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Journal of The Association of Physicians of India ■ Vol. 65 ■ May 201760

Consensus Document on Home Nebulization for Maintenance Treatment of Obstructive Airway Diseases: A Joint Initiative by the National Allergy Asthma Bronchitis Institute (NAABI) and Chest Research Foundation (CRF) Aloke G Ghoshal1, Sundeep Salvi2, Raja Dhar1,6, Randeep Guleria3, Ashok Mahashur4, Anshuman Mukhopadhyay1, RMPL Ramanathan5

1National Allergy Asthma Bronchitis Institute (NAABI), Kolkata, West Bengal; 2Chest Research Foundation (CRF), Pune, Maharashtra; 3All India Institute of Medical Sciences (AIIMS), New Delhi; 4PD Hinduja Hospital, Mumbai, Maharashtra; 5PSG Hospital, Coimbatore, Tamil Nadu; 6Fortis Hospitals, Kolkata, West BengalReceived: 19.10.2016; Accepted: 30.03.2017

C O N S E N S U S S T A T E M E N T

AbstractRecent years have seen an increase in the use of nebulizers for delivering maintenance therapy in obstructive airway diseases (OADs) such as asthma and chronic obstructive pulmonary disease (COPD). The probable factors associated with this increase at home are: convenience of drug delivery, technological advances making the nebulizer equipment more efficient and portable, increase in the prevalence of OADs and the ageing population which may impact the optimal use of handheld inhalers such as pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Although there is increase in the use of maintenance therapy with nebulization, there has been no such increase in the evidence base available for the appropriate use of nebulizers. The last international guidelines were published in 2001. Hence there is a need to address this knowledge gap especially with the widespread use of home nebulization in India. With this objective, we organized a consensus meeting to address certain critical questions pertaining to the use of nebulizers for maintenance treatment in OADs. This article presents the findings of the consensus panel on the use of maintenance treatment of OADs with nebulization at home.

Introduction

Globally, there are an estimated 334 million and 384 million

individuals suffering from asthma and chronic obstructive pulmonary disease (COPD), respectively.1,2 The approximate prevalence rate of asthma and COPD in India is around 17.23 million and 15 mil l ion, respect ively , 1,2 which possibly could be under-reported since questionnaire-based data may not reflect the true prevalence.

But, when categorized together as obstructive airway diseases (OADs), they account for being the second most commonly diagnosed condition in the primary healthcare practice in India.3-5 Although global trends in the asthma mortality rate show a decline, it remains high

in the low- and middle-income countries.1,6 More cause for concern is the mortality rate of COPD, both globally and in India. Currently the third most common cause of death worldwide, COPD is the second leading cause of death in India and kills around half a million individuals every year.7,8

While the increasing mortality r a t e s o f C O P D a r e c e r t a i n l y distressing, the morbidity brought forth by this condition is further perturbing. The Global Burden of Disease (GBD) reveals that COPD is among the top ten causes of disabil i ty in India, ranking at number five.9 With changing demographics in the form of an ageing population coupled with the fact that COPD is a progressive disease often diagnosed in middle age, India is soon going to see vast numbers of individuals disabled by this condition. Additionally, the burden of comorbidities in COPD increases as the disease progresses and many patients suffer from cognitive or manual impairments either due to the disease or ageing10,11 which may

Journal of The Association of Physicians of India ■ Vol. 65 ■ May 2017 61

make them partially or completely h o m e b o u n d . T h e i n c r e a s i n g comorbidities, which reduce the cognitive and manual abil it ies of patients, adversely affect the most important aspect of COPD management – the correct use of inhalation therapy.

I n h a l a t i o n t h e r a p y i s t h e mainstay for drug del ivery in OADs and consists of pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), breath-actuated inhalers (BAIs), soft mist inhalers (SMIs) and nebulizers. All inhalation devices require training the patient on the correct inhalation technique as it determines the drug delivery to the lungs and, consequently, the effectiveness of the treatment. The use of inhaler d e v i c e s d e p e n d s o n va r i o u s factors, which include efficacy and safety of the medicat ion, clinical setting, ability to use the

device with multiple medications patient’s age and ability to use the device, and patient preference and convenience.12

Several studies have shown that some people, especially the elderly people, f ind it diff icult to use inhaler devices effectively. Some of the common issues with the use of inhalers in the elderly are as follows: 1) lack of hand-breath coordination, 2) short breath-holding period, 3 ) t o o r a p i d i n s p i r a t i o n , 4 ) inadequate shaking of the inhaler, 5) stopping inhalation abruptly, and 6) improper actuation.13 In addition, the use of inhaler devices is challenging for the elderly as t h e y h a ve d e c r e a s e d m a n u a l dexteri ty, impaired cognit ion, muscle weakness/pain, cannot use handheld inhalers despite repeated instructions, are unable to produce enough inspiratory efforts, have decreased vital capacity and need long-term therapy due to frequent exacerbations.11,14,15

I n s u c h c l i n i c a l s c e n a r i o s , n e b u l i z e r s c o u l d b e a u s e f u l alternative to handheld inhalers because optimum drug delivery is not completely dependent on patient effort. Nebulization can

be used in the home setting, in a long-term care setting, in a hospital setting, and in an emergency room setting.16-18 Moreover, there have been several advances in nebulizer technology, making them more patient- and pocket-friendly along with increased avai labi l i ty of nebul ized drug formulat ions . According to crude estimates, such factors have led to an increase in the number of patients being prescribed nebulization in both in-patient and out-patient settings.19 Nebul izers , however , are not without drawbacks, particularly that of increased risk of adverse e f f e c t s ( A E s ) a n d a c q u i r e d infections. Hence, it is imperative that nebulizers be prescribed to patients after careful deliberation.

However, there is insufficient evidence to guide the correct and appropriate use of nebulizers, which is a valid concern amongst many respiratory physicians. The Brit ish Thoracic Society (BTS) and European Respiratory Society (ERS) have released guidelines on nebulization in 1997 and 2001, respectively.20,21 The last consensus document, specifically on home nebul izat ion in OADs, by the National Association for Medical Direct ion of Respiratory Care (NAMDRC), USA, was released in 1996 – that is, nearly 20 years ago.14 There are no recommendations available from India on the correct use of nebulizers (hospital or home) although (anecdotally), the use of nebulizers in increasing in the country.

With the objective of addressing this knowledge gap in the use o f home nebul iza t ion for the maintenance treatment of OADs, a consensus meeting was jointly organized by NAABI and CRF. The following is a report of this meeting.

Objective

The objective of this consensus meeting was to formulate expert views, using the available evidence,

Fig. 1: Workflow of consensus meeting and preparation of the document

Panel 1: Topics identified as a background work to the consensus meeting

1. What should be the appropriate terminology and def ini t ion to describe maintenance treatment with nebulization at home?

2. How should one identify/select patients suitable for maintenance treatment with nebulizers?

3. What should be the duration of m a i n t e n a n c e t r e a t m e n t w i t h nebulization?

4. Which are the drugs that can be prescribed for maintenance treatment with nebulizers and with which type of nebulizer equipment?

5. What i s the long- term sa fe ty of maintenance treatment with nebulization at home?

6. Are there any special precautions for OAD patients with comorbid conditions such as cardiovascular diseases (CVDs) and diabetes?

7. What are the cleaning and maintenance recommendations that need to be communicated to patients using long-term nebulization?

8. Should oxygen-driven nebulization be used in COPD patients on maintenance treatment with nebulization at home?

9. At what time intervals should patients using nebulization at home be assessed?

10. How should the success of therapy be assessed and adherence ensured in patients using long-term nebulization?

11. Can home nebulization be prescribed in other chronic respiratory diseases?

Conveners (Aloke G. Ghoshal and Sundeep Salvi) iden�fied 5 experts and ques�ons to be

addressed during the mee�ng

Conveners assigned ques�ons for discussion amongst the working group (conveners and

experts)

Presenta�on of the findings by the individual par�cipants

Discussion on the ques�ons and arrival at consensus on the day of the mee�ng

Prepara�on of the consensus document post the mee�ng


on the optimal use of maintenance treatment with nebulization at home.

