standard care in patients who met the criteria for readiness for extubation but who developed respiratory failure after mechanical ventilation was discontinued. ^22,37 Those two studies showed a longer time to reintubation for patients randomized to NIPPV but no differences in the rate of reintubation between the two groups and no difference in the lengths of stay in the intensive care unit.

Of greater concern, one study showed a higher rate of death in the intensive care unit in the NIPPV group than in the standard therapy group (25% vs 14%, respectively).²² This finding suggests that NIPPV delayed necessary reintubation in patients developing respiratory failure after extubation, with a consequent risk of fatal complications.

 

 

Prevention of respiratory failure after extubation

Other studies used NIPPV to prevent respiratory failure after extubation rather than wait to apply it after respiratory failure developed.^38–41

Nava et al,⁴⁰ in a trial in patients successfully weaned but considered to be at risk of reintubation, found that fewer of those randomized to NIPPV had to be reintubated than those who received standard care (8% vs 24%), and 10% fewer of them died in the intensive care unit. Risk factors for reintubation (and therefore eligibility criteria for this trial) included a Paco₂ higher than 45 mm Hg, more than one consecutive failure of weaning, chronic heart failure, other comorbidity, weak cough, or stridor.

Extubated patients are a heterogeneous group, so if some subgroups benefit from a transition to NIPPV after extubation, it will be important to identify them. For instance, a subgroup analysis of a study by Ferrer et al³⁸ indicated the survival benefit of NIPPV after extubation was limited to patients with chronic respiratory disorders and hypercapnia during a trial of spontaneous breathing.

In a subsequent successful test of this hypothesis, a randomized trial showed that the early use of noninvasive ventilation in patients with hypercapnia after a trial of spontaneous breathing and with chronic respiratory disorders (COPD, chronic bronchitis, bronchiectasis, obesity-hypoventilation, sequelae of tuberculosis, chest wall deformity, or chronic persistent asthma) reduced the risk of respiratory failure after extubation and the risk of death within the first 90 days.³⁹

Others in which this approach may be helpful are obese patients who have high Paco₂ levels. Compared with historical controls, 62 patients with a body mass index greater than 35 kg/m² who received NIPPV in the 48 hours after extubation had a lower rate of respiratory failure, shorter lengths of stay in the intensive care unit and hospital, and, in the subgroup with hypercapnia, a lower hospital mortality rate.⁴¹

NIPPV to facilitate weaning

In several studies, mechanically ventilated patients who had failed a trial of spontaneous breathing were randomized to undergo either accelerated weaning, extubation, and NIPPV or conventional weaning with pressure support via mechanical ventilation.^42–46 Most patients developed hypercapnia during the spontaneous breathing trials, and most of the patients had COPD.

A meta-analysis⁴⁷ of the randomized trials of this approach concluded that, compared with continued invasive ventilation, NIPPV decreased the risk of death (relative risk 0.41) and of ventilator-associated pneumonia (relative risk 0.28) and reduced the total duration of mechanical ventilation by a weighted mean difference of 7.33 days. The benefits appeared to be most significant in patients with COPD.

NIPPV IN ASTHMA AND STATUS ASTHMATICUS

Noninvasive ventilation is an attractive alternative to intubation for patients with status asthmaticus, given the challenges and conflicting demands of maintaining ventilation despite severe airway obstruction.

In a 1996 prospective study of 17 episodes of asthma associated with acute respiratory failure, Meduri et al⁴⁸ showed that NIPPV could progressively improve the pH and the Paco₂ over 12 to 24 hours and reduce the respiratory rate.

In a subsequent controlled trial, Soroksky et al⁴⁹ randomized 30 patients presenting to an emergency room with a severe asthma attack to NIPPV with conventional therapy vs conventional therapy only. The study group had a significantly greater increase in the forced expiratory volume in 1 second compared with the control group (54% vs 29%, respectively) and a lower hospitalization rate (18% vs 63%).

Another randomized trial of NIPPV, in patients with status asthmaticus presenting to an emergency room, was prematurely terminated due to a physician treatment bias that favored NIPPV.⁵⁰ The preliminary results of that study showed a 7.3% higher intubation rate in the control group than in the NIPPV group, along with trends toward a lower intubation rate, a shorter length of hospital stay, and lower hospital charges in the NIPPV group.

