Domiciliary noninvasive ventilation for chronic respiratory diseases

Abstract

Patients with chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), neuromuscular diseases, kyphoscoliosis and obstructive sleep apnoea-obesity hypoventilation syndrome (OSA-OHS), are at a higher risk of decompensation in the form of hypercapnic respiratory failure leading to intensive care unit (ICU) admission and increased mortality. This article reviews the evidence of role of domiciliary noninvasive ventilation (NIV) in patients with diseases with chronic ventilatory failure, including the mechanism of the effect of (NIV).

Introduction

Type 2 respiratory failure occurs due to the inability of the respiratory system to remove carbon dioxide (CO₂), which leads to hypercapnia. Diseases commonly leading to hypoventilation and hypercapnia include chronic obstructive pulmonary disease (COPD), neuromuscular diseases, obstructive sleep apnoea-obesity hypoventilation syndrome (OSA-OHS), postinfective lung sequelae and chest wall deformity (early onset scoliosis and postthoracoplasty). Noninvasive ventilation (NIV) has been shown to be an effective therapy in these conditions improving quality of life (QoL) and decreasing morbidity and mortality. The review will discuss the chronic lung diseases leading to respiratory failure and the role of NIV in these conditions.

Hypercapnia, hypoventilation and ventilation failure

Hypercapnia refers to the rise in the arterial partial pressure of carbon dioxide (PCO₂), and it can occur due to decreased minute ventilation or increased CO₂ production. The latter will not usually be a problem, as the respiratory system has huge capacity to increase ventilation. However, the individual with a compromised respiratory system may be able to maintain a normal CO₂ until CO₂ production increases while on exercise or with intercurrent disease. Minute ventilation is delivered by the respiratory pump, which consists of chest wall, muscles of respiration and the central as well as peripheral nervous system leading to lung inflation with deflation almost always occurring passively. Failure of the respiratory pump leads to hypoventilation and hypercapnia.^1,2 Adequate ventilation requires an optimum interplay between the respiratory pump, the load against which it must work and central drive. Ventilatory failure occurs when respiratory muscle capacity is reduced, the load on respiratory muscles is increased or central drive is reduced. The reduction in central drive is due to reduced cortical input to the respiratory centre and is exaggerated especially during the rapid eye movement (REM) cycle of sleep. During REM sleep, ventilation is entirely dependent on the diaphragm, with absent activation of the intercostal and postural muscles. There is also reduction in input to the upper airway muscles, which leads to increased upper airway resistance. The reduction on capacity can be due to intrinsic weakness of respiratory muscles like in neuromuscular diseases or can be acquired due to mechanical disadvantage from chest wall deformity or due to COPD-related hyperinflation. Increased load can be due to airway obstruction, reduced lung compliance due to loss of lung elasticity and reduced chest wall compliance.^{2, 3, 4, 5, 6, 7} The dysfunction of load, drive and capacity in various chronic lung diseases is elaborated in Table 1.

Table 1.

The interplay of load, drive and capacity in various chronic lung diseases requiring NIV.

Disease	Load	Drive	Capacity
NMD	Increased due to: •Micro and macro atelectasis •Upper airway resistance due to bulbar weakness	No abnormality	Reduced due to •Intrinsic weakness of respiratory muscles
CWD	Increased due to: •Reduced chest wall compliance •Reduced lung compliance	No abnormality	Reduced due to •Mechanical disadvantage
COPD	Increased due to: •Airway obstruction •Intrinsic PEEP	No abnormality	Reduced due to •Hyperinflation-related mechanical disadvantage
OHS	Increased due to: •mechanical load of excess adipose tissue in chest wall •Lower airway resistance •PEEPi	Reduced	Reduced due to: •Diaphragmatic dysfunction •Decreased lung compliance

COPD, chronic obstructive pulmonary disease; CWD, chest wall disease; NMD, neuromuscular disease; OHS, obesity hypoventilation syndrome, PEEP, positive end-expiratory pressure; PEEPi, intrinsic positive end-expiratory pressure.