Methodology

The consensus meeting was convened through an expert panel cons i s t ing o f pu lmonolog is t s from dif ferent geographies in India as well as different clinical settings (medical colleges, research institutes, private hospitals and private clinics). Prior to the meeting, common questions on maintenance treatment with nebulizers (Panel 1) were identified by the conveners and individual panellists were assigned to research the available evidence with respect to a particular question (Figure 1). At the meeting, the individual panellists presented their findings and a consensus was arrived at through discussion (Figure 1).

Scope of the Consensus Document

This consensus document can have application in the following areas:1. Physicians treating chronic

OADs such as asthma and COPD.

2. P h y s i c i a n s c o n s i d e r i n g prescribing nebulization for long-term use at home.

3. Patients with chronic OADs such as asthma and COPD.

4. P a r a m e d i c s m a n a g i n g patients with OADs through nebulization at home.

The consensus panel does not intend to promote the use of nebulizers over other handheld devices and urges all physicians treating respiratory diseases to not replace handheld inhalers such as pMDIs and DPIs with nebulizers, and to make all possible efforts to ensure that patients use the pMDIs and DPIs optimally.

Q 1 : W h a t s h o u l d b e t h e appropriate terminology and definition to describe maintenance

treatment with nebulization at home?

I t h a s b e e n o b s e r ve d t h a t m a i n t e n a n c e t r e a t m e n t w i t h nebul izat ion at home is of ten referred to as ‘home nebulization’. T h i s t e r m i n o l o g y p r o b a b l y a rose f rom prev ious s tudies , reviews and also some consensus s tatements . 14,18 ,20 ,22 ,23 The other t e r m i n o l o g y o b s e r ve d i n t h e literature was ‘domiciliary use’ of nebulizers.14,21,24 However, the panel noted that both these terminologies are unclear about chronic use or intermittent use of nebulizers at home. Hence, we suggest that the appropriate terminology should be ‘maintenance nebulization’, which would imply the chronic use of nebulizers for delivering maintenance treatment at home. It can be defined as a physician-prescribed therapy to deliver long-term maintenance drugs (≥3 weeks duration) in carefully selected patients.

B o t h t h e t e r m s ‘ h o m e nebulization’ and ‘maintenance nebul izat ion’ have been used interchangeably. However, we suggest that acute use and short-term use (<3 weeks) of nebulizers at home be a part of the umbrella term ‘home nebul izat ion’ and be considered different from the term ‘maintenance nebulization’ proposed in this document. Rescue use of nebulization at home should be considered as a part of the maintenance regimen for OADs.

The key terms in the proposed d e f i n i t i o n a r e ‘ p h y s i c i a n -prescribed’, ‘maintenance drugs’ a n d ‘ a p p r o p r i a t e l y s e l e c t e d patients’. These key terms should be considered central to the concept of maintenance nebulization.Recommendation

M a i n t e n a n c e t r e a t m e n t o f OADs with nebulization at home can be referred to as ‘maintenance nebulization’ rather than ‘home nebulization’ to specifically imply long-term chronic use (≥3 weeks).• Maintenance nebul iza t ion

can be defined as physician-prescribed therapy to deliver long-term maintenance drugs (≥3 weeks) in appropriately selected patients with OADs.

Q2: How should one identify/s e l e c t p a t i e n t s s u i t a b l e f o r m a i n t e n a n c e t r e a t m e n t w i t h nebulizers?

Given the potential for misuse of nebulization in patients with OADs, the consensus panel recommends a careful screening of patients for maintenance nebulizat ion. We reviewed the recommendations avai lable from two guidel ines (BTS 1997 and ERS 2001) and one consensus report (NAMDRC 1 9 9 6 ) . 1 4 , 2 0 , 2 1 A d d i t i o n a l l y , we examined original reports and review ar t i c les publ i shed t i l l March 2015 through PubMed and Google Scholar for identifying the patient categories most suitable for maintenance nebulizat ion. In most o f the l i t e ra ture , we observed a descriptive approach for selecting patients for maintenance nebulization, including a clinical review by Dolovich and Dhand (2011),11 which lists the various c l in i ca l s cenar ios in pa t ients with COPD where maintenance nebulization may be preferred over handheld inhalers.

However , we rea l ized tha t having an algorithmic approach to selecting a patient for maintenance nebulization is more practically r e l e va n t . F i g u r e 2 d e s c r i b e s the algorithm proposed by the consensus panel after review of the literature at the convened meeting.Recommendation

Patients should be carefully screened before prescr ipt ion of maintenance nebulizat ion. More importantly, the screening should focus on the ability to use handheld inhaler devices and every effort should be made to introduce/re-introduce drug administration through handheld inhalers . Pat ient sat is fact ion and choice should also be taken into account when considering


Fig. 2: Algorithm to identify OAD patients for maintenance nebulization

*Clinical improvement should be assessed as recommended by the respective treatment guidelines. #Device technique should be assessed as per the patient information literature provided with the device.

+Unsatisfactory device technique is any deviation from the recommended device technique described in thepatient information literature provided with the device.

Device technique unsatisfactory but clinical improvement

Retrain on the device. Investigate the reason for clinical improvement (natural history of the disease? no triggers? disease variability? other treatments?)

Check the reasons for unsatisfactory device technique/suboptimal improvement: � Inspiratory flow/breath-holding capacity inadequate? � Cognitive impairment? � Physical impairment? � Comorbidities? � Need high doses? Prescribe trial maintenance nebulization for 3 weeks.

If there is clinical improvement, prescribe maintenance nebulization and follow-up every 1 month initially and, later, annually. Check possibility of re-introducing handheld inhalers either alone or concomitantly with nebulizers. If no clinical improvement, then investigate further on the diagnosis.

Device technique satisfactory and clinical improvement

Device technique satisfactory but no/suboptimal clinical improvement

Device technique unsatisfactory+ and no/suboptimal clinical improvement

Continue with regular follow-up every 3 months

Switch to the other handheld device (change to pMDI/DPI, based on initial prescription)

Maximize treatment accordingly, based on guideline recommendations

Check clinical improvement and device technique after 2–3 weeks

Clinical improvement with satisfactory device technique

No/suboptimal clinical improvement and unsatisfactory device technique

Clinical improvement but unsatisfactory device technique

Patient with a confirmed diagnosis of OAD

Prescribe appropriate guideline-based treatment + through a handheld inhaler (pMDI/DPI), taking patient preference into account.

After 2–3 weeks, check clinical improvement* along with device technique.#


h a n d h e l d i n h a l e r s v e r s u s nebulizers for long-term use. Additionally, the advantages and drawbacks of all inhaler devices, including nebulizers, should be explained to the patients so as to facilitate an informed decision.

Q3: What should be the duration of maintenance treatment with nebulization?

S i n c e t h e m i n i m u m a n d maximum duration of therapy cannot be defined in the realm o f c h r o n i c t r e a t m e n t , t h e panel reviewed the l i terature wi th regards t o main tenance nebul izat ion. The durat ion of maintenance nebulization could last from a minimum of 2–3 weeks (ERS guidelines and NAMDRC guidelines)14,20 to an indeterminable period of time. One prospective study by O’ Driscoll and Bernstein25 with 49 asthma and COPD patients found the survival rates to be similar amongst patients using maintenance nebulization (n=32) and pMDI + spacer (n=17) over a period of 5 years. Additionally, t h e r e h a ve b e e n s t u d i e s t h a t have assessed the safety of the n e b u l i z e d l o n g a c t i n g b e t a 2 agonists (LABAs) over a period of 1 year (formoterol and arformoterol studies).26-28 In view of the available evidence, we concluded that the minimum durat ion for which maintenance nebulization can be safely prescribed in patients with OADs is (but not limited to) 3 weeks. However, we cannot make a similar recommendation for the maximum duration of therapy with maintenance nebulization since it is subject to disease mechanisms and the requirement of the patients, a l though there are publ i shed studies that indicate a 1-year safety period for certain nebulized formulations such as LABAs. Recommendation

The minimum durat ion o f maintenance therapy that can be prescribed in a patient with OAD is 3 weeks. However, no recommendation can be made on the maximum duration of therapy.

