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Original Research: PEDIATRIC PROBLEMS |

Aerosol Therapy by Pressured Metered-Dose Inhaler-Spacer in Sleeping Young Children*: To Do or Not to Do? FREE TO VIEW

José Esposito-Festen, MD, PhD; Hanneke Ijsselstijn, MD PhD; Wim Hop, PhD; Frans van Vliet, BSc; Johan de Jongste, MD, PhD; Harm Tiddens, MD PhD
Author and Funding Information

*From the Department of Pediatrics (Drs. Esposito-Festen, de Jongste, and Tiddens), Division of Respiratory Medicine, Erasmus MC-Sophia, Rotterdam, the Netherlands; St. Franciscus Gasthuis (Dr. Ijsselstijn), Rotterdam, the Netherlands; and the Department of Biostatistics (Dr. Hop), and the Hospital Pharmacy (Mr. van Vliet), Erasmus MC, Rotterdam, the Netherlands.

Correspondence to: Harm Tiddens, MD, PhD, Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC-Sophia Children’s Hospital, University Medical Center, PO Box 2060, 3000 CB Rotterdam, the Netherlands; e-mail: H.Tiddens@erasmusmc.nl



Chest. 2006;130(2):487-492. doi:10.1378/chest.130.2.487
Text Size: A A A
Published online

One third of young children are distressed during inhalation therapy. It has been suggested that administration during sleep could be a good alternative for these children. A laboratory study in our department using an infant upper airway model showed significantly higher lung doses from a pressured metered-dose inhaler (pMDI)-spacer for sleep-breathing patterns compared with wake-breathing patterns.

Objective: We set up a daily life study to investigate the feasibility of aerosol administration by means of pMDI-spacer in sleeping young children.

Design: Over a period of 3 weeks, 30 children (age range, 6 to 23 months) with recurrent wheeze daily inhaled 1 puff of budesonide aerosol (200 μg) while awake and 1 puff during sleep. Filters positioned between the chamber and the facemask trapped the budesonide aerosol. Parents scored the child’s asthma symptoms, degree of cooperation, and feasibility of administration on diary cards.

Results: In 69% of the sleep administrations, the children woke up, and in 75% of these cases the children were distressed. The mean filter dose (expressed as the percentage of the nominal dose) while awake was 47%, and during sleep it was 16% (p = 0.007). The median within-subject dose variability while awake was 50%, and during sleep it was 110% (p = 0.007).

Conclusion: Aerosol administration by means of pMDI-spacer during sleep offers no advantage and is not a feasible treatment option in most young children.

Figures in this Article

The pressured metered-dose inhaler (pMDI) combined with a spacer is commonly used to deliver inhalation medication to infants and young children.14 However, the efficiency of drug delivery using a pMDI-spacer is influenced by device-related and patient-related factors.1,510 An important patient-related factor in young children is the highly variable breathing pattern, which is affected by the child’s level of cooperation.911 Cooperative young children with quiet tidal breathing have low breathing volumes and inspiratory flows. These children can efficiently clear the aerosol cloud from a small volume spacer and generate relatively high lung depositions.3 Unfortunately, about 30% of young children are distressed during inhalation therapy.1213 When crying, they have high inspiratory flows and long pauses between breaths, resulting in low lung deposition and high oropharyngeal deposition.3,9 Therefore, crying during the inhalation therapy is likely to reduce the efficacy of the anti-asthma treatment.

Administering the aerosol during sleep has been suggested to overcome cooperation problems in young children.10,1415 Indeed, in a model study we found significantly higher lung doses for sleep-breathing patterns compared with wake-breathing patterns.14 However, the feasibility of aerosol administration during sleep in a daily-life situation has never been studied systematically. Therefore, we carried out a daily-life study to investigate the feasibility of drug administration by means of pMDI-spacer in sleeping young children.

