Noninvasive ventilation coupled to nebulization by scintigraphy in COPD
Valdecir Castor Galindo-Filhoa, Maria Eveline Ramosa, Catarina Souza Ferreira
Rattes Limaa, Antônio Konrado Barbosab, Simone Cristina Soares Brandãob, James Finkc, Armèle Dornelas de Andradea
aDepartment of Physicaltherapy, Universidade Federal de Pernambuco, Recife,
Pernambuco, Brazil
bDepartment of Nuclear Medicine, Hospital das Clínicas de Pernambuco, Recife,
Pernambuco, Brazil
cPhysicaltherapy Department, Georgia State University, Atlanta, Georgia, United
States of America
Corresponding Author:
Valdecir Castor Galindo-Filho. Av. dos Reitores, Cidade Universitária, 50670- 420, Recife, PE, Brazil
Tel.: +55 81 21268496. E-mail addresses: [email protected] (V.C. Galindo-Filho) [email protected] (M.E.Ramos) [email protected] (C.S.F.R.Lima) [email protected] (A.K.Barbosa) [email protected] (S.C.S.Brandão SCS) [email protected] (J.Fink)
127 Abstract
Background: Beneficial effects from noninvasive ventilation (NIV) in acute COPD are well-established, but couple to nebulization is still challenging. Aim: To compare radiaoaerosol pulmonary deposition and radioaerosol mass balance in the different compartments (pulmonary and extrapulmonary) using vibrating mesh nebulizer (VMN) and jet nebulizer (JN) coupled to NIV. Methods: It was a crossover study involving 9 stable moderate to severe COPD randomly allocated for both phases of the study: Phase 1(NIV+MN,n=9) and phase 2(NIV+JN,n=9). Bronchodilators were delivered during NIV using a facemask (pressures of 12 cmH2O and 5 cmH2O - inspiratory and expiratory, respectively). Radioactivity
counts were performed using a gamma camera and regions of interest(ROIs) were delimited. We determine aerosol mass balance from the lungs, upper airways, stomach, nebulizer, circuit, inspiratory and expiratory filters, and mask as a percentage. Results: Radiolabelled aerosol was delivery in a higher amount using VMN in comparison to JN (1867044±456120 counts vs 579729±312261 counts, p = 0.008). Inhaled dose reached 19.90±3.18% in VMN against 7.03±2.97% from JN (p=0.008) in correlation to the percentage of lung deposition of 8.75±2.23% in VMN against 2.82±1.21% to JN (p=0.008). Residual volume was lower in VMN than in JN (3.20±1.33% versus 49.53±6.40%, p=0.008). Thus, peripheral deposition of radiaoerosol was significantly lower. Conclusions: According to our results VMN deposited more than 3 fold radiaoerosol into the lungs in comparison to JN and could be an alternative to ensure effective bronchodilators deposition in those COPD patients unable to perform other cathegories of inhaler devices.
128 Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a progressive and systemic inflammatory disease characterized by a variable airflow limitation, which presents a range of vary between individuals (1,2). It is considered the fourth cause of death in the world, consisting in a public health problem which lead to social, economic and quality of life repercussions worldwide (3,4).
Inhalation of short-acting beta-agonists are central to treat all stages of the disease and evidence from data published in the literature showed the long- term benefits of using inhalation therapy in COPD (4). However, particle size, velocity of the aerosol plume, different inhalers designs, ability to use correctly the inhaler device, and breathing patterns are some factors that directly affect the efficacy of pulmonary drug deposition (5-10). Studies involving different inhalers demonstrated a high deposition of aerosol in the oral pharynx and less than 20% of the nominal dose reaches the lungs (6,7,11).
Nowadays, there are evidences from the literature suggesting that many stable COPD are unable to use prescribed inhalers properly, recommending the use of jet nebulizers (JN) (4,12,13), mainly because those devices have some advantages as such: aerosol generated from water-soluble drugs, facilities to perform the technique (press and breathe) and the absence of propellants (4,12- 14).