The decision to end/continue maintenance nebulization lies with the prescribing physician after taking into account the subjective and objective improvement along with ensuring that there are no concerns regarding AEs with the prescribed nebulized formulations.

Q4: Which are the drugs that can be prescribed for maintenance treatment with nebulizers and with which type of nebulizer equipment?

In keeping with the advances i n t h e n e b u l i z e r d e s i g n a n d technology, there has been an e x p o n e n t i a l i n c r e a s e i n t h e approvals for nebulized drugs available in the market. Table 1 lists the approved nebulized drugs that can be prescribed for maintenance nebulization in OADs. This list contains the drugs that can be used on an as-needed, short-term or long-term basis.

S i n c e c o m p a t i b i l i t y o f t h e nebulizer and the drug formulation is important for optimum drug deposit ion, selecting the right nebulizer is equally important. Various factors such as output rate , performance var iabi l i ty , effect of nebulization on drug formulat ion and cleaning and maintenance should be considered when selecting a nebulizer for the patient (Table 3).11

Recommendation

Selecting the right drug and the right nebulizer is important for the success of maintenance nebulization in OADs. Prescribers are advised to refer to the exact i n d i c a t i o n s , p o s o l o g y a n d administration available in the prescribing information of the available drugs.

Q5: What is the long-term safety of maintenance treatment with nebulization at home?

There is a paucity of data in terms of the long-term safety of maintenance nebulization. This is probably due to the logistical difficulties in conducting long-term, randomized, controlled trials

with maintenance nebulization.20 Moreover, most of the long-term clinical trials with maintenance nebulization, which have been published (to our knowledge), involved drugs in respect of which there are some concerns about AEs with long-term use, such as LABAs. In a 1-year, open-label study with 569 COPD pat ients rece iv ing either nebulized formoterol (20 mcg b.i.d.) or DPI formoterol (12 mcg b.i.d.), no differences were observed between the dosage forms in terms of AEs, cardiac and laboratory parameters.27 The only published study (to the best of our knowledge) , which has assessed the long-term safety of maintenance nebulization for more than a year, is the 5-year s u r v i va l s t u d y b y O ’ D r i s c o l l a n d B e r n s t e i n 2 5 m e n t i o n e d previously. Table 3 reviews the safety evaluation performed across various published studies with nebulized formulations of steroids and bronchodilators.

L o o k i n g a t t h e l i m i t e d evidence base available, the panel recommends a regular review of the patients on maintenance nebulization for local and systemic A E s a n d , p o s s i b l y ( a t l e a s t annually, based on the 1-year safety studies with LABAs),27,28

also of the laboratory and cardiac parameters (Table 4). Baseline ECG and an echocardiography and a close follow-up after 1 month (may be with an ECG) in association with a cardiologist is recommended for patients with known heart disease. Recommendation

To ascertain long-term safety in pat ients wi th OADs, i t i s recommended to perform a regular review (at least every 6 months).

Q 6 : A r e t h e r e a n y s p e c i a l precautions for OAD patients with comorbid conditions such as CVDs and diabetes?

A l t h o u g h t h e r e i s s o m e theoretical concern about the use of nebulized drugs in OAD patients with comorbid conditions such as


841 COPD patients (age ≥40 years, baseline FEV1 ≤65%) receiving either nebulized arformoterol or placebo for 1 year, there was no conscious effort made to exclude patients with an underlying CVD. Although there were numerically m o r e s e r i o u s c a r d i a c A E s i n patients taking arformoterol (3.1%) than placebo (2.4%), no significant differences were observed between the treatment groups in terms of time to the first serious cardiac AE.28 The BTS guidelines on the use of nebulizers in COPD recommends ECG monitoring as a precaution after the first dose of nebulized bronchodilator is administered to the COPD pat ient wi th an underlying cardiac condition.21

Just as is the case with nebulized beta2-agonists, there are no studies that have evaluated the effects of nebulized corticosteroids in OAD patients with underlying comorbid diabetes. One study by Faul et al.45 assessed the effects of high-dose fluticasone (880 mcg/day) on asthma or COPD patients with comorbid type 2 diabetes mell i tus for 12 weeks and did not find any significant effect of the treatment on glycosylated haemoglobin. However, the authors recommended monitoring blood glucose levels in patients taking high-dose ICS with concomitant diabetes.

One of the concerns with the use of nebulized beta2-agonists is the transient and dose-dependent decrease in serum potassium levels, as noted by a few studies.46-48 There are no recommendations available to suggest at what intervals should the serum potassium levels be monitored in patients using beta2-agonists through maintenance nebulization.

In view of the available evidence, the present panel realizes that although monitoring blood glucose in OAD patients with diabetes is possible, regular monitoring of pat ients for cardiac events may not be practically feasible. As recommended prev ious ly ,

Table 1: Approved or recommended nebulized drugs in India for use in home nebulization

Drug class Molecule Recommended use (in adults)*

Short-acting beta2-agonist (SABA)

Salbutamol As-needed use in OADsLevosalbutamol

Long-acting beta2-agonist (LABA)

Formoterol Long-term maintenance in COPDArformoterol

Short-acting muscarinic antagonist (SAMA)

Ipratropium bromide Long-term maintenance in COPD

Inhaled Corticosteroids (ICS) Fluticasone Long-term maintenance in asthmaBudesonide

SABA + SAMA Salbutamol + ipratropium Long-term maintenance in COPD/ as-needed use in maintenance regimen in COPDLevosalbutamol + ipratropium

ICS + SABA Budesonide + levosalbutamol Long-term maintenance in asthmaBudesonide + salbutamol

ICS + LABA Budesonide + formoterol Long-term maintenance in OAD

Mucolytics N-acetylcysteine Short-term adjuvant use in OAD in case of mucus hypersecretionAmbroxol

*For exact indications, posology and administration, please refer to the prescribing information available from the manufacturer of the respective products.

Table 2: Characteristics of different types of nebulizers

Jet Ultrasonic Vibrating meshFeaturesPower source Compressed gas or

electrical mainsElectrical mains Batteries or electrical

mainsPortability Restricted Restricted PortableTreatment time Long Intermediate ShortOutput rate Low Higher HighestResidual volume 0.8-2.0 mL Variable but low ≤0.2 mLEnvironmental contaminationContinuous use High High HighBreath-activated Low Low LowPerformance variability

High Intermediate Low

Formulation characteristicsTemperature Decreases* Increases† Minimum changeConcentration Increases Variable Minimum changeSuspensions Low efficiency Poor efficiency Variable efficiencyDenaturation Possible‡ Probable‡ Possible‡Cleaning Required, after single

useRequired, after multiple use

Required, after single use

Cost Very low High High*For jet nebulizers, the temperature of the reservoir fluid decreases about 15°C during nebulisation because of evaporation; †For ultrasonic nebulizers, vibration of the reservoir fluid causes a temperature increase during aerosol generation, which can be as high as 10–15°C.; ‡Denaturation of DNA occurs with all the nebulisers; (With permission from Dolovich M, Dhand, R; The Lancet 2011)

CVD and diabetes, the panel did not come across any study specifically evaluating the effect of nebulized drugs in such specific populations. The safety tr ia ls of nebulized LABAs such as formoterol and arformoterol generally exclude COPD patients with underlying

cardiac conditions.26,27,44 However, i t i s poss ib le that h igh doses of drugs such as beta-agonist bronchodilators may be harmful in COPD patients with underlying cardiac disease.21 In a recently published randomized controlled trial by Donohue et al.28 involving


for the purpose o f long- term sa fe ty wi th nebul ized drugs , OAD patients with comorbidities such as CVD and diabetes should be reviewed regularly (at least annually) for blood glucose and cardiac parameters. Since it is practically difficult to measure serum potassium in patients taking long-term nebulized beta2-agonists, it is prudent to advise the patient and the carers to be aware of the general signs and symptoms of hypokalaemia and report to the emergency department if noticed. Recommendation

OAD patients with complicating comorbidities such as CVD and d i a b e t e s s h o u l d b e r e v i e we d regularly (every 6 months) for blood glucose and cardiac parameters.