Despite these initial favorable results, a Cochrane review concluded that the use of NIPPV in patients with status asthmaticus is controversial.⁵¹ NIPPV can be tried in selected patients such as those with mild to moderate respiratory distress (respiratory rate greater than 25 breaths per minute, use of accessory muscles to breathe, difficulty speaking), an arterial pH of 7.25 to 7.35, and a Paco₂ of 45 to 55 mm Hg.⁵² Patients with impending respiratory failure or the inability to protect the airway should probably not be considered for NIPPV.⁵²

IN ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME

The most challenging application of NIPPV may be in patients with acute lung injury and the acute respiratory distress syndrome.

Initial trials of NIPPV in this setting have been disappointing, and a meta-analysis of the topic concluded that NIPPV was unlikely to have any significant benefit.⁵³ An earlier study that used CPAP in patients with acute respiratory failure predominantly due to acute lung injury showed early physiologic improvements but no reduction in the need for intubation, no improvement in outcomes, and a higher rate of adverse events, including cardiac arrest, in those randomized to CPAP.⁵⁴

A subsequent observational cohort specifically identified shock, metabolic acidosis, and severe hypoxemia as predictors of NIPPV failure.⁵⁵

A more recent prospective study demonstrated that NIPPV improved gas exchange and obviated intubation in 54% of patients, with a consequent reduction in ventilator-associated pneumonia and a lower rate of death in the intensive care unit.⁵⁶ A Simplified Acute Physiology Score (SAPS) II greater than 34 and a Pao₂/Fio₂ ratio less than 175 after 1 hour of NIPPV were identified as predicting that NIPPV would fail.⁵⁶

 

MISCELLANEOUS APPLICATIONS

The more widespread use of NIPPV has encouraged its use in other acute situations, including during procedures such as percutaneous endoscopic gastrostomy (PEG)^57,58 or bronchoscopy,^59,60 for palliative use in patients listed as “do-not-intubate,”^61–63 and for oxygenation before intubation.⁶⁴

NIPPV during PEG tube insertion

NIPPV during PEG tube placement is particularly useful for patients with neuromuscular diseases who are at a combined risk of aspiration, poor oral intake, and respiratory failure during procedures. The experience with patients with amyotrophic lateral sclerosis⁵⁸ and Duchenne muscular dystrophy⁵⁷ indicates that even patients at high risk of respiratory failure during procedures can be successfully managed with NIPPV. The most recent practice parameters for patients with amyotrophic lateral sclerosis propose that patients with dysphagia may be exposed to less risk if the PEG procedure is performed when the forced vital capacity is greater than 50% of predicted.⁶⁵

In randomized trials of CPAP⁵⁹ or pressure-support NIPPV⁶⁰ in high-risk hypoxemic patients who needed diagnostic bronchoscopy, patients in the intervention groups fared better than those who received oxygen alone, with better oxygenation during and after the procedure and a lower risk of postprocedure respiratory failure. Improved hemodynamics with a lower mean heart rate and a stable mean arterial pressure were also reported in one of those studies.⁶⁰

Palliative use in ‘do-not-intubate’ patients

In patients who decline intubation, NIPPV appears to be most effective in reversing acute respiratory failure and improving mortality rates in those with COPD or with cardiogenic pulmonary edema.^61,62 Controversy surrounding the use of NIPPV in “do-not-intubate” patients, particularly as a potentially uncomfortable life support technique, has been addressed by a task force of the Society of Critical Care Medicine, which recommends that it be applied only after careful discussion of goals of care and parameters of treatment with patients and their families.⁶³

Oxygenation before intubation

In a prospective randomized study of oxygenation before rapid-sequence intubation via either a nonrebreather bag-valve mask or NIPPV, the NIPPV group had a higher oxygen saturation rate before, during, and after the intubation procedure.⁶⁴
 

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Acknowledgment: The authors wish to thank Jodith Janes of the Cleveland Clinic Alumni Library for her help with reference citations and with locating articles.