Study Population

Thirty children between the ages of 6 and 23 months were recruited from the outpatient clinics of Erasmus MC-Sophia Children’s Hospital (Rotterdam, the Netherlands), St. Franciscus Gasthuis (Rotterdam, the Netherlands), Reinier de Graaf Gasthuis (Delft, the Netherlands), and Albert Schweitzer Ziekenhuis (Dordrecht, the Netherlands). They all had been treated with twice-daily inhalation therapy for recurrent wheeze for at least the previous month. Children with cardiac disease or another disorder that might affect lung function were excluded from the study. Written informed consent was obtained from all parents. The ethics review committee of Erasmus MC Rotterdam approved the study.

Materials

A metal chamber (NebuChamber, 250 mL; AstraZeneca; Lund, Sweden) in combination with a facemask (Galemed; Galemed Corporation; I-Lan, Taiwan) was used to administer 200 μg of budesonide aerosol (Pulmicort, 200 μg; AstraZeneca) to the child. We used the facemask, a round resuscitation mask with a thick and flexible rim, because it has been shown that the use of this mask improved aerosol delivery compared with a preshaped facemask (NebuChamber; AstraZeneca).13 Each child received a new budesonide pMDI, primed by shaking and firing 10 waste puffs. A filter (MQ303; Marquest; Englewood, CO) inserted between the spacer and the facemask trapped the aerosol inhaled from the spacer. The filter holders fitted tightly to the mouthpiece of the chamber (Nebuchamber; AstraZeneca). The filter holder added 38 mL of dead space. The pressure drop over the filter is 230 Pa at 60 L/min.1

Study Design

The study period encompassed 3 weeks (ie, one run-in week followed by two actual test weeks). Over these 3 weeks, we visited the children four times at home. Parents were asked to follow standardized instructions on the use of inhalation therapy, as previously described by Janssens et al.12 The efficiency of drug delivery was assessed by adding 1 puff of a budesonide aerosol twice daily to the child’s regular inhalation therapy, which was continued as before. Before each administration of the study medication, parents placed a new filter between the chamber (NebuChamber; AstraZeneca) and the mask to trap the budesonide aerosol. In the 1-week run-in period, the parents practiced the study procedure with a placebo pMDI when the child was awake and before regular inhalation therapy. In the mornings of weeks 2 and 3, they administered 1 puff of budesonide aerosol before the child’s regular inhalation treatment, hereafter called awake administration. In the evenings of weeks 2 and 3, they administered the child’s regular inhalation treatment before the child went to bed. In addition, they administered 1 puff of budesonide aerosol after the child had fallen asleep, hereafter called sleep administration (Fig 1 ).

To monitor asthma symptoms and cooperation, parents filled out a validated diary card after each administration procedure.12 The symptoms cough, wheeze, and shortness of breath were each assigned a score ranging from 0 (no symptoms) to 4 (severe symptoms). The total asthma symptom score, with a maximum of 12, was defined as the sum of the scores for cough, wheeze, and shortness of breath. Cooperation during drug administration was assigned a score ranging from 0 (good cooperation) to 3 (fighting).

In addition, parents addressed two questions about the sleep administration procedure. First, did your child sleep throughout the administration procedure? Scores could range from 0 (slept through administration procedure) to 1 (half-awake but tranquil), 2 (half-awake but distressed), 3 (fully awake but tranquil), and 4 (fully awake and distressed). Second, was it easy to place the mask on the face? Scores could range from 0 (impossible) to 1 (possible, but extremely difficult), 2 (possible, but difficult), and 3 (possible without any problems). If parents rated the mask placement as 0, 1, or 2, they were asked to clarify why it was difficult to place the mask on the face by marking one of the following two options: A (child’s position in bed); or B (child’s restlessness).

Filter Analysis

All filters were analyzed in a blinded fashion by the Erasmus MC Hospital Pharmacy. The filters were washed with ethanol containing an internal standard (fluocinolone acetonide). Budesonide amounts were measured by high-performance liquid chromatography, using an ethanol-water (43:57) mobile phase and a reversed-phase column (Supelcosil LC-18 [inner diameter of 5-μm particles, 5 × 0.46 cm]; Sigma-Aldrich; St. Louis, MO). Budesonide was detected by ultraviolet spectrophotometry at a wavelength of 254 nm. The coefficient of variation (CV) for the method was < 3%.