Q7: What are the cleaning and maintenance recommendations that need to be communicated to the patients using long-term nebulization?

Nebul izers requi re regular cleaning and maintenance. Ideally, nebulizers should be cleaned after every use; however, since this may not be practically possible, we r e c o m m e n d c l e a n i n g a n d disinfecting the nebulizer at least once a day. Many manufacturers of nebulizers also recommend c leaning and dis infect ing the nebulizer before using for the first time and if the nebulizer has not been used for a long time.

Since it depends on the nebulizer and the frequency of use , the ins t ruct ions for c leaning and maintenance of the nebulizer should follow the recommendations made by the respective manufacturers since nebulizers are of different t y p e s a n d m a n u f a c t u r e d b y different companies. Table 5 lists the general instructions for the cleaning and maintenance of jet, ultrasonic and mesh nebulizers. Recommendation

Patients should be educated on the cleaning and maintenance of their nebulizers, and a periodic review of the nebulizer should

be performed by the prescribing physician. Patients should be advised to clean the nebulizer accessories at least once a day.

Q8: Should oxygen-dr iven nebulization be used in COPD patients on maintenance treatment with nebulization at home?

L o n g - t e r m o x y g e n t h e r a p y (LTOT) for more than 15 hours is recommended by the guidelines as a treatment to improve survival in patients with COPD49 and a patient with COPD being treated with maintenance nebulization may have been prescribed LTOT. Drugs can be administered to patients requiring oxygen through nebulization by converting an air-driven jet nebulizer into an oxygen-driven jet nebulizer. However, such an arrangement should not be recommended for home use because of the r isk of carbon dioxide retention, especially with bronchodilators, in such patients.21 Recommendation

Patients (especially those with COPD) should not be prescribed maintenance nebulization with oxygen-dr iven je t nebul izers because of the risk of carbon dioxide retention, especially with bronchodilators.

Q9: At what t ime intervals should patients using nebulization at home be assessed?

Regular fol low-up is key to the successful management of any chronic disease. Patients who have been prescribed maintenance nebulization should be assessed for the following: 1. Effectiveness of the prescribed

treatment2. Adherence to the treatment3. N e e d f o r c o n t i n u i n g

maintenance nebulization 4. Possibility of re-introducing

handheld inhalersT h e E u r o p e a n R e s p i r a t o r y

Society Task Force, which has formulated guidelines on the use of nebulizers, recommends initiating

follow-up approximately 1 month after the start of maintenance nebulizat ion. A re-assessment of the need for and effectiveness o f maintenance nebul iza t ion , a long with adherence , can be made annually. The present panel endorses these recommendations because of their feasibi l i ty in clinical practice. Recommendation

Initial follow-up should be performed 1 month after the start of maintenance nebulization and, later, at least annually.

Q10: How to should the success o f t h e r a p y b e a s s e s s e d a n d adherence ensured in patients using long-term nebulization?

Adherence to medicat ion is a well-known challenge in any chronic pharmacotherapy and is defined as “the extent to which a person’s behaviour (in terms of taking medications, following diets, or executing lifestyle changes) coincides with medical or health advice”.50

I n c a s e o f t h e i n h a l a t i o n technique, the ease of use of a device may impact adherence to medication. Although patients have shown a preference to nebulizers in surveys, there are no established means to ident i fy and ensure adherence in patients who have been prescr ibed maintenance nebulization. In a study of 985 patients (aged 30–74 years) with moderate-to-severe COPD who were prescr ibed maintenance nebulization (with beta2-agonists), the adherence to treatment was observed to be 50.6%, as measured objectively.51 The predictors of adherence were older age, better education, having a stable lifestyle, report of therapy making the patient feel better, marital status, history of emphysema and more b r e a t h l e s s n e s s , p o o r e r l u n g function, and having little smoking and alcohol history.

The present panel believes that, in clinical practice, adherence to any treatment can only be judged by

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i.d.

of p

lace

bo (n

=63)

or B

DP

pMD

I (3–

4 pu

ffs)

b.i.d

. 1,5

00–2

,000

/day

with

spa

cer +

pla

cebo

ne

buliz

atio

n b.

i.d. (

n=61

) Re

scue

: sal

buta

mol

Both

trea

tmen

ts w

ell t

oler

ated

. Tre

atm

ent-

rela

ted

AEs

wer

e se

en in

9.5

% o

f pat

ient

s in

th

e BD

P ne

buliz

atio

n gr

oup

vers

us 8

.2%

in th

e BD

P pM

DI g

roup

. N

umbe

r of t

reat

men

t-rel

ated

AEs

in th

e BD

P ne

buliz

atio

n gr

oup

vers

us th

e BD

P pM

DI

grou

p: 2

0.6%

ver

sus

11.5

%.

Bous

quet

et a

l.30D

oubl

e-bl

ind,

dou

ble-

du

mm

y, ra

ndom

ized

, pl

aceb

o-co

ntro

lled,

par

alle

l-gr

oup

3 w

eeks

N=4

0 (a

ge: 1

8–60

yea

rs),

inte

rmitt

ent (

as p

er G

INA

) as

thm

a

Neb

uliz

ed B

DP

(1,6

00 m

cg/d

ay) (

n=10

) or

nebu

lized

BD

P (3

,200

mcg

/day

) (n=

10) o

r BD

P pM

DI +

spa

cer (

800

mcg

/day

) (n=

10) o

r pla

cebo

(n

=10)

All

trea

tmen

ts w

ell t

oler

ated

. A

Es w

ere

repo

rted

by

5 pa

tient

s ea

ch in

the

thre

e gr

oups

(neb

uliz

ed B

DP

1,60

0 m

cg/d

ay,

BDP

pMD

I, an

d pl

aceb

o) a

nd 7

pat

ient

s in

the

nebu

lized

BD

P 3,

200

mcg

/day

gro

up.

Num

ber o

f AEs

: 13

in n

ebul

ized

BD

P 1,

600

mcg

/day

, 34

in n

ebul

ized

BD

P 3,

200

mcg

/day

, 19

in B

DP

pMD

I, an

d 15

in p

lace

bo.

AEs

wer

e m

ild-to

-mod

erat

e in

sev

erity

, with

th

e m

ost c

omm

only

repo

rted

bei

ng h

eada

che

and

sore

thro

at. W

ith re

spec

t to

chan

ge in

m

ean

rand

om m

orni

ng c

ortis

ol le

vels

, no

sign

ifica

nt d

iffer

ence

s fr

om p

re-tr

eatm

ent

leve

ls, a

nd b

etw

een

grou

ps.

Terz

ano

et a

l.31

Rand

omiz

ed, a

ctiv

e-co

ntro

lled,

par

alle

l-gro

up12

wee

ksN

=205

(age

: 18–

65 y

ears

), m

oder

ate

pers

iste

nt a

sthm

aN

ebul

ized

BD

P b.

i.d. (

2,40

0 m

cg/d

ay)

(n=1

03) o

r neb

uliz

ed F

P b.

i.d. (

2,00

0 m

cg/d

ay)

(n=1

02)

Both

trea

tmen

ts w

ere

wel

l tol

erat

ed. U

p to

22

.5%

of p

atie

nts

in th

e BD

P gr

oup

and

32%

of

patie

nts

in th

e FP

gro

up re

port

ed o

ne o

r mor

e A

Es.

Num

ber o

f AEs

was

30

in th

e BD

P gr

oup

and

46 in

the

FP g

roup

. All

AEs

wer

e m

ild in

se

veri

ty.