Airway obstruction leads to the development of intrinsic positive end-expiratory pressure (PEEP), which acts as an inspiratory threshold and wasting of initial inspiratory effort.^{3, 4, 5} NIV has been extensively used in many chronic diseases with hypoventilation, and these are reviewed.

Role of NIV in neuromuscular diseases

Neuromuscular diseases (NMDs) comprise a group of diseases that affects the nerves controlling the voluntary muscles and even the respiratory group of muscles. NMD leads to progressive impairment, leading to difficulty in ambulation, swallowing difficulties, worsening respiratory muscle weakness and, finally, death from respiratory failure. NMD is a common cause of increased morbidity and mortality in Western countries; however, with the advent of improved technologies in the form of NIV, the survival of these patients has improved.^{8, 9, 10}

The NMD leads to loss of central drive, loss of function at the neuron or neuromuscular junction, or destruction of muscle fibres. This progression can be acute like in myasthenia crisis, gradual like in muscular dystrophy, or rapidly progressive like in amyotrophic lateral sclerosis.^8,9 The neuromuscular respiratory dysfunction in NMD can be divided on the basis of their function: (1) inspiratory muscle involvement leading to impaired ventilatory function; (2) involvement of inspiratory, expiratory and glottic function, leading to impaired cough and secretion management dysfunction; and (3) dysfunction of swallowing and airway protection due to the involvement of glottis. The bulbar dysfunction in these patients not only leads to swallowing and speaking difficulties with limitation of airway secretion clearance but also leads to earlier development or worsening of sleep-disordered breathing due to upper airway obstruction. These issues can occur separately or even in combination with others. The progression of muscular weakness leads to alveolar hypoventilation, oxygen desaturation and hypercapnia. The inspiratory muscle dysfunction leads to an increase in work of breathing due to decreased pulmonary distention due to microatelectasis and later macroatelectasis and diminished distensibility of the chest wall due to muscle weakness–related secondary deformities.^{8, 9, 10, 11}

The NMD patients are at risk of frequent apnoeas and hypopneas during sleep due to the underlying respiratory muscle weakness and upper airway obstruction, and this nocturnal hypoventilation leads to increased PCO₂ levels, causing decreased central drive. The speed of progression of disease determines the worsening and survival.^8,9 The NMD with gradual weakness of respiratory muscles may present initially with vague symptoms such as headaches, nightmares, and generalised tiredness, which may be overlooked, and later, these patients complain of dyspnoea and orthopnoea finally progressing to frank respiratory failure. The initial symptoms usually develop during sleep, and there can be features of nocturnal hypoventilation such as broken sleep pattern, nightmares, nocturnal confusion, morning headaches, mental clouding, and increased somnolence. On examination, these patients may appear breathless and use the accessory muscles of respiration, signifying severe respiratory muscle weakness or respiratory failure. These patients are usually unable to speak sentences in one breath and have difficulty to count 1 to 20 in a single breath, indicating severe decrease in vital capacity (VC) or forced VC. It is important to monitor these patients in the form of spirometry, maximum inspiratory pressure (MIP), maximum expiratory pressure and sniff nasal inspiratory pressure, cough peak flow, pulse oximetry and arterial blood gas PaCO₂ levels. The MIPs, maximum expiratory pressures and sniff nasal inspiratory pressures are early markers and serve as markers for the progression of the disease. A VC of <1.11 L has been shown to predict an increased risk of pneumonia with a sensitivity of 90.5 and a specificity of 70.8%. Cough peak expiratory flow is also a sensitive test of cough efficiency, and a peak expiratory flow <270 mL/min is a marker of ineffective cough.^{8,9,11, 12, 13}