Statistical Analysis

A statistical software package (SPSS for Windows, version 9.0; SPSS; Chicago, IL) was used for statistical analyses. Filter dose, calculated as the amount of budesonide deposited on the filter, was expressed as a percentage of the nominal dose. Filter dose variability was expressed as the within-subject CV.

The mean (± SD) number of filter doses and CVs were calculated for each child. To determine the efficiency of administration during sleep, only filter doses and CVs of children sleeping throughout the administration procedure were compared, using the Wilcoxon signed rank test.

The mean total symptom scores and mean cooperation scores obtained from the weekly diary cards were compared using the Friedman test. A p value of ≤ 0.05 (two-sided) was considered to indicate significant differences.

Thirty children (18 boys) entered the study. The results from three children were excluded from analysis because the parents had not complied with the protocol. Six children did not complete the third study week, because they were too distressed during the “sleep administration.” The missing data for these children were accounted for in the analysis. Twenty-one children fully completed the study. A total number of 350 and 331 filters, respectively, were collected for awake administration and sleep administration. The median age was 15 months (age range, 6 to 23 months). The mean symptom score (± SD) during the two actual study weeks was 1.4 (2.2).

Figure 2 shows the mean filter dose (top, A) and the mean filter dose variability (bottom, B) for the awake administration and the sleep administration. The mean (± SD) filter dose for the awake administration was 47 ± 26%, and that for the sleep administration was 16 ± 13% (p = 0.007). The median filter dose variability for the awake administration was 50% (range, 21 to 198%), and that for the sleep administration 110% (range, 47 to 152%; p = 0.007).

Poor cooperation (a score of 2 or 3) was recorded in 29% of the awake administration procedures. In 69% of the sleep administration procedures, the child woke up, and in 75% of these cases the children were distressed. Seven children showed poor cooperation during three or more awake administration procedures. These seven children slept in 47% of the sleep administration procedures. In three of them, the sleep dose was higher than the awake dose (Fig 2, top, A).

In 22% of the cases of children sleeping throughout the sleep administration procedure, the parents reported mask-positioning problems. In 96% of cases, this was caused by the child’s position in the bed, and in 4% by the child’s restlessness.

The aim of our study was to investigate the feasibility of aerosol administration in sleeping young children in a daily-life situation. Sleep administration was found to be possible in no more than one third of the children. Moreover, filter doses of sleeping children were substantially lower than the filter doses obtained during the awake administration.

Several studies23,8,16 have shown that inhalation therapy by means of pMDI-spacer can be effective in the treatment of recurrent wheezing in young children. However, up to 30% of the children < 2 years of age cannot be treated effectively because they become distressed during the administration procedure.1213 Distress, with its problems in obtaining a good facemask seal and its high inspiratory flows during crying, results in low lung deposition.3,9Aerosol administration during sleep has been suggested to be an option to treat these uncooperative children.10,1415 In a previous laboratory study,14 we first recorded the breathing patterns of 18 young children during sleep and while awake. Subsequently, an anatomically correct upper airway model (ie, the Sophia Anatomical Infant Nose-Throat model) “inhaled” the drug with the recorded breathing patterns replayed by a computer-controlled breathing simulator. Lung dose was measured by placing a filter between the model and the breathing simulator. We found that the breathing patterns during sleep resulted in significantly higher lung doses compared with the wake-breathing patterns.,14

How can we explain the discrepancy between the findings from this laboratory study and from our daily-life study? First, the laboratory study was performed under optimal conditions with an ensured airtight fit of the mask on the Sophia Anatomical Infant Nose-Throat model, whereas in our daily-life study the airtight fit of the mask on the child’s face was not guaranteed. Fear of awaking the child may have kept the parents from firmly pressing the mask onto the child’s face. Furthermore, about one fifth of the parents indicated that it was difficult to place the mask, because of either the child’s position in bed or restlessness. As shown in a previous study,17 even a tiny leak considerably reduces the amount of drug that can be inhaled from the spacer. Breathing patterns provide a second explanation for the discrepancy between the laboratory study and our daily-life study. Breathing patterns used in the laboratory study were recorded prior to infant lung function testing while the children were awake and while they were sedated with chloralhydrate. We observed that the wake-breathing patterns were irregular and that the sleep-breathing patterns were regular.14 Apparently, the sedated children had all been recorded during quiet, non-rapid eye movement (REM) sleep.14 In contrast, in our daily-life study aerosol therapy was administered when the children were in a deep natural sleep. It is possible that at the time of aerosol administration the children were in REM sleep. During REM sleep, the breathing pattern is irregular with variable respiratory rate and tidal volume, and frequent central apneas.1820 Therefore, the breathing pattern during REM sleep is likely to result in low doses being inhaled from the spacer.2122