Del

acou

rt e

t al.32

Rand

omiz

ed, c

ontr

olle

d,

open

-labe

l, pa

ralle

l-gro

up12

wee

ksN

=120

(age

: 6 m

onth

s to

6

year

s) s

ever

e pe

rsis

tent

as

thm

a

Neb

uliz

ed B

DP

b.i.d

. (80

0 m

cg/d

ay) +

ora

l ke

totif

en (n

=58)

or n

ebul

ized

BU

D b

.i.d.

(7

50 m

cg/d

ay) +

ora

l ket

otife

n (n

=62)

Uri

nary

cor

tisol

and

uri

nary

cor

tisol

/cre

atin

ine

ratio

s no

t sig

nific

antly

affe

cted

. Of 3

38 A

Es

obse

rved

in th

e ra

ndom

ized

trea

tmen

t per

iod,

16

8 w

ere

repo

rted

in th

e BD

P gr

oup

and

170

in th

e BU

D g

roup

. Ove

rall,

the

freq

uenc

y an

d pr

ofile

of A

Es w

ere

equi

vale

nt fo

r the

two

trea

tmen

ts, w

ith s

ide

effec

ts g

ener

ally

bei

ng

asso

ciat

ed w

ith th

e ea

r, no

se a

nd th

roat

, and

re

spir

ator

y sy

stem

.Bi

sca

et a

l.33

Dou

ble-

blin

d, d

oubl

e-du

mm

y, m

ultic

entr

e,

rand

omiz

ed, p

aral

lel-g

roup

4 w

eeks

N=1

51 (a

ge: 6

–16

year

s),

havi

ng m

oder

ate-

to-s

ever

e as

thm

a ex

acer

batio

n at

en

try

Neb

uliz

ed B

DP

b.i.d

. (1,

600

mcg

/day

) (n

=75)

or B

DP

pMD

I + s

pace

r b.i.

d. (8

00 m

cg/

day)

(n=7

6)

Num

ber o

f pat

ient

s re

port

ing

AEs

: 25

in

nebu

lized

BD

P ve

rsus

26

in B

DP

pMD

I. N

umbe

r of A

Es: 4

3 in

neb

uliz

ed B

DP

and

48 in

BD

P pM

DI.

Journal of The Association of Physicians of India ■ Vol. 65 ■ May 201768Ta

ble

3: R

evie

w o

f stu

dies

eva

luat

ing

the

safe

ty o

f neb

uliz

ed s

tero

ids

and

bron

chod

ilato

rsSt

udy

Stud

y de

sign

Stud

y du

ratio

nPa

tient

sIn

terv

entio

nSa

fety

eva

luat

ion

Neb

uliz

ed s

tero

ids:

Bud

eson

ide

Shap

iro

et a

l.34

Rand

omiz

ed, d

oubl

e-bl

ind,

pl

aceb

o-co

ntro

lled,

par

alle

l-gr

oup

12 w

eeks

N=1

78 (a

ge: 4

–8 y

ears

), di

agno

sed

with

ast

hma,

ta

king

dai

ly IC

S

Neb

uliz

ed B

UD

0.2

5 m

g or

0.5

0 m

g or

1.0

mg

b.i.d

. or p

lace

boD

ropo

uts

due

to a

sthm

a w

orse

ning

wer

e si

gnifi

cant

ly fe

wer

(P≤0

.015

). A

Es a

nd b

asal

an

d A

CTH

-stim

ulat

ed c

ortis

ol re

spon

ses

not

diffe

rent

bet

wee

n gr

oups

. Cha

nge

in A

CTH

-st

imul

ated

cor

tisol

leve

ls fr

om b

asel

ine

to e

nd

of tr

eatm

ent:

–9.1

nm

ol/L

in p

lace

bo (n

=8);

and

41.2

, 54.

7 an

d –5

6.3

nmol

/L in

the

0.25

m

g (n

=14)

, 0.5

0 m

g (n

=11)

or 1

.0 m

g (n

=13)

ne

buliz

ed B

UD

gro

ups,

resp

ectiv

ely.

Mur

phy

et a

l.35

Rand

omiz

ed, p

artia

lly

blin

ded,

act

ive-

cont

rolle

d,

para

llel-g

roup

12 w

eeks

+

2 w

eeks

’ fo

llow

-up

N=6

0 (a

ge: ≥

12 y

ears

), m

oder

ate-

to-s

ever

e as

thm

a N

ebul

ized

BU

D 0

.5 m

g o.

d. o

r neb

uliz

ed B

UD

1.

0 m

g o.

d. o

r neb

uliz

ed B

UD

1.0

mg

b.i.d

. or

nebu

lized

BU

D 2

mg

b.i.d

. or B

UD

pM

DI 4

00

mcg

b.i.

d.

AEs

and

sev

erity

of A

Es w

ere

sim

ilar a

cros

s al

l gro

ups.

The

mos

t com

mon

AE:

upp

er

resp

irat

ory

trac

t inf

ectio

n (6

.9%

).

Cet

inka

ya e

t al.3

6Ra

ndom

ized

, con

trol

led

tria

l12

wee

ksN

=31

(age

: 6–2

4 m

onth

s),

recu

rren

t or p

ersi

sten

t w

heez

ing

Neb

uliz

ed B

UD

0.2

5 m

g or

neb

uliz

ed F

P 0.

25

mg

b.i.d

. for

6 w

eeks

and

at h

alf t

he d

ose

for

anot

her 6

wee

ks

Mea

n pr

e-tr

eatm

ent m

orni

ng c

ortis

ol w

as

low

er in

FP

than

in B

UD

. No

diffe

renc

e in

A

CTH

, ser

um H

bA1C

, sod

ium

, chl

orid

e,

pota

ssiu

m le

vels

, wei

ght a

nd h

eigh

t bet

wee

n gr

oups

. Sz

efler

et a

l.37

Ope

n-la

bel,

rand

omiz

ed,

activ

e-co

ntro

lled,

m

ultic

entr

e

52 w

eeks

N=3

95 (a

ge: 2

–8 y

ears

), m

ild a

sthm

a or

recu

rren

t w

heez

ing

Neb

uliz

ed B

UD

0.5

mg

o.d.

(n=1

97) o

r m

onte

luka

st (4

mg

or 5

mg)

o.d

. (n=

198)

Sim

ilar A

Es b

etw

een

grou

ps M

ost A

Es w

ere

mild

to m

oder

ate

in in

tens

ity. S

imila

r inc

reas

es

in h

eigh

t fro

m b

asel

ine

to e

nd o

f tre

atm

ent.

Neb

uliz

ed s

tero

ids:

Flu

ticas

one

Wes

tbro

ek e

t al.3

8M

ultic

entr

e, ra

ndom

ized

, do

uble

-blin

d, p

aral

lel-

grou

p

12 w

eeks

N=3

01 (a

ge: ≥

17 y

ears

), or

al

ster

oid-

depe

nden

t ast

hma

Neb

uliz

ed F

P 2

mg

(n=1

02) o

r 0.5

mg

(n=1

03)

b.i.d

. or p

lace

bo (n

=96)

Both

trea

tmen

ts w

ell t

oler

ated

. Ora

l ca

ndid

iasi

s m

ost c

omm

only

repo

rted

: 12%

in

FP 4

mg/

day

grou

p, 1

4% in

FP

1 m

g/da

y, a

nd

8% in

pla

cebo

. Ser

ious

AEs

: 14%

in p

lace

bo, 9

%

in F

P 1

mg/

day,

and

6%

in F

P 4

mg/

day.

Ser

um

cort

isol

low

er in

FP

4 m

g/da

y th

an F

P 1

mg/

day

or p

lace

bo, a

lbei

t with

in th

e no

rmal

rang

e.