In addition to this, some studies in animal model and in vitro involving a new generation of nebulizers, named vibrating mesh nebulizers (VMN) have
129 demonstrated efficacy to deposit more than 2 fold from the nominal aerosol dose, less time to nebulize, lower particle size and residual volume(15-19).
Randomized controlled trials and meta-analysis have demonstrated some benefits obtained with the application of NIV in COPD patients. Those clinical benefits include reduction in work of breathing, respiratory discomfort, need of intubation, hospital stay and hospital mortality (20-27). Plant et al conducted a prospective multicenter randomized controlled trial involving 236 mild to moderate acute COPD to compare the use of NIV with standard therapy (24). They observed that NIV group presented significant reduction in the need of intubation (15% in NIV group versus 27% in standard therapy group) and in- hospital mortality (10% in NIV group versus 20% in standard therapy group).
However, there is a lack of information about the effects of coupling NIV to nebulizers in this population and one study involving NIV and delivery of bronchodilators in COPD did not found clinical benefits (28). In the literature researched, we did not find studies coupling NIV to nebulization and results using VMN in association to positive pressure seems to be very promising. For this reason, we hypothesis that delivery of bronchodilators using VMN will increase the amount of radiolabeled aerosol deposited into the lungs in COPD.
The aims of this study were: 1) to compare inhaled dose of radioaerosol into the lungs and determine distribution across horizontal and vertical gradients, and 2) to quantify mass balance of the delivery aerosol in different compartments (intrapulmonary and extrapulmonary).
130 Material and Methods
Study design and sample
It was a crossover study involved 9 moderate to severe stable COPD, from both sexes, age between 18 to 65 years and was performed in the Department of Nuclear Medicine and Cardiorespiratory Laboratory at Physiotherapy Department from Universidade Federal de Pernambuco in association to Georgia State University between. Data collection was performed after approved protocol by Human Ethics Institutional Committee and all participants gave written informed consent to participate.
Inclusion and exclusion criteria
Inclusion criteria were considered as follows: moderate to severe stable COPD (50% ≤ FEV1 < 80% from predicted values or 30% ≤ FEV1 < 50% from
predicted values)(4); none exacerbation in the last six months; age between 18 - 60 years; both sexes; no smoking history; able to understand verbal commands, and consent to participate in this protocol. On the other hand, exclusion criteria were: presence of dyspnea; cardiopulmonary diseases (chronic obstructive pulmonary disease, pneumonia, cardiac failure, myocardial infarction, pneumothorax); hyperthermia; hemodynamic instability (heart rate > 150 bpm and systolic blood pressure < 90 mmHg); arrhythmia absence; pregnancy; and contraindications for use of NIV (29).
131 Anthropometric and Cardiopulmonary measurements
Anthropometric data was the first step in the initial assessment from the patients consisted of collecting anthropometric data (age, height, weight and body mass index - BMI). For cardiopulmonary parameters we considered: respiratory rate (RR); peripheral oxygen saturation (SpO2); systolic blood
pressure (SBP) and diastolic blood pressure (DBP) using pulse oxymetry (ACTIVE -Ecafix, São Paulo, Brazil) and a manual pressure manometer (Welch AllynTM DS 44-11 Beaverton, Oregon, USA). Then, to conclude respiratory assessment, spirometry was performed (Micro Loop 8 / Cardinal Health, England, UK), based on American Thoracic Society, which considered a variance of 0.2 L allowed between tests and the average of three measurements was recorded (30).
Inhalation protocol
Inhalation protocol was divided into two phases: Phase 1 – NIV+JN (control group) and Phase 2 – NIV+VMN (experimental group). The order nebulizers to be tested was randomized (Random Allocation Software – version 2.0) for each patient and the second measurement was taken one week before, to avoid radioactive waste into the respiratory tract between using one and another nebulizer, thereby avoiding possible bias.