Children who are uncooperative during inhalation therapy are the most important target group for aerosol administration during sleep. However, with this daily-life study we have demonstrated that the success rate of inhalation therapy during sleep is low, since most children woke up during the sleep administration. Nevertheless, three of the seven uncooperative children obtained higher filter doses during sleep administration compared with those during awake administration. Moreover, two uncooperative children, who showed higher filter doses during the awake administration, had most likely been crying. In these children, filter doses are known to overestimate lung doses substantially.3,9 Therefore, aerosol therapy during sleep could be appropriate in children who do not cooperate during the awake administration and remain asleep during the sleep administration. Hence, inhalation therapy during sleep can be attempted in uncooperative children, although with little chance of success.

It should be noted that, in this study, the dose found on the filters represents the amount of aerosolized drug delivered to the patient. It does not provide information on the clinical efficacy or lung deposition of the drug. However, the filter method was sufficient to investigate the feasibility of aerosol administration during sleep.

In conclusion, many children were found to wake up when receiving aerosol therapy during sleep, and in 75% of these cases the children were found to be distressed. In addition, in the children who slept throughout the inhalation therapy filter doses were low and filter dose variability was high. Therefore, aerosol therapy by means of pMDI-spacer during sleep is not a feasible treatment option for most young children. The administration of the drug during sleep can be attempted in cases of particularly uncooperative children. However, parents should be made aware that the success rate of inhalation therapy during sleep is low.

Abbreviations: CV = coefficient of variation; pMDI = pressured metered-dose inhaler; REM = rapid eye movement

This study was supported by an unrestricted grant from AstraZeneca, the Netherlands.

Drs. Hop and de Jongste have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Aerosol administration in a young sleeping child. Failure to place the mask in an airtight manner on the face because of the position of the child in bed.Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: mean filter dose, expressed as the percentage of the nominal (nom) dose, during the awake administration and during the sleep administration, for those children who slept through the administration procedure. Bottom, B: mean filter dose variability (CV%) during the awake administration and during the sleep administration, for those children who slept through the administration procedure. Straight line = cooperative child; dotted line = uncooperative child during awake administration.Grahic Jump Location

The authors thank all of the children and parents for their participation in this study. Dr. R. Schornagel and Dr. P.J.C van der Straaten are gratefully acknowledged for the recruitment of patients in their hospitals.

Bisgaard, H (1995) A metal aerosol holding chamber devised for young children with asthma.Eur Respir J8,856-860. [PubMed]
 
Conner, WT, Dolovich, MB, Frame, RA, et al Reliable salbutamol administration in 6- to 36-month-old children by means of a metered dose inhaler and Aerochamber with mask.Pediatr Pulmonol1989;6,263-267. [CrossRef] [PubMed]
 
Wildhaber, JH, Devadason, SG, Hayden, MJ, et al Aerosol delivery to wheezy infants: a comparison between a nebulizer and two small volume spacers.Pediatr Pulmonol1997;23,212-216. [CrossRef] [PubMed]
 
Fok, TF, Lam, K, Ng, PC, et al Delivery of salbutamol to nonventilated preterm infants by metered-dose inhaler, jet nebulizer, and ultrasonic nebulizer.Eur Respir J1998;12,159-164. [CrossRef] [PubMed]
 
Janssens, HM, Devadason, SG, Hop, WC, et al Variability of aerosol delivery via spacer devices in young asthmatic children in daily life.Eur Respir J1999;13,787-791. [CrossRef] [PubMed]
 