No

labo

rato

ry a

bnor

mal

ities

.N

ebul

ized

bro

ncho

dila

tors

: For

mot

erol

Gro

ss e

t al.3

9 Ra

ndom

ized

, dou

ble-

blin

d,

doub

le-d

umm

y tr

ial

12 w

eeks

N=3

51 C

OPD

(FEV

1 44%

pr

edic

ted)

20 m

cg/2

ml F

FIS

b.i.d

. or 1

2 m

cg F

F D

PI b

.i.d.

or

pla

cebo

sol

utio

n or

pla

cebo

DPI

Dru

g-re

late

d A

Es in

the

FFIS

arm

with

a

freq

uenc

y >1

% a

nd e

xcee

ding

pla

cebo

wer

e dr

y m

outh

, nau

sea,

and

inso

mni

a.N

elso

n et

al.4

0Ra

ndom

ized

, dou

ble-

blin

d,

doub

le-d

umm

y tr

ial

12 w

eeks

N=3

51 C

OPD

(sm

okin

g hi

stor

y of

≥10

pac

k-ye

ars)

20 m

cg/2

ml F

FIS

b.i.d

. or 1

2 m

cg F

F D

PI b

.i.d.

or

pla

cebo

sol

utio

n or

pla

cebo

DPI

No

clin

ical

ly m

eani

ngfu

l effe

cts

of F

FIS

or

FF D

PI tr

eatm

ent o

n m

ean

or m

axim

um H

R,

vent

ricu

lar p

rem

atur

e be

ats,

or i

ncid

ence

. Tr

eatm

ent-e

mer

gent

car

diac

AEs

occ

urre

d in

4.

1%, 3

.5%

and

4.4

% o

f pat

ient

s in

the

FFIS

, FF

DPI

and

pla

cebo

gro

ups,

resp

ectiv

ely;

w

ithdr

awal

s du

e to

pos

sibl

e ca

rdia

c AEs

oc

curr

ed in

1 p

atie

nt p

er tr

eatm

ent g

roup

. No

deat

hs o

r ser

ious

car

diac

AEs

occ

urre

d du

ring

th

e tr

eatm

ent p

erio

d. M

ean

chan

ges

from

ba

selin

e in

HR,

PR

inte

rval

, QRS

com

plex

, QT

inte

rval

, and

RR

inte

rval

wer

e co

mpa

rabl

e be

twee

n th

e th

ree

trea

tmen

t gro

ups

at e

ach

time

poin

t.

Journal of The Association of Physicians of India ■ Vol. 65 ■ May 2017 69Ta

ble

3: R

evie

w o

f stu

dies

eva

luat

ing

the

safe

ty o

f neb

uliz

ed s

tero

ids

and

bron

chod

ilato

rsSt

udy

Stud

y de

sign

Stud

y du

ratio

nPa

tient

sIn

terv

entio

nSa

fety

eva

luat

ion

Don

ohue

et a

l.27

Ope

n-la

bel s

afet

y ex

tens

ion

52 w

eeks

N=5

69 C

OPD

FFIS

20

μg b

.i.d.

inha

latio

n so

lutio

n or

12

μg

FF D

PIRe

sults

of s

afet

y m

onito

ring

for A

Es,

labo

rato

ry v

alue

s, a

nd c

ardi

ac c

hang

es w

ere

sim

ilar b

etw

een

trea

tmen

t gro

ups.

The

re w

ere

no c

linic

ally

impo

rtan

t cha

nges

from

bas

elin

e in

labo

rato

ry te

sts,

incl

udin

g se

rum

pot

assi

um

and

gluc

ose,

or v

ital s

igns

and

no

trea

tmen

t-re

late

d in

crea

ses

in c

ardi

ac a

rrhy

thm

ias,

hea

rt

rate

or Q

Tc p

rolo

ngat

ion.

Neb

uliz

ed b

ronc

hodi

lato

rs: A

rfor

mot

erol

Ba

umga

rtne

r et a

l41

Mul

ticen

tre,

rand

omiz

ed,

doub

le-b

lind,

dou

ble-

dum

my,

pla

cebo

- and

ac

tive-

cont

rolle

d tr

ial

12 w

eeks

N=7

17 (a

ge: ≥

35 y

ears

) C

OPD

, FEV

1 pre

dict

ed ≤

65%

an

d FE

V1/F

VC

≤70

%

ARF

15

mcg

b.i.

d. (n

=141

), A

RF 2

5 m

cg b

.i.d.

(n

=143

), A

RF 5

0 m

cg q

.d. (

n=14

6)

SAL

pMD

I 42

mcg

b.i.

d. (n

=144

), Pl

aceb

o (n

=143

)

The

AEs

in th

e A

RF g

roup

s w

ere

sim

ilar t

o SA

L an

d pl

aceb

o, in

clud

ing

seri

ous A

Es a

nd

CO

PD A

Es. F

requ

ency

of C

OPD

exa

cerb

atio

ns

duri

ng th

e fir

st 3

wee

ks: 6

.4%

in A

RF 1

5 m

cg,

6.3%

in 2

5 m

cg, a

nd 2

.1%

in 5

0 m

cg; 5

.6%

in

SAL;

and

4.9

% in

pla

cebo

. Dur

ing

the

last

3

wee

ks, t

he ra

tes

wer

e 4.

0%, 5

.2%

, 3.2

%, 3

.3%

, an

d 6.

1%, r

espe

ctiv

ely.

D

ose-

rela

ted

decr

ease

in th

e A

RF g

roup

s in

po

tass

ium

con

cent

ratio

ns a

t wee

k 12

rang

ed

from

–0.

05 to

–0.

19 m

Eq/L

at 2

hou

rs a

nd –

0.12

to

–0.

18 m

Eq/L

at 6

hou

rs a

fter a

dmin

istr

atio

n;

SAL

rang

ed fr

om –

0.02

to –

0.14

mEq

/L a

nd

plac

ebo

rang

ed fr

om 0

.00

to –

0.10

mEq

/L,

resp

ectiv

ely)

. Th

e m

ean

incr

ease

s in

glu

cose

con

cent

ratio

ns

in th

e A

RF g

roup

s at

wee

k 12

rang

ed fr

om 6

.2

to 2

6.0

mg/

dL a

t 2 h

ours

and

9.1

to 1

8.8

mg/

dL

at 6

hou

rs a

fter a

dmin

istr

atio

n; S

AL

was

14.

7 an

d 8.

0 m

g/dL

; and

pla

cebo

was

3.8

and

4.7

m

g/dL

, res

pect

ivel

y).

At w

eek

12, d

ose-

rela

ted

incr

ease

s in

hea

rt

rate

, mea

sure

d 2

hour

s af

ter s

tudy

dru

g ad

min

istr

atio

n, w

ere

foun

d w

ith in

crea

sing

do

ses

of A

RF (r

ange

, 1.2

–5.5

bpm

); SA

L (2

.1

bpm

); an

d, p

lace

bo (0

.6 b

pm).

Don

ohue

et a

l28

Mul

ticen

tre,

dou

ble-

blin

d,

rand

omiz

ed, p

lace

bo-

cont

rolle

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taking into account the subjective and objective reports (lung function measurements, symptom scores, exacerbation history). Ensuring adherence in a non-adherent patient is challenging. However, some general strategies that have been suggested in the literature are monitoring and feedback, extensive patient education and regular follow-up either via telephone or home visits , and providing medication tables/patient diaries. However, we believe that the best way to ensure adherence is to establish a strong and participative doctor-patient relationship. Recommendation

S u c c e s s o f m a i n t e n a n c e nebulization should be assessed on i) effectiveness of the treatment (object ive and subject ive) ; i i ) adherence to treatment; iii) need f o r c o n t i n u i n g m a i n t e n a n c e nebulization; iv) Adverse effect of home nebulizat ion; and v) the possibility of re-introducing handheld inhalers.• Es tab l i sh ing a s t rong and

participative doctor-patient r e l a t i o n s h i p m a y h e l p t o identify and ensure adherence to maintenance nebulization.

Q11: Can home nebulization be prescribed in other chronic respiratory diseases?