NIV has been shown to improve mortality and QoL in NMD patients. The most common indication of NIV in NMD includes amyotrophic lateral sclerosis, Duchenne's muscular dystrophy, Becker's muscular dystrophy, Spinal muscular dystrophy and rarely myasthenia gravis. The timely initiation of NIV in these patients is of paramount importance in improving survival and reducing mortality.^{9, 10, 11, 12} NIV should ideally be initiated in these patients at the onset of clinical features of nocturnal hypoventilation (Table 2). There has been evidence that starting NIV in these patients once pCO₂ > 45 mm Hg may be too late, and these patients should be evaluated for nocturnal hypoventilation in the form of clinical symptoms, overnight oximetry for initiation of NIV therapy. The benefits of NIV in NMD are multifactorial, which include rest to the respiratory muscles, improved central drive, changes in respiratory mechanics and improved sleep architecture. NIV has also been shown to prevent nocturnal hypoventilation and improve central drive to CO₂, ventilation and gas exchange during daytime. The use of NIV in these patients improves pulmonary function by increased recruitment of atelectatic zones, increased pulmonary distensibility and improved ventilation-perfusion ratios.^13,14 NIV is one of the most important pillars of therapy in these patients, which has shown to improve survival and QoL.^{9,11, 12, 13, 14, 15}

Table 2.

Indication of initiation of NIV in NMD patients.

Clinical symptoms

Daytime hypersomnolence

Tiredness, cognitive impairment, generalised fatigue

Morning headaches

Signs

FVC< 50% of predicted value

MIP/SNIP <60 mm Hg

Daytime pCO2 >45 mm Hg

Nocturnal room air SaO2 <88% for more than 5 min

SNIP/MIP <65 mm H2O for Men or 55 cm H2O for women plus any symptoms or signs of respiratory impairment especially orthopnoea

FVC, forced vital capacity; MIP, maximum inspiratory pressure; SNIP, sniff nasal inspiratory pressure.

Role of NIV in diseases involving chest wall

Kyphoscoliosis (KS) is a progressive chest wall restrictive disease caused by vertebral anomalies, leading to excessive spinal curvature in coronal and sagittal planes. The aetiology of KS can be multiple, including traumatic injury in childhood, tuberculosis of spine, postrachitic or neuromuscular KS due to poliomyelitis in childhood. The most common form of KS however is idiopathic KS. The onset of idiopathic scoliosis is generally before 8 years of age and can later usually leads to respiratory failure in 4th or 5th decade, whereas the adolescent-onset scoliosis is usually much less severe and does not lead to ventilatory failure. These patients are of short stature with reduced rib cage and trunk with a hump created by deformed thoracic cavity.^{3,16, 17, 18}

KS is characterised by decreased chest wall compliance and reduced respiratory mechanics, which leads to progressive hypoventilation, hypercapnia and, finally, chronic respiratory failure. Patients with KS are also at a higher risk of secondary pulmonary infection due to microatelectasis and impaired cough clearance. These patients are at a higher risk of progressive muscle fatigue, leading to hypoventilation and have a reduced QoL.^{17, 18, 19, 20} NIV has shown promising results in patients with KS and improved mortality in these patients. Domiciliary NIV has proved to reduce hospital admission and number of exacerbations. The use of NIV in KS improves daytime PCO₂ and even PO₂ levels.^{21, 22, 23} A study by Gustafson et al. had shown that domiciliary NIV increases the survival in KS by three times when compared with long-term oxygen therapy alone.²⁴ Another study by Ellis et al. confirmed that using NIV in KS improved the length and quality of REM sleep, increased PO₂ and decreased PCO₂ levels; however, there was no improvement in spirometry parameters.²⁵ A review article by Turkington and Elliott clearly described the benefit of domiciliary NIV in KS, which included (1) improved nocturnal blood gas and decreased sleep disturbance leading to increased respiratory drive and (2) improvement in the chest wall and lung compliance due to “stretching action,” which leads to higher functional residual capacity, opening of low ventilation/perfusion lung segments, thus reducing the shunts.³ Domiciliary NIV in KS has also been documented to improve the MIP levels in these patients. In a study by Leger et al. constituting 276 patients of KS or post tubercular sequelae including post thoracoplasty, the addition of NIV to the therapy showed significant improvement in PaCO₂ and PO₂ and reduced admission in hospital for acute exacerbation.²⁶