Inhalation was performed using diethilene triamine penta-acetic technetium (99mTc-DTPA) with radioactivity of 25 millicuries (31). Both
132 nebulizers were charged with 2.5 mg of salbutamol and 0.25 mg of ipratropium bromide and 3 mL of saline solution was added to complete 3 Ml. JN (Mist yMax, Air Life, Yorba Linda, USA) was positioned in the circuit using a “T” piece, particle size generation in a 5 µm range (according to the manufacturer information) and flow oxygen tritated at 8 L/min. VMN (Aeroneb Solo, Galway, Ireland) was positioned in the mask using an elbow (Elbow Kit, Respironics®, Murrysville, Pennsylvania, USA), particle size generation in a 1 µm and connected to electrical energy. Bilevel positive pressure (BiPAP Synchrony, Respironics®, Murrysville, Pennsylvania, USA) was applied through face mask (Comfort Full 2, Respironics®, Murrysville, Pennsylvania, USA) attached with straps and pressure adjusted were 12 cmH2O of inspiratory pressure and 5 cmH2O of
expiratory pressure after a period of adaptation before beginning the procedure to avoid ventilator-patient asynchrony (32,33).
Immediately after inhalation, participants sat in a chair with the back positioned in front to the gamma camera (STARCAM 3200 GE, California, USA) to obtain radioactivity counts from the posterior thorax during a period of 300 seconds on a matrix of 256 X 256. After, participants were positioned sitting in front to the gama camera to obtain images from face. Then, the same procedure was performed to analysis deposition in the nebulizer, circuits, inspiratory filter, expiratory filter and face mask. Counts representing stomach were obtained from posterior thorax and corrections for decay of technetium were used to during extrapulmonary measurements. The analysis of deposition in pulmonary and extrapulmonary compartments was expressed as a percentage from the count in each compartment to the total radioaerosol mass generated by nebulizers. The
133 inhaled radioaerosol was considered the sum of deposition into the upper airways, lungs and stomach (15).
Regions of interest were delimited based on a previous protocol and RDI was expressed as absolute values and was calculated according to the counts generated from each regions of interest(31).
Statistical analysis
The sample size was calculated based on a pilot study involving 5 subjects to obtain standard deviation of repeated observations in the same individual and later is the standard deviation of the difference between two measurements in the same individual, considering percentage in lung deposition. A total of 5 stable COPD patients entered in this two-treatment crossover study. The probability is 84% that the study will detect a treatment difference at a two-sided 0.05 significance level, if the true difference between treatments is 1.830 units. It was based on the assumption that within-patient standard deviation of the response variable is 0.72. However, this study was carried out with 9 individuals, against the possibility of subjects not completing the protocol. For the sample size calculation we used the software developed by David Schoenfeld, support from the MGH Mallinckrodt General Research Center. Javascript version developed by REMorse.
Primary outcomes consisted of radioaerosol deposition index into the lungs and we considered as secondary outcomes, radioaerosol mass balance that reached pulmonary and extrapulmonary compartments. For statistical analysis were used Kolmogorov-Smirnov Test to analysis normality and after was
134 applied Wilcoxon Test, Friedman Test and Dunn´s Multiple Comparison Test, considering as an interval of confidence 95% (p<0.05) through the software SPSS 20.0(SPSS Inc., Chicago, Illinois, USA) and GraphPad Prisma 4.0(Graph Pad Software In., San Diego, California, USA).
Results
Despite 12 CPOD patients were enrolled in this study, only 9 completed the entire protocol. The reasons to be excluded from this protocol were: 1 presented claustrophobia during application of NIV and 2 did not meet the inclusion criteria, as demonstrated in the study flow chart (Figure1). Anthropometric, cardiorespiratory and spirometric data are shown in table 1.
NIV+VMN group reached higher radiolabelled aerosol in both lungs in comparison to NIV+JN group (1867044±456120 counts versus 579729±312261 counts, p = 0.008), as shown in figure 2. Deposition in right and left lungs was higher when using mesh device coupled to NIV (right lung: 971375±284808 counts versus 303657±172738 counts, p = 0.008 and left lung: 896779±205960 counts vs 276072±143392 counts), as shown in figure 3.