Barry, PW, O’Callaghan, C The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler.Br J Clin Pharmacol1995;40,76-78. [CrossRef] [PubMed]
 
Everard, ML, Devadason, SG, Summers, QA, et al Factors affecting total and “respirable” dose delivered by a salbutamol metered dose inhaler.Thorax1995;50,746-749. [CrossRef] [PubMed]
 
Wildhaber, JH, Janssens, HM, Pierart, F, et al High-percentage lung delivery in children from detergent-treated spacers.Pediatr Pulmonol2000;29,389-393. [CrossRef] [PubMed]
 
Iles, R, Lister, P, Edmunds, AT Crying significantly reduces absorption of aerosolised drug in infants.Arch Dis Child1999;81,163-165. [CrossRef] [PubMed]
 
Tal, A, Golan, H, Grauer, N, et al Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction.J Pediatr1996;128,479-484. [CrossRef] [PubMed]
 
Janssens, HM, De Jongste, JC, Hop, WC, et al Extra-fine particles improve lung delivery of inhaled steroids in infants: a study in an upper airway model.Chest2003;123,2083-2088. [CrossRef] [PubMed]
 
Janssens, H Aerosol delivery from spacers in wheezy infants: a daily life study.Eur Respir J2000;16,850-856. [CrossRef] [PubMed]
 
Esposito-Festen, JE, Ates, B, van Vliet, FJM, et al Aerosol delivery to young children by pMDI-spacer: is facemask design important?Pediatr Allergy Immunol2005;16,348-353. [CrossRef] [PubMed]
 
Janssens, HM, van der Wiel, EC, Verbraak, AF, et al Aerosol therapy and the fighting toddler: is administration during sleep an alternative?J Aerosol Med2003;16,395-400. [CrossRef] [PubMed]
 
Murakami, G, Igarashi, T, Adachi, Y, et al Measurement of bronchial hyperreactivity in infants and preschool children using a new method.Ann Allergy1990;64,383-387. [PubMed]
 
Bisgaard, H, Munck, SL, Nielsen, JP, et al Inhaled budesonide for treatment of recurrent wheezing in early childhood.Lancet1990;336,649-651. [CrossRef] [PubMed]
 
Esposito-Festen, JE, Ates, B, Van Vliet, FJM, et al Effect of a facemask leak on aerosol delivery from a pMDI-spacer system.J Aerosol Med2004;17,1-6. [CrossRef] [PubMed]
 
Poets, CF, Stebbens, VA, Alexander, JR, et al Breathing patterns and heart rates at ages 6 weeks and 2 years.Am J Dis Child1991;145,1393-1396. [PubMed]
 
Poets, CF, Stebbens, VA, Samuels, MP, Southall, DP Oxygen saturation and breathing patterns in children.Pediatrics1993;92,686-690. [PubMed]
 
Marcus, CL Sleep-disordered breathing in children.Am J Respir Crit Care Med2001;164,16-30. [PubMed]
 
Dolovich, MA Influence of inspiratory flow rate, particle size, and airway caliber on aerosolized drug delivery to the lung.Respir Care2000;45,597-608. [PubMed]
 
Laube, BL, Edwards, AM, Dalby, RN, et al The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.J Allergy Clin Immunol1998;101,475-483. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Aerosol administration in a young sleeping child. Failure to place the mask in an airtight manner on the face because of the position of the child in bed.Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: mean filter dose, expressed as the percentage of the nominal (nom) dose, during the awake administration and during the sleep administration, for those children who slept through the administration procedure. Bottom, B: mean filter dose variability (CV%) during the awake administration and during the sleep administration, for those children who slept through the administration procedure. Straight line = cooperative child; dotted line = uncooperative child during awake administration.Grahic Jump Location

Tables

References

Bisgaard, H (1995) A metal aerosol holding chamber devised for young children with asthma.Eur Respir J8,856-860. [PubMed]
 
Conner, WT, Dolovich, MB, Frame, RA, et al Reliable salbutamol administration in 6- to 36-month-old children by means of a metered dose inhaler and Aerochamber with mask.Pediatr Pulmonol1989;6,263-267. [CrossRef] [PubMed]
 
