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Long-term non-invasive ventilation therapies in children: a scoping review
Maria L. Castro-Codesal, Kristie Dehaan, Robin Featherstone, Prabhjot K. Bedi, Carmen Martinez Carrasco, Sherri L. Katz, Elaine Y. Chan, Glenda N. Bendiak, Fernanda R. Almeida, Deborah Olmstead, Rochelle Young, Vicki Woolf, Karen A. Waters, Collin Sullivan, Lisa Hartling, Joanna E. MacLean
PII: S1087-0792(17)30046-1
DOI: 10.1016/j.smrv.2017.02.005
Reference: YSMRV 1021
To appear in: Sleep Medicine Reviews
Received Date: 4 August 2016 Revised Date: 16 November 2016 Accepted Date: 22 February 2017
Please cite this article as: Castro-Codesal ML, Dehaan K, Featherstone R, Bedi PK, Martinez Carrasco C, Katz SL, Chan EY, Bendiak GN, Almeida FR, Olmstead D, Young R, Woolf V, Waters KA, Sullivan C, Hartling L, MacLean JE, Long-term non-invasive ventilation therapies in children: a scoping review, Sleep Medicine Reviews (2017), doi: 10.1016/j.smrv.2017.02.005.
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TITLE: Long-term non-invasive ventilation therapies in children: a scoping review SHORT TITLE: Long-term non-invasive ventilation in children
14 1 13 1
Maria L Castro-Codesal' , Kristie Dehaan , Robin Featherstone ' , Prabhjot K Bedi , Carmen Martinez Carrasco5, Sherri L Katz6, Elaine Y Chan7, Glenda N Bendiak8, Fernanda R Almeida9, Deborah Olmstead4, Rochelle Young4, Vicki Woolf11, Karen A Waters10, Collin Sullivan10, Lisa Hartling1'3, Joanna E MacLean1,2,4
1 Department of Pediatrics, 2Women & Children's Health Research Institute, 3Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, AB, Canada; 4Stollery Children's Hospital, Edmonton, AB, Canada; 5Department of Pediatrics, Hospital La Paz, Madrid, Spain; 6Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; 7Department of Respiratory Medicine, Great Ormond Street Hospital for Children, London, UK; 8Department of Pediatrics, University of Calgary, Calgary, AB, Canada; 9Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada; 10Sydney Medical School, University of Sydney, Sydney, NSW Australia; 11Sleep Medix Inc, Edmonton, AB, Canada.
CORRESPONDING AUTHOR: Maria Luisa Castro Codesal
4-590 Edmonton Clinic Health Academy, 11405 87 Ave NW
Edmonton, AB T6G 1C9, Canada
E-mail: castroco@ualberta.ca
Telephone number: +1 780 248 1781
Fax number: +1 888 353 1323
ACKNOWLEDG EM ENTS
MCC, RF, LH, and JM conceived the idea of this study and designed the methodology. KW, CM, SK, EC, GB, CS, FA, RY, DO, and VW reviewed and provided suggestions on the methods. RF conducted the literature searches. MCC, JM screened all articles. MCC, KD and PB performed the data extraction with contributions from SK, GB, EC, RY, DO, JM. MCC and JM interpreted the data. MCC wrote the initial draft of the manuscript. All authors reviewed the manuscript and approved the final version.
Women and Children's Health Research Institute (WCHRI) kindly supported this study through the Alberta Research Centre for Health Evidence. MCC received salary support through a Stollery Clinical Research Fellowship funded by the Stollery Children's Hospital Foundation. LH is supported by a CIHR New Investigator Salary Award. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. VW has a financial interest in a private company that sells non-invasive ventilation products. No other conflicts of interest have been disclosed.