Intragroup analysis of radioaerosol pulmonary index for ROI across vertical and horizontal gradients is shown in table 2. When analyzing intergroup deposition in different ROI across vertical and horizontal gradients, we found that NIV+VMN group had higher counts in comparison to NIV+VMN group, as shown in table 3.
135 The percentage of radioaerosol inhaled was significantly higher in NIV+VMN group when compared to NIV+JN group (19.90 ± 3.18% versus 7.03 ± 2.97%, p=0.008). VMN presented a lower residual volume (3.20 ± 1.33% versus 48.53 ± 6.40%, p=0.008) and more radiaerosol deposited in the face mask and upper airways, in comparison to jet nebulizer during NIV. Our results showed that JN demonstrated a significant deposition of radioaerosol in the expiratory filter than mesh device. Thus, none differences were found regarding to radioaerosol mass balance found in the stomach, circuit and inspiratory filter for both groups. Table 4 represents the radiaerosol mass balance obtained in each compartment from both groups.
Figure 4 demonstrated the individual pattern deposition of radiolabelled aerosol using VMN and JN during application of NIV.
Discussion
This is the first study to compare deposition and distribution of aerosol during NIV to COPD patients. Our results showed a higher amount of radioaerosol deposited into the lungs and a higher percentage from nominal dose charged in the nebulizers. In addition to this, VMN presented a lower residual volume which possibly delivery more aerolized drugs to COPD patients.
Analysis of radiaoerosol using JN coupled to NIV demonstrated a lower amount of particles deposited into the lungs in comparison to spontaneously breathing in normal subjects (32). Although there many studies reporting the benefits obtained from NIV in COPD patients (20-27), we did not
136 found in the database researched, any study using VMN coupled to NIV evaluated through scintigraphy in COPD.
However, we found just one study involving the use of NIV and nebulization in COPD reported by Mukhopadhway et al, aiming to analysis the effects of withdrawing NIV in 19 exacerbated COPD to delivery medications on physiologic (RR, HR, BP, SpO2, pH, PaCO2 and Borg Score) and dyspnea sensation. Results from this assessment did not showed significant change in physiologic parameters and oxygenation between NIV and nebulization periods. They observed increase in SBP and HR after inhalation, probably due to the systemic adrenergic effects of bronchodilator and decrease in SpO2 between both phases in the study. As a conclusion, short-term cessation of NIV to nebulize did not demonstrated discomfort or physiologic alterations (28).
Our findings regarding the difference in deposition during NIV is consistent with reports of aerosol deposited in patients submitted to conventional mechanical ventilation (CMV). Fuller et al analyzed deposition of radiotagged aerosol via JN and metered dose inhaler (pMDI) during CMV and found similar levels of lung dose with JN (1 – 3%) and higher levels of deposition with pMDI coupled to spacer (6 – 8%) (34). Their findings using JN is consistent with our results, because percentage using JN was 2.82%.
In a vitro model of adult mechanical ventilation, Ari et al compared aerosol delivery with JN, pMDI, VMN and ultrasonic nebulizer (UN) (35). Under similar conditions as Fuller, deposition distal to endotracheal tube was 3.6%in JN, while pMDI, VMN and USN were similar at 17%. According to this results, the same relative deposition for pMDI and VMN in vitro, it is reasonable to expect that in
137 vivo deposition would be similar. Consequently, our reported deposition with JN and VMN appear to agree with reports with CMV.
Assessing the efficacy of VMN coupled to NIV has been very promising, because radioaerosol deposition reached more than two fold (15-19,36-39). In this study, our results observed a higher amount of radiolabelled aerolized bronchodilator counts in stable moderate to severe COPD more than three folds in the comparison between VMN and JN. Abdelrahim et al, applied NIV in association to nebulization in a breathing simulator using 20 cmH2O (inspiratory
pressure) and 5 cmH2O (expiratory pressure) with parameters set to simulate
COPD patients (tidal volume of 500 ml, 15 breaths/min and 1:3 as I:E ratio) to compare VMN and JN in different positions. They found that VMB reached much more radiolabelled aerosol than JN in both tested positions. Thus, Dubus et al, observed more than 20 fold deposited into the lungs after comparing VMN to JN in a macaque model of mechanical ventilation to neonates (16).