Wildhaber, JH, Devadason, SG, Hayden, MJ, et al Aerosol delivery to wheezy infants: a comparison between a nebulizer and two small volume spacers.Pediatr Pulmonol1997;23,212-216. [CrossRef] [PubMed]
 
Fok, TF, Lam, K, Ng, PC, et al Delivery of salbutamol to nonventilated preterm infants by metered-dose inhaler, jet nebulizer, and ultrasonic nebulizer.Eur Respir J1998;12,159-164. [CrossRef] [PubMed]
 
Janssens, HM, Devadason, SG, Hop, WC, et al Variability of aerosol delivery via spacer devices in young asthmatic children in daily life.Eur Respir J1999;13,787-791. [CrossRef] [PubMed]
 
Barry, PW, O’Callaghan, C The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler.Br J Clin Pharmacol1995;40,76-78. [CrossRef] [PubMed]
 
Everard, ML, Devadason, SG, Summers, QA, et al Factors affecting total and “respirable” dose delivered by a salbutamol metered dose inhaler.Thorax1995;50,746-749. [CrossRef] [PubMed]
 
Wildhaber, JH, Janssens, HM, Pierart, F, et al High-percentage lung delivery in children from detergent-treated spacers.Pediatr Pulmonol2000;29,389-393. [CrossRef] [PubMed]
 
Iles, R, Lister, P, Edmunds, AT Crying significantly reduces absorption of aerosolised drug in infants.Arch Dis Child1999;81,163-165. [CrossRef] [PubMed]
 
Tal, A, Golan, H, Grauer, N, et al Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction.J Pediatr1996;128,479-484. [CrossRef] [PubMed]
 
Janssens, HM, De Jongste, JC, Hop, WC, et al Extra-fine particles improve lung delivery of inhaled steroids in infants: a study in an upper airway model.Chest2003;123,2083-2088. [CrossRef] [PubMed]
 
Janssens, H Aerosol delivery from spacers in wheezy infants: a daily life study.Eur Respir J2000;16,850-856. [CrossRef] [PubMed]
 
Esposito-Festen, JE, Ates, B, van Vliet, FJM, et al Aerosol delivery to young children by pMDI-spacer: is facemask design important?Pediatr Allergy Immunol2005;16,348-353. [CrossRef] [PubMed]
 
Janssens, HM, van der Wiel, EC, Verbraak, AF, et al Aerosol therapy and the fighting toddler: is administration during sleep an alternative?J Aerosol Med2003;16,395-400. [CrossRef] [PubMed]
 
Murakami, G, Igarashi, T, Adachi, Y, et al Measurement of bronchial hyperreactivity in infants and preschool children using a new method.Ann Allergy1990;64,383-387. [PubMed]
 
Bisgaard, H, Munck, SL, Nielsen, JP, et al Inhaled budesonide for treatment of recurrent wheezing in early childhood.Lancet1990;336,649-651. [CrossRef] [PubMed]
 
Esposito-Festen, JE, Ates, B, Van Vliet, FJM, et al Effect of a facemask leak on aerosol delivery from a pMDI-spacer system.J Aerosol Med2004;17,1-6. [CrossRef] [PubMed]
 
Poets, CF, Stebbens, VA, Alexander, JR, et al Breathing patterns and heart rates at ages 6 weeks and 2 years.Am J Dis Child1991;145,1393-1396. [PubMed]
 
Poets, CF, Stebbens, VA, Samuels, MP, Southall, DP Oxygen saturation and breathing patterns in children.Pediatrics1993;92,686-690. [PubMed]
 
Marcus, CL Sleep-disordered breathing in children.Am J Respir Crit Care Med2001;164,16-30. [PubMed]
 
Dolovich, MA Influence of inspiratory flow rate, particle size, and airway caliber on aerosolized drug delivery to the lung.Respir Care2000;45,597-608. [PubMed]
 
Laube, BL, Edwards, AM, Dalby, RN, et al The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.J Allergy Clin Immunol1998;101,475-483. [CrossRef] [PubMed]
 
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