SUMMARY
Long-term non-invasive ventilation (NIV) is a common modality of breathing support used for a range of sleep and respiratory disorders. The aim of this scoping review was to provide a summary of the literature relevant to long-term NIV use in children. We used systematic methodology to identify 11581 studies with final inclusion of 289. We identified 76 terms referring to NIV; the most common term was NIV (22%). Study design characteristics were most often single center (84%), observational (63%), and retrospective (54%). NIV use was reported for 73 medical conditions with obstructive sleep apnea and spinal muscular atrophy as the most common conditions. Descriptive data, including NIV incidence (61%) and patient characteristics (51%), were most commonly reported. Outcomes from sleep studies were reported in 27% of studies followed by outcomes on respiratory morbidity reduction in 19%. Adverse events and adherence were reported in 20% and 26% of articles respectively. Authors reported positive conclusions for 73% of articles. Long-term use of NIV has been documented in a large variety of pediatric patient groups with studies of lower methodological quality. While there is considerable data for the most common conditions, there is less data to support NIV use for many additional conditions.
KEYWORDS: Artificial respiration; Continuous positive airway pressure; Pediatrics; Respiratory insufficiency; scoping review; Sleep apnea.
GLOSSARY OF TERMS
Auto-PAP: auto positive airway pressure.
CPAP: Continuous positive airway pressure
DMD: Duchenne muscular dystrophy
IMV: invasive mechanical ventilation
NIV: Non-invasive ventilation
NMD: Neuromuscular disease
NPPV: Non-invasive positive pressure ventilation
OSA: Obstructive sleep apnea
PAP: Positive airway pressure
SMA: Spinal muscular atrophy
INTRODUCTION
Non-invasive ventilation (NIV), where assistance to breathing or full ventilation is delivered through an interface outside the airway, has become the first line therapy for a wide range of sleep and respiratory disorders in children including upper airway obstruction [1-3], musculoskeletal weakness and chest wall restriction [4-9], chronic lung diseases [10-12], central nervous system disorders [13-15], and other systemic disorders with respiratory insufficiency [16-18]. Technological advances in NIV have provided children requiring long-term respiratory support and their families an acceptable alternative to invasive mechanical ventilation (IMV) via tracheostomy [19]. Additional contributors to the increase in long-term NIV use include increased survival of children with complex medical conditions [20], a shift in health care from hospital to home-based care [20], and increased awareness of the consequences of sleep breathing disorders and their possible treatments [21, 22]. NIV use has increased worldwide [23-34], resulting in a reduction in the number of admissions to pediatric intensive care units and a greater number of children living at home using NIV [35-37].
There are gaps in our present knowledge on the benefit of long-term NIV in children. For instance, the literature on decreased mortality and morbidity rates and improved longevity with long-term NIV has focused primarily on neuromuscular diseases (NMD) such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), with limited data on the impact on survival in other populations [23, 38, 39]. Other outcomes, such as improvement in quality of life, neurocognitive and behavioral outcomes have been demonstrated in children using NIV for the treatment of obstructive sleep apnea (OSA); however, these benefits may not generalize to children with other conditions needing NIV [1, 40]. Long-term NIV use has been reported for
conditions including a range of syndromes [3, 17, 41-46], congenital heart defects [47], obesity [48], sickle cell disease [16], and cancer [49].
In addition to an expanding range of conditions where NIV may be beneficial, the increase in long-term NIV use at home, as opposed to in hospital, has resulted in a shift in the responsibility of care to parents and caregivers [17, 50]. Long-term NIV presents challenges including the use of a mask interface [51, 52], adherence [53-55], and funding for equipment as well as access to support services in the community [56]. With increasing use of this technology, it is important to define the evidence-base to support the use of long-term NIV therapy in children, identify evidence gaps, and develop a research strategy to begin to address these gaps in knowledge.
To date, there has been no review of long-term NIV use in children employing systematic methodology. While prior systematic reviews have included information on long-term NIV in children, the focus of these reviews has been on diagnosis or treatment for specific conditions such as OSA, achondroplasia, global developmental delay or chronic cough [1, 15, 57-63]. The aim of this scoping review is to provide an overview of the literature relevant to long-term NIV use in children. The results of this scoping review will provide a map of all existing literature and will define the volume and characteristics of the primary research pertinent to long-term NIV use in children. We will use this map to identify data appropriate for systematic review and to highlight gaps in knowledge relevant to improving the care of children using long-term NIV.