Another result from this study, concerned about the lung deposition of 8.75% to VMN versus 2.82% to JN in line with the values observed in the inhaled dose of 19.90% .to VMN versus 7.03% to JN. Our results corroborates to those found by Abdelrahim et al, after assessing in vitro radioaerosol deposition through a breath simulator using VMN and NIV and reported around 51% of inhaled dose in VMN against 24% to JN (16). Similarly, AlQuami et al analyzed the inhaled dose of radioaerosol that reached in vitro test breath simulator in three different inhalers and found a higher percentage of 28.83 in VMN, 23.5% delivered by pMDI attached to spacer and only 13.2% in JN (40).
138 Mc Peck et al compared different modes of ventilation and demonstrated that radioaerosol inhaled dose of vary among these parameters set using VMN and JN. They found 14.3% versus 6.4% (using 10-5 cmH2O by BiPAP), 15.4%
versus 3.6% (applying 15-8 cmH2O by BiPAP) and 14.6% versus 7.2% (using 5
cmH2O by CPAP) (18).
VMN has got three advantages, regarding to no need of gas during nebulization in a pressurized circuit, small particles sizes generated by device and a lower residual volume (15-19, 28, 29). Our results demonstrated, according to this last advantage, a lower residual volume using VMN of 3.20% versus 49.53% to JN. A lower residual volume means that much more aerolized drugs will be kept into the recipe at the end of nebulization and probably more generated particles will reach the respiratory tree, mainly in those COPD patients to reduce dynamic hyperinflation and avoid increase of functional residual capacity.
In accordance to our results, Dubus et al compared two VMN and one JN in the macaque model of pediatric ventilation and pointed out 2.7% (APN-S model of VMN) and 9.9% (APN-C model of VMN) against 22.4% (15). In addition to this, similarly to our results, Mc Peck et al, reported a lower residual volume of 3.49% (VMN) versus 54.9% (JN) (18).
Analyzing deposition across the vertical and horizontal gradients, we found that intergroup deposition was higher comparing VMN to JN in different regions of interest for both lungs. While there is 2 - 3 fold more aerosols in all regions of interest with VMN than JN, we found similar ratios of distribution. It appears that distribution of aerosol is different between subjects, and between
139 the two nebulizer groups that are not obvious from analysis of regions of interest. Although the images were taken at one week intervals for each subject, individual subjects appear to have similar areas of aerosol concentration between the two types of aerosol generator used. These concentrations of aerosols in the lung likely represent localized areas of obstruction in each lung.
Among the factors that influence aerosol deposition along the airways, the respiratory pattern seems to contribute reducing the amount of drugs reaching the site of action. We believe that respiratory pattern adopted by COPD patients during NIV delivery influenced the standard deposition of radiolabelled aerolized bronchodilators in this study. Probably, we should consider the level of obstruction represented by those patients in the different stage of the disease.
We found a lower deposition in peripheral areas in both groups when analyzing ROIs, it should be explained because this sample of COPD patients presented lower values of FEF 25-75% (0.71 L – around 31.35% from predicted values), which correlates to prominent destruction of small airways presented by physiophatology of this disease. We found more depositing in this group of patients, similarly to Abdelrahim et al, but those authors used a simulator in which respiratory parameter was set and did not differ during the time of using NIV. However, in our in vivo protocol, respiratory parameters changed in each respiratory duty cycle during NIV (16).
The scintigraphy images obtained in this study from COPD patients presented hot spots, which concentrates more aerosol in some areas due to pulmonary obstruction and similar areas of hot spots were reported by Dolovich
140 et al, which demonstrating that using aerosol generators with two different particle sizes, distribution of aerosol changes beyond the hot spots (41).
Another concerning is about the higher percentage of deposition in the upper airways and face mask using VMN in comparison to JN. Probably, it should be a result of inhaled dose available to breath offered by VMN, the position of this device in the face mask and high inspiratory flows generated by BiPAP. In a randomized controlled trial performed by our group to assess