Nebulizers have been used for a fairly long time to deliver drugs such as tobramycin, dornase alfa and rhDNAse in cystic fibrosis.20,21 Nebulized antibiotics have also been studied in bronchiectasis. However , i t i s not c lear as to whether nebul ized ant ibiot ics can be prescribed for home use in COPD because of the associated r i s k o f a n t i b i o t i c r e s i s t a n c e development. Nonetheless, with active research going on in the field of inhaled antibiotics and with the manufacture of more efficient, portable and patient-friendly nebulizers, the future of nebulization looks interesting.

Recommendation

A l t h o u g h n e b u l i z a t i o n i s u s e d f o r t h e a d m i n i s t r a t i o n of antibiotics in other chronic respiratory diseases such as cystic fibrosis, the prescriber has to be careful about the associated risk of antibiotic resistance.

Summary of the Recommendations

1. Maintenance t rea tment in OADs with nebulization at home can be referred to as ‘maintenance nebulization’ rather than ‘home nebulization’ to specifically imply chronic use.

2. Pat ients must be careful ly screened before prescription of maintenance nebulization. More importantly, the screening should focus on the ability to use handheld inhaler devices and every effort should be made to introduce/re-introduce drug administration through handheld inhalers

3. The minimum durat ion of maintenance therapy that can be prescribed in a patient with OAD is 3 weeks. However, no recommendation can be made on the maximum durat ion of therapy. The decision to end/cont inue maintenance nebul izat ion l ies wi th the prescribing physician after t a k i n g i n t o a c c o u n t t h e s u b j e c t i v e a n d o b j e c t i v e i m p r o v e m e n t a l o n g w i t h ensuring that there are no valid concerns regarding AEs with the prescribed nebulized formulations.

4. S e l e c t i n g t h e r i g h t d r u g and the r ight nebul izer i s important for the success of maintenance nebulization in OAD. Prescribers are advised to refer to the exact indications, posology and administration available in the prescribing information of the available drugs.


Table 4: The safety check list

Safety measures for equipment used1. Checking the filter: Filter should be checked every month as a routine. Blackening of the

filter should be reported to the manufacturer and blackened filter should be changed immediately

2. Every 6-12 months filter should be changed routinely [or as suggested by the information brochure provided by the manufacturer].

3. No liquids, even for cleaning purposes should be applied to compressor.Safety of Accessories• Safety in regard to nebulizer accessories is for microbiological perspective (Infection/

Contamination).• The tubing and the nebulizer chamber should be replaced every 4-6 weeks. They should

be cleaned on a daily basis (see cleaning section).• If a patient develops an LRTI and has a sputum test which shows a positive culture, it

would be prudent to do swabs for culture from the nebulizer and the accessories.Any positive swab culture would mean an immediate change of the accessories or a cleaning of the equipment. [If this is not possible from a logistic stand point, tubing and nebulization chamber should be replaced compulsorily every 4 weeks. Positive culture from accessories should mandate a sputum culture/sensitivity from the patient to check whether same microorganism is growing in the bronchial secretions/airways.]Safety of common drugs used in home nebulizationSafety precautions for Long Acting β2 Agonist (LABA), Short Acting β2 Agonist (SABA), Short Acting Anti-muscarinic (SAMA)• A baseline Echocardiogram (ECG) should be recorded for all patients initiating Home

Nebulization.• Any baseline ECG abnormality should be investigated further. Ideally with a cardiology

consultation.• Any prolongation of QT interval should preclude the use of LABA & SABA.• A baseline K+ (Potassium) level should be checked in patients receiving Salbutamol or

Levosalbutamol.• K+ level should be rechecked at the end of one month and again at 3 months in patient

on long term Home Nebulization.• Patients complaining of intermittent palpitation should be advised to undergo ECG and

if normal a 24 hours Holter monitoring should be performed.• Inspection of the oral cavity and oropharynx should be done regularly in patients on

nebulized steroids to check for fungal (Candida) infection.• Regular stringent mouth washing and cleaning of nebulizer & accessories daily should

be advocated at each contact by a trained health personnel.

of nebulizers, and an occasional review of the nebulizer should be performed by the prescribing physician. Patients should be advised to clean the nebulizer accessories at least once a day.

7. Patients (especially those with COPD) should not be prescribed maintenance nebulization with oxygen-driven jet nebulizers because of the risk of carbon dioxide retention, especially with bronchodilators.

8. Initial follow-up should be p e r f o r m e d 1 m o n t h a f t e r t h e s t a r t o f m a i n t e n a n c e nebulization and, later, at least annually.

9. S u c c e s s o f m a i n t e n a n c e n e b u l i z a t i o n s h o u l d b e assessed on, i) effectiveness of the treatment (object ive and subjective); ii) adherence to t reatment ; i i i ) need for c o n t i n u i n g m a i n t e n a n c e n e b u l i z a t i o n ; i v ) A d ve r s e effect of home nebulization; and v) the possibility of re-introducing handheld inhalers.

10. Es tab l i sh ing a s t rong and participative doctor-patient r e l a t i o n s h i p m a y h e l p t o identify and ensure adherence to maintenance nebulization.

11. A l t h o u g h n e b u l i z a t i o n i s used for the administration of antibiotics for other chronic respiratory diseases such as cystic fibrosis, the prescriber has to be careful about the associated risk of antibiotic resistance.

Conclusion

M a i n t e n a n c e n e b u l i z a t i o n f o r O A D s i s a n d s h o u l d b e considered as an alternative for drug administration and not as a substitute for handheld inhaler devices. These recommendations should be viewed as a reference and not as guidelines for prescribing m a i n t e n a n c e n e b u l i z a t i o n . There is a definite need for more evidence on the long-term safety of maintenance nebulization in patients with OADs.

Table 5: General instructions for cleaning and maintenance of different nebulizers

Jet nebulizers Ultrasonic nebulizers Mesh nebulizersWash all accessories except the tubing in warm water/ mild detergent solution. Rinse with warm water to remove detergent residue and leave to air-dry.

Wash all the accessories such as mouthpiece/mask, extension tube, medication cap and air filter with a mild detergent or a commercially available disinfectant.

Medication container, mesh cap, mask adapter and mouthpiece/mask should be washed in warm soapy solution and later left to air-dry.

Wipe the outer surface of the tubing and the compressor with a clean cloth. If there is some water in the tubing, connect it to the compressor and blow air through the tubing for a few seconds.

Wipe the main body with a damp, soft cloth.

Do not touch/remove the mesh cap. The remaining medication in the mesh holes can be removed by nebulizing clean water after re-assembling the unit.

Change the air filter as soon as it changes colour.

Wipe the main unit with a clean cloth.

5. To ascertain the long-term s a f e t y i n p a t i e n t s w i t h OAD, especially those with complicating comorbidities such as CVDs and diabetes, it

is recommended to perform a regular rev iew (a t l eas t annually).

6. Patients should be educated on the cleaning and maintenance


Acknowledgements

We thank Cipla Ltd. for the unrestricted educational grant and logistical support provided for the consensus meeting.

References1. Jindal SK, Aggarwal AN, Gupta D, Agarwal

R, Kumar R, Kaur T et al. Indian study on epidemiology of asthma, respiratory symptoms and chronic bronchitis in adults (INSEARCH). Int J Tuberc Lung Dis 2012; 16:1270-7.

2. Gupta D, Agarwal R, Aggarwal AN, Maturu VN, Dhooria S, Prasad KT et al. for COPD Guidelines Working Group; Indian Chest Society; National College of Chest Physicians (India). Guidelines for diagnosis and management of chronic obstructive pulmonary disease: joint recommendations of Indian Chest Society and National College of Chest Physicians (India). Indian J Chest Dis Allied Sci 2014; 56:5–54.

3. The Global Asthma Report 2014. Auckland, New Zealand: Global Asthma Network, 2014.

4. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health 2015; 5:020415.

5. Salvi S, Apte K, Madas S, Barne M, Chhowala S, Sethi T et al. Symptoms and medical conditions in 204 912 patients visiting primary health-care practitioners in India: a 1-day point prevalence study (the POSEIDON study). Lancet Glob Health 2015; 3:e776-84.

6. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385:117-71.

7. Burney PG, Patel J, Newson R, Minelli C, Naghavi M. Global and regional trends in COPD mortality, 1990–2010. Eur Respir J 2015; 45:1239–1247.

8. Salvi S, Agrawal A. India needs a national COPD prevention and control programme. J Assoc Physicians India 2012; 60 Suppl: 5-7.

9. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 386:743-800.

10. Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in

elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm 2011; 68:1221-32.

11. Dolovich M, Dhand R, Aerosol drug delivery: developments in device design and clinical use. The Lancet 2011; 377:1032–1045.

12. Vincken W, Dekhuijzen PR, Barnes P; ADMIT Group. The ADMIT series - Issues in inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD. Prim Care Respir J 2010; 19:10–20.

13. Fink JB, Rubin BK. Problems with inhaler use: A call for improved clinician and patient education. Respir Care 2005; 50:1360–1374.

14. O’Donohue WJ Jr et al. Guidelines for the use of nebulizers in the home and at domiciliary sites. Report of a consensus conference. National Association for Medical Direction of Respiratory Care (NAMDRC) Consensus Group. Chest 1996; 109:814–820.

15. Jarvis S, Ind PW, Shiner RJ. Inhaled therapy in elderly COPD patients; time for re-evaluation? Age Ageing 2007; 36:213–218.

16. Barta SK, Crawford A, Roberts CM. Survey of patients’ views of domiciliary nebuliser treatment for chronic lung disease. Respir Med 2002; 96:375–381.

17. Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL et al.; American College of Chest Physicians; American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005; 127:335–371.

18. American Thoracic Society. Statement on home care for patients with respiratory disorders. Am J Respir Crit Care Med 2005; 171:1443–1464.

19. Competitive yet Growing Market of Nebulizers. Medical Buyer [Updated 3 r d J u l y 2 0 0 9 ] . A v a i l a b l e f r o m : h t t p : / / w w w . m e d i c a l b u y e r .c o . i n / i n d e x . p h p ? o p t i o n = c o m _content&task=view&id=1727 (As accessed on 30th December 2015).

20. Boe J, Dennis JH, O’Driscoll BR, Bauer TT, Carone M, Dautzenberg B, Diot P, Heslop K, Lannefors L. European Respiratory Society Guidelines on the use of nebulizers. Eur Respir J 2001; 18:228–242.

21. Muers MF, Ahmedzai S, Barry PW et al. BTS guidelines on current best practice for nebuliser treatment. Thorax 1997; 52 (Supplement 2).

22. Melani AS, Sestini P, Aiolfi S et al. GENebu Projec t : home nebul izer use and maintenance in Italy. Eur Respir J 2001; 18:758-63.

23. Demoly P, Jaffuel D, Sahla H et al. The use

of home nebulizers in adult asthma. Respir Med 1998; 92:624-7.

24. Smyth CM, Ryland I, Earis JE. Domiciliary nebulised bronchodilator therapy in chronic obstructive pulmonary disease. Prim Care Respir J 2001; 10:103-105.

25. O’Driscoll BR, Bernstein A. A long-term study of symptoms, spirometry and survival amongst home nebulizer users. Respir Med 1996; 90:561-6.

26. Nelson HS, Gross NJ, Levine B et al. Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Clin Ther 2007; 29:2167-78.

27. Donohue JF, Hanania NA, Fogarty C et al. Long-term safety of nebulized formoterol: results of a twelve-month open-label clinical trial. Ther Adv Respir Dis 2008; 2:199-208.

28. Donohue JF, Hanania NA, Make B et al. One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD. Chest 2014; 146:1531-42.

29. Grzelewska-Rzymowska I, Kroczynska-Bednarek J, Zarkovic J. Comparison of the efficacy and safety of high doses of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in steroid-dependent adults with moderate to severe asthma. Respir Med 2003; 97 Suppl B: S21-6.

30. Bousquet J, Meziane H, Chanez P et al. The response of two different dosages of beclometasone dipropionate suspension for nebulization versus a standard dose of beclometasone dipropionate via a metered-dose inhaler on bronchoprovocation testing in adults with asthma. Respir Med 2003; 97 Suppl B: S11-4.

31. Terzano C, Ricci A, Burinschi V et al. C o m p a r i s o n o f t h e e f f i c a c y o f beclometasone dipropionate and fluticasone propionate suspensions for nebulization in adult patients with persistent asthma. Respir Med 2003; 97 Suppl B: S35-40.

32. Delacourt C, Dutau G, Lefrançois G et al. Comparison of the efficacy and safety of nebulized beclometasone dipropionate and budesonide in severe persistent childhood asthma. Respir Med 2003; 97 Suppl B: S27-33.

33. Bisca N, Cernatescu I, Dragomir D et al. Comparison of the efficacy and safety of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in paediatric patients with moderate to severe exacerbation of asthma. Respir Med 2003; 97 Suppl B: S15-20.

34. Shapiro G, Mendelson L, Kraemer MJ


et al. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998; 102:789-96.

35. Murphy K, Noonan M, Silkoff PE, Uryniak T. A 12-week, multicenter, randomized, partially blinded, active-controlled, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaled corticosteroids with a metered-dose or dry powder inhaler. Clin Ther 2007; 29:1013-26.

36. Cetinkaya F, Kayiran P, Memioglu N et al. Effects of nebulized corticosteroids therapy on hypothalamic-pituitary-adrenal axis in young children with recurrent or persistent wheeze. Pediatr Allergy Immunol 2008; 19:773-6.

37. Szefler SJ, Baker JW, Uryniak T et al. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007; 120:1043-50.

38. Westbroek J, Saarelainen S, Laher M et al. Oral steroid-sparing effect of two doses of nebulized fluticasone propionate and placebo in patients with severe chronic asthma. Respir Med 1999; 93:689-99.

39. Gross NJ, Nelson HS, Lapidus RJ et al. Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. Respir Med 2008; 102:189-97.

40. Nelson HS, Gross NJ, Levine B et al. Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double- blind, double-dummy, placebo- and active-controlled trial. Clin Ther 2007; 29:2167-78.

41. Baumgartner RA, Hanania NA, Calhoun WJ et al. Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Clin Ther 2007; 29:261-78.

42. Hanania NA, Donohue JF, Nelson H et al. The safety and efficacy of arformoterol and formoterol in COPD. COPD 2010; 7:17-31.

43. The COMBIVENT Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 1997; 112:1514-21.

44. Hillas G, Perlikos F, Tsiligianni I, Tzanakis N. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:95-109.

45. Faul JL, Wilson SR, Chu JW, Canfield J, Kuschner WG. The effect of an inhaled corticosteroid on glucose control in type 2 diabetes. Clin Med Res 2009; 7:14-20.

46. Millar EA, Connell JM, Thomson NC. The effect of nebulized albuterol on the activity of the renin-angiotensin system in asthma. Chest 1997; 111:71-4.

47. Gross NJ, Kerwin E, Levine B, Kim KT, Denis-Mize K, Hamzavi M et al. Nebulized formoterol fumarate: Dose selection and pharmacokinetics. Pulm Pharmacol Ther 2008; 21:818-23.

48. Taylor DR, Wilkins GT, Herbison GP, Flannery EM. Interaction between corticosteroid and beta-agonist drugs. Biochemical and cardiovascular effects in normal subjects. Chest 1992; 102:519-24.

49. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2016). Available from: www.goldcopd.org (As accessed on 20th May 2016).

50. Restrepo RD, Alvarez MT, Wittnebel LD et al. Medication adherence issues in patients treated for COPD. Int J Chron Obstruct Pulmon Dis 2008; 3:371-84.

51. Turner J, Wright E, Mendella L, Anthonisen N. Predictors of patient adherence to long-term home nebulizer therapy for COPD. The IPPB Study Group. Intermittent Positive Pressure Breathing. Chest 1995; 108:394-400.

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