MATERIALS AND METHODS
The scoping review protocol was designed based on the frameworks developed by Bragge and colleagues and Arksey and O'Malley [64, 65] with full details of the protocol published elsewhere [66]. Scoping reviews are used to examine the main sources and types of evidence available with a broad approach to a topic; this is in contrast to a systematic review which usually addresses a narrow research question. As a result, scoping reviews are used to identify the boundaries and context of a topic area as well as summarize the key characteristics and results of included studies rather than appraise the quality of the evidence or provide a synthesis of the data. We created an advisory committee of experts in systematic reviews, pediatric respiratory and sleep medicine, and NIV therapies, to advise on the search strategy as well as in the reporting of the results.
Search strategy: An information specialist developed the search strategy for Ovid Medline with terms related to NIV and a validated child search filter [67], and then translated this into Ovid Embase, PubMed (last year only), CINAHL via EbscoHOST, and Wiley Cochrane Library (including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the NHS Economic Evaluation Database; see On-line supplement for search strategy). Searches were limited to human studies published after 1990 because the first study of long-term NIV use in children we identified was published in 1992. No language or study design restrictions were applied to the search. Database searches were run between November 17 and November 28, 2014. An update of the literature search was conducted in 5 databases (Ovid Medline, Cochrane Library, Ovid Embase, CINAHL and PubMed) on April 29,
2016 using the same search strategy to identify recently published studies and abstracts. Grey literature sources were searched between January 7 and January 21, 2015. We searched peer-reviewed abstracts from 10 selected conferences on respiratory medicine, sleep medicine, and neuromuscular medicine conducted between January 2012 and December 2014. We also searched theses and dissertations from 1990 onward via ProQuest Dissertations & Theses Global, trial registries from 2012 to 2014 via ClinicalTrials.gov and WHO's International Clinical Trials Registry Platform, and regulatory agencies and manufacturer reports from 1990 onward.
Inclusion criteria: Child was defined as newborn to 18 years of age. Studies with both adults and children as subjects were included if data for children were reported separately. Studies which included children and young adults were included if the mean age of the subjects was 18 years or younger. We defined NIV as any mode of ventilatory support that was delivered with a non-invasive interface which avoids tracheal intubation. This included both positive pressure, such as continuous positive airway pressure (CPAP) and bilevel positive airway pressure, and negative pressure ventilation (see on-line supplement for the 48 terms used to define NIV). Long-term use was defined as at least three months of use outside an acute care environment. Study selection was not limited by study design or outcomes assessed. Case reports with three or more subjects were included. Comments, editorials, letters and reviews were excluded.
Study selection: Two reviewers screened English titles and abstracts of retrieved studies for eligibility. The same two reviewers screened full-text studies for the final list of included studies. Discrepancies were resolved by consensus. Studies written in English, Spanish, French, Portuguese, Italian and Catalan were included, with all other languages excluded.
Data extraction: Data extraction was completed using a pre-designed form and entered into a Microsoft Access Database (Microsoft, Redmond, Washington, USA). Extracted data included study design and duration, NIV terms used, medical conditions of studied populations, NIV intervention type and outcomes of interest identified in the methods' section of included articles. Data on NIV terms and medical conditions was exactly extracted as described by authors in the methods sections, with no interpretation of terms (e.g. if authors said OSA, we did not reword it into sleep disordered breathing). More than one term related to NIV or several medical conditions could be extracted from the same paper. Data about sample size, additional outcomes, adverse events, and adherence was extracted from the results sections. Outcomes were not defined a priori and were classified according to the data source (e.g. reported clinical information from medical letters, sleep study results, downloads from NIV machine, etc.). Comparisons where the statistical test had a p<0.05 were considered to show statistically significant differences. Data on author's conclusions and identified gaps in knowledge were gathered from the conclusion sections. Conclusions about NIV were defined as positive, if authors stated a benefit from the NIV therapy, negative, if they concluded a lack of benefit or identified significant adverse events or complications from the NIV therapy, neutral if they did not clearly state positive or negative conclusions, and indeterminate if reviewers were unable to classify authors' conclusions under other headings. Twenty per cent of the extracted data was verified by a second reviewer for accuracy and completeness.