Role of NIV in COPD

COPD is a common chronic respiratory disease, which is characterised by persistent respiratory symptoms and airflow limitation. The prevalence of COPD is ever increasing due to increase in smoking population and even in nonsmoking groups, especially in developing countries using biomass as fuel. The COPD-related deaths are expected to be 5.4 million annually by 2060. The COPD cases in India have increased from 28.1 million in 1990 to 55.3 million in 2016, and COPD is the second commonest cause of disease-related death in India.²⁷

COPD is a progressive disease, and many patients usually develop respiratory failure, which can be hypoxemic or hypercapnic. Hypoxia occurs due to impaired gas exchange, whereas hypercapnia is secondary to impaired ventilation. Some patients with COPD only develop type 2 respiratory failure with exacerbations.^28,29 Patients with chronic hypercapnia are more prone to hospitalisation and with more rapid clinical deterioration. COPD patients may develop nocturnal hypoventilation especially during the REM cycle of sleep. Decreased central respiratory drive may also contribute.^{28, 29, 30, 31} An elevation in PaCO₂ (>5 mm Hg) has been shown to increase the mortality in these patients.³¹

NIV is an effective modality for the management of acute exacerbation of COPD with type 2 respiratory failure; it reduces the need for endotracheal intubation, the length of hospital admission and mortality in such patients.^{3,32, 33, 34, 35, 36} There are some studies on the use of NIV in stable COPD, which have shown favourable results. It has been shown to reduce lung hyperinflation, diaphragmatic contractile dysfunction, workload of respiratory muscles, and increased ventilatory chemosensitivity to carbon dioxide. The other documented benefits include reduced dyspnoea, improved exercise tolerance, health-related QoL, improved benefit from pulmonary rehabilitation and even better neuropsychological function.^{32, 33, 34, 35, 36, 37, 38} The addition of NIV to stable hypercapnic COPD has also shown to improve lung function in the form of improved forced expiratory volume in 1 s, which can be due to reduced airway oedema, effect of PEEP and stretch opening of chronically fibrosed airways. There is insufficient data regarding the use of domiciliary NIV in hypercapnic COPD patients. Initial meta-analysis and a Cochrane systematic review did not show benefit to COPD patients with domiciliary NIV in terms of hospitalisation risk or mortality and improvement in lung function; however, some of these studies did show reduction in PaCO₂ levels and improvement in QoL.^{3,28,32, 33, 34, 35, 36, 37, 38}

There have been conflicting results of domiciliary NIV in initial studies; however, some recent studies have shown significant results in favour of home NIV in stable hypercapnic COPD patients.^{39, 40, 41} A study by Galli et al. showed a significant reduction in hospital admission due to acute exacerbation of COPD in patients using home NIV, whereas another study by Coughlin et al. showed that patients requiring recurrent admission for COPD had reduction in number of admissions when NIV was added as an adjunct therapy to their medical management.^42,43 There have been further studies showing improved QoL, exercise tolerance and even anxiety levels in patients on domiciliary NIV.^44,45 According to a multicentre trial from Germany and Austria, which compared domiciliary NIV with standard care in stable hypercapnic COPD patients, the study included 195 patients with stable COPD (PaCO₂ >51.9 mm Hg and pH > 7.35), and there was a significant reduction in mortality in patients using NIV within 1 year.⁴⁶