Data synthesis: Data was collated in order to present a narrative account of the existing literature [64, 65]: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) 2015 statement was followed in the reporting of the results [68].
Interpretations or grouping of terms related to NIV therapies were avoided to ensure authors' original terms were preserved. For the data synthesis, MeSH terms (PubMed) were used to define a medical condition when authors used multiple terms to refer to the same medical condition to avoid overlapping. Medical conditions were then classified into disease categories attending to the underlying pathophysiology. Word cloud software (http://www.tagxedo.com) was used to produce qualitative syntheses of NIV terms and medical conditions.
Statistical analysis: SPSS version 24 (1989, 2016) was used for statistical analysis. Descriptive data was reported as absolute numbers and percentages and medians and ranges were calculated for quantitative variables. Age was provided as mean and standard deviation. Pearson Chi- Square or Fisher's Exact Test were used to calculate differences by subgroups such as age and disease category.
RESULTS
We identified 11581 potentially relevant studies; 289 are included in this scoping review (Figure 1). The majority of the studies were published as journal articles (74%, 215/289). The contributions from grey literature sources represented 26% of included studies (74/289) and these were predominantly conference abstracts (22%, 63/289). The first article on long-term NIV in children identified with our search strategy was published in 1992 with a median year of publication of 2011 (Figure 2). The majority of studies were conducted in North America (41%, 119/289) and Europe (36%, 104/289) (Figure 3). A total of 91 studies were excluded due to language: 53 from European countries and 38 from Asian countries. Non-invasive ventilation terms
Seventy-six terms were used to describe NIV (Figure 4). The most common terms included non-invasive ventilation (NIV 22%, 65/289), non-invasive positive pressure ventilation (NPPV 12%, 35/289) and positive airway pressure (PAP 9%, 27/289). Different terms were also used to refer to specific NIV modalities including continuous positive pressure ventilation (CPAP 33%, 95/289), bi-level positive airway pressure ventilation (Bi-level 16%, 46/289) and autopositive airway pressure (Auto-PAP 2%, 7/289). Study design
Study designs (Table 1) were predominantly quantitative (91%, 263/289) with few qualitative (2%, 5/289), biomedical (6%, 17/289) and manufacturer reports (1%, 4/289). The most common quantitative study design was observational (63%, 182/289) including cohort studies (42%, 122/289), case-control studies (4%, 12/289), and case series (17%, 48/289). Twelve percent of studies (34/289) were cross-sectional surveys with 7% (19/289) randomized and non-randomized controlled trials and 10% (28/289) within subject interventional controlled before-after studies. The majority of studies were single center studies (84%, 244/289) with 16% (45/289) multicenter studies. Only 4% (2/45) of the multicenter studies were also multinational. Fifty-four percent (155/289) of the studies were retrospective. The overall median sample size of included studies was 14 (range 3-658). Multicenter studies had median sample size of 24 (range 6-658). Only 23% (66/289) of studies included a control or comparison group. Median study duration was 40 months (range 1-552 months); study duration for interventional studies, however, was shorter, with median of 25 months (range 1-102). The duration of intervention was only reported in 42% (122/289) of the studies. For the studies reporting NIV duration, the median duration of NIV use was 12 months (0-180 months).
Subject characteristics
NIV was used for a broad range of medical conditions (Figure 5). Seventy-three medical conditions were identified from the methods section of the included studies. The most common medical conditions reported included OSA (29%, 84/289), SMA (8%, 22/289), sleep disordered breathing (6%, 16/289), and NMD (5%, 14/289). When grouping medical conditions (Table 2), the majority of the studies investigated disorders of upper airway obstruction (33%, 94/289) or neuromuscular and other musculoskeletal disorders (22%, 63/289). Studies investigating NIV as a treatment for sleep disordered breathing in the context of childhood obesity were only published in the last 10 years, with the first study published in 2006. Over time, there has been an increasing proportion of studies focused on cohorts of children using long-term NIV regardless of the medical condition, with 73% (55/75) of the studies with this study design published in the last 10 years.
There was considerable variability in the age when NIV was started. The mean age of NIV initiation was 8.06 ± 3.08 years with the majority of the studies reporting data on children across a wide age span (0-24 years; Figure 6). Although 39% of the studies (114/289) included infants (under 2 years of age) in their target populations, only 9% of studies (27/289) were exclusively undertaken in this population. The medical conditions studied differed by age group (Fisher's Exact Test 102.820, p<0.05). In studies focused on infants, the predominant medical condition was upper airway disorders (52%, 14/27) followed by 33% (10/27) of studies focused on NMD (9 of which were on SMA type 1), 4% (1/27) on congenital central hypoventilation syndrome, and 7% (2/27) on multiple conditions. In studies that included children over 2 years of age (30%, 88/289), 41% (36/88) were focused on upper airway diseases, 20% (18/88) on
NMD, 10% (9/88) on sleep disordered breathing related to obesity, 8% (7/88) on pulmonary disease, and 10% (9/88) on multiple diseases. The use of NIV for treatment of obesity related sleep disordered breathing and pulmonary diseases was only reported in older children. Conversely, the studies focused on multiple disease categories where data on age was reported (55/289) were mostly cohorts of children aged 0 to 18 years (78%, 43/55). NIV equipment
CPAP use was reported in 25% (73/289) of studies compared to 21% (61/289) for bilevel therapies and 2% (7/289) for auto-PAP; 22% (63/289) of the studies reported data on combined CPAP and bi-level therapies and 20% (57/289) on disaggregated data for NIV and IMV therapies (Table 2). In 24% (39/289) of the studies, there is no specific description in the methodology of the non-invasive intervention used; that is, CPAP and/or bilevel were not specified. There was only one study reporting on negative pressure ventilation exclusively and 11 articles included negative pressure ventilation among other ventilator therapies.
There were differences in NIV type use according to the disease category (Fisher's Exact Test 166.164, p<0.05). Seventy-eight percent (62/79) of studies reporting on CPAP included children with upper airway disorders, obesity or other medical conditions. Studies on bilevel therapies were focused on children with musculoskeletal diseases (46%, 29/63), cohorts of children including multiple medical conditions (17%, 11/63), and children with pulmonary conditions (16%, 10/63), with few reports in children with upper airway disorders (6%, 4/63). Studies reporting CPAP and bilevel interventions together were mostly done in children with upper airway disorders (46%, 29/63) and cohorts of children including multiple medical conditions (33%, 21/63), with few reports in children with musculoskeletal diseases (11%,
7/63). Studies including NIV and IMV therapies together reported data mostly on cohorts of children with multiple medical conditions (54%, 31/57) and children with musculoskeletal diseases (21%, 12/57).
The interface type was only specified in 46% (132/289) of studies. In those where details of the interface were reported, nasal masks were most commonly used alone (52%, 69/132) or in combination with full face masks (20%, 27/132). Outcomes of interest
A wide range of outcomes of interest were described. This included objective measurements (e.g. apnea-hypoapnea index, blood gas measurements, oxygen saturation, validated questionnaire scores, adherence rate from NIV machine downloads) in 63% (182/289) of the studies, subjective information from medical letters (e.g. improvement on clinical symptoms reported by physician, adverse events) in 50% (145/289) of the studies, subjective data collected directly from patients and families in 10% (30/289), and surveys of health care providers asking for descriptive data of their patient populations, practice patterns or assessing their knowledge in 9% (27/289).