Role of NIV postacute exacerbation of COPD

In Respiratory Support in COPD after acute exacerbation trial, patients who were initiated on domiciliary NIV after admission with acute decompensated type 2 respiratory failure did not show significant mortality benefit or reduction in number of admissions in the first year postdischarge.⁴⁷ However, there has been evidence in favour of domiciliary NIV in a recent randomised control trial by Murphy et al, which included 116 patients with persistent hypercapnia (PaCO₂ >53 mmHg) 2–4 weeks after an acute exacerbation of COPD. They randomised these patients to NIV with home oxygen vs home oxygen alone during clinic visit after 2–4 weeks of discharge from hospital following an acute exacerbation of COPD requiring NIV in hospital. There was significant reduction in time to readmission and death within 12 months of discharge from the hospital in these patients.⁴⁸

The European Respiratory Society guidelines on long-term home NIV for the management of COPD published in 2019 clearly recommend optimum management of hypercapnia in COPD patients with chronic respiratory failure for improving the outcome in these patients. The society had recommended the use of domiciliary NIV in patients with hypercapnic failure to reduce exacerbations and hospital admissions. The NIV therapy in these patients should be targeted to reduce the PaCO₂ levels.³²

These studies excluded patients with significant obesity; such patients may be expected to gain from NIV, given the data from patients with OHS. In one study, patients with body mass index (BMI) >30 kg/m² had better survival when compared with patients with lower BMI.^{49, 50, 51}

Pulmonary rehabilitation may be an issue for some COPD patients because of their difficulty in performing prolonged exercise training. These patients while exercising tend to develop dynamic hyperinflation due to increase in end-expiratory volume, which is caused by increased respiratory rate and decreased expiratory flow. NIV has been postulated to offload these respiratory muscles and improve exercise capacity when added during the exercise training. There have been small studies, which have shown that adding home NIV with exercise training leads to greater improvement in blood gases and even 6-minute walk test (6MWT) distance; however, this role still needs to be validated by larger studies.^{52, 53, 54, 55, 56, 57, 58}

Role of NIV in OSA-OHS

Obesity hypoventilation syndrome includes morbid obesity (BMI >30 kg/m²), daytime hypercapnia (arterial carbon dioxide level >45 mm Hg) during wakefulness with features of sleep-disordered breathing with absence of any other neuromuscular, mechanical or metabolic cause. These patients have significant comorbidities such as hypertension, coronary artery disease, metabolic syndrome, heart failure and pulmonary hypertension. These patients have clinical features of daytime hypercapnia in the form of early morning headaches and can be confirmed by raised PaCO₂ on arterial blood gas. The mechanism includes obesity-related alteration in respiratory system mechanics and drive- and sleep-related breathing abnormalities. The hypercapnia in these patients is also contributed by excess retained CO₂ during the apnoea spell, which is more than what is disposed of during the arousal-mediated hyperventilation. Most of the patients of OHS (>70%) have concomitant severe OSA with apnoea/hypopnea index >30 events per hour. The American Academy of Sleep Medicine has defined sleep-related hypoventilation as PaCO₂ >55 mm Hg for >10 min or an increase in PaCO₂ >10 mm Hg compared with an awake supine value to 50 mm Hg for >10 min. The presentation of these patients can be as an acute on chronic type 2 respiratory failure. These patients are usually very obese (BMI > 40 kg/m²) and have features of hypoventilation and can also have findings of complications such as cor pulmonale. The alveolar hypoventilation can be confirmed by an arterial blood gas at room air, and a serum bicarbonate of value >27 has a 92% sensitivity for identifying awake hypercapnia in obese individuals. A serum bicarbonate of value <27 mEq/L has a negative predictive value of more than 97% for excluding the diagnosis.^{59, 60, 61, 62, 63, 64}

The pathophysiology includes (1) obesity-related changes in respiratory mechanics, (2) alterations in the respiratory drive and (3) sleep-related breathing abnormalities. These patients have an excess deposit of adipose tissue in their abdominal and chest wall, which reduces the Functional Residual Capacity (FRC) and ERV and can have direct mechanical effects on respiratory mechanics such as reduced diaphragmatic excursion and lung compliance and increased lower airway resistance. This premature airway closure causes an intrinsic PEEP, which leads to ventilation/perfusion mismatch. This increased respiratory load initially causes increase in respiratory drive; however, in these patients, this increased drive cannot be maintained, leading to hypoventilation, which is initially confined to REM sleep. During REM sleep, there is generalised muscle hypotonia, and the ventilation is dependent on diaphragmatic activity and central drive. In OHS patients, there is diaphragmatic dysfunction and reduced central drive, which causes REM-related hypoventilation, and this repeated event can lead to secondary depression of respiratory centres, leading to daytime hypercapnia and OHS. There is also intrinsic central resistance to leptin, which further deteriorates the respiratory function.^{59, 60, 61, 62, 63, 64, 65}

Continuous Positive Airway Pressure (CPAP) has conventionally been used to treat patients with OHS and has proven to be beneficial in these patients with improvement in gas exchange, leading to decreased daytime PCO₂ and increased arterial PO₂ tension. CPAP therapy in these patients has shown to improve sleepiness, dyspnoea and even their QoL. CPAP has shown similar improvements compared with bi-level ventilation, and this effect can be due to the fact that in OHS, there is a major component of upper airway collapse, which is improved by both CPAP and bi-level Positive Airway Pressure (PAP). Domiciliary NIV has shown to improve mortality in these patients from 5% to 32%.^{66, 67, 68, 69, 70} In a randomised control trial by Borel et al, domiciliary NIV led to significant decrease in daytime PaCO₂ and improvement in sleep-disordered breathing when compared with just lifestyle modifications.⁶⁶ The Pickwick project including more than 300 patients with severe OSA showed beneficial effects of home NIV in terms of daytime PaCO₂, sleep parameters and health-related QoL.⁶⁵ The use of NIV also improved the functional parameters such as FRC, forced expiratory volume in 1 s and 6MWT.^{62, 63, 64, 65, 66, 67, 68, 69, 70, 71} There has been increased incidence of cardiac complications in OHS patients such as right ventricular dysfunction and pulmonary hypertension. There have been some studies, which have shown benefits of NIV in cardiac outcomes with reduced pulmonary systolic artery pressure in patients with initial baseline echocardiographic evidence of right ventricular overload and increased 6MWT.^72,73 The Pickwick project also showed improvement in systolic pulmonary artery pressure and left ventricular hypertrophy.⁷³ Adherence plays a major role in the beneficial effects of NIV.

Palliative role of NIV

Breathlessness is a cardinal symptom of end-stage chronic lung disease and has a major impact on the QoL of these patients. Patients with advanced COPD and end-stage pulmonary malignancies have a major element of breathlessness, and the American Thoracic Society has recommended that these patients should be given palliative care and all efforts should be made in ameliorating this symptom. However, there is not much evidence of using NIV in advanced COPD for palliation.^{74, 75, 76} The use of NIV in these patients can offload the fatigued respiratory muscles, leading to decreased work of breathing and symptoms. A randomised trial by Nava et al. of 200 patients with solid tumours showed a benefit in dyspnoea as measured by the Borg scale.⁷⁷ However, there are many issues, which can limit the widespread use of NIV as palliation, including perceptions among the patients and caregiver that it can prolong the agony, uncomfortable mask, claustrophobia etc.

Conclusion

Patients with chronic lung diseases have a poor QoL and are at a risk of decompensation in the form of hypoventilation and type 2 respiratory failure. NIV is a simple and effective treatment for these patients. It has multiple benefits, and a good adherence to this therapy can lead to improved survival and QoL. NIV has been traditionally advocated for neuromuscular patients with chronic respiratory failure, but there is enough evidence present now which warrants its use even in patients with chronic hypercapnic COPD and other chronic lung diseases.

Disclosure of competing interest

The authors have none to declare.