Descriptive data such as the number of patients initiated on NIV, patient characteristics and NIV discontinuation rates were reported on 61% (177/289), 51% (147/289) and 7% (20/289) respectively (Table 3). A variety of diagnostic tests to measure efficacy of NIV were used, which was most commonly data from sleep studies, including polysomnography (24%, 69/289) and polygraphy (2%, 6/289). Examples of measured outcomes from sleep studies were apnea-hyponea index, end tidal or transcutaneous carbon dioxide, oxygen saturation, sleep architecture, arousal index). A combination of home overnight pulse oximetry and
transcutaneous carbon dioxide levels were reported in 1% (2/289) of the studies. In a smaller proportion, blood gas measurements (e.g. partial pressure of oxygen and carbon dioxide) were used (5%, 14/289) to measure efficacy of NIV. Fifteen per cent (43/289) of the studies reported reduction of respiratory morbidity such as improvement of respiratory symptoms, tracheostomy avoidance or decannulation, or reduction in post-operative complications. Reduction of healthcare encounters related to respiratory exacerbations was reported in 5% (13/289) of the studies. Improvements of symptoms in other areas affected by sleep breathing disorders were not well described. For instance, improvements in sleep symptoms, neurocognitive outcomes, mood and behaviour, and quality of life were reported in 5% or less (14/289, 13/289, 5/289 and 14/289, respectively) of studies. Mortality rates were an outcome of interest in 6% (18/289) of the studies. Ten per cent of the studies (28/289) tested the efficiency of NIV technology either assessing NIV machine settings or interfaces.
Some of the outcomes of interest differed by disease category. Of 69 studies reporting outcomes from sleep studies (including polysomnography, polygraphy and limited channel studies), 54% (37/69) of studies were conducted in children with upper airway obstruction disorders, 22% (15/69) in children with musculoskeletal and neuromuscular diseases, and 14% (10/69) in cohorts combining children with multiple underlying conditions (Fisher's Exact Test 19.035, p< 0.05). Studies reporting data on mortality (6%, 18/289) were exclusively conducted in children with musculoskeletal and neuromuscular diseases (44%, 8/18) or cohorts of children with multiple underlying conditions (50%, 9/18) (Fisher's Exact Test 16.462, p<0.05). Looking at studies reporting respiratory morbidity or reduction of health care encounters due to respiratory exacerbations (17%, 50/289), 24% (12/50) were in children with upper airway
obstruction disorders, 38% (19/50) in musculoskeletal and neuromuscular diseases, and 26% (13/50) on children with multiple diseases, (Fisher's Exact Test 11.412, p<0.05). The proportion of studies reporting outcomes on sleep symptoms, mood and behaviour, neurocognition and quality of life did not differ by disease category.
Adverse events were reported in 20% (59/289) of the studies. The most common complications found were skin lesions (e.g. irritation, redness, breakdown; 6%, 18/289), mask intolerance, leak or NIV therapy intolerance (5%, 15/289), nasal symptoms (e.g. congestion, rhinorrhea, epistaxis, sinusitis; 2%, 7/289), device failure (2%, 7/289), midface hypoplasia (2%, 6/289), abdominal distension (2%, 6/289), and death (2%, 5/289).
Adherence to NIV was reported in 26% (74/289) of the studies. Of note, while the first report on adherence was in 1992, the majority of studies reporting on adherence (77%, 57/74) were published in the last 10 years. Only 3% of the studies (10/289) analyzed data on treatment burden of long-term NIV for children and their caregivers. Statistical analysis
Purely descriptive data was reported in 28% of the studies (81/289), while 63% of studies (182/289) were designed to measure differences in outcomes between groups or time points. Seven percent (21/289) of the studies reported only narrative data on NIV, including case series (4%, 12/289), qualitative studies (2%, 5/289), and manufacturer reports (1%, 4/289). There were ongoing interventional studies (2%, 5/289) for which data is not yet available. Authors' conclusions
In the majority of studies, the authors stated a conclusion about NIV (96%, 278/289). Overall, 73% (203/278) of the studies included a conclusion that the long-term use of NIV in
children may provide benefits while 4% (10/278) had a negative conclusion (i.e. no benefit of NIV or adverse events), 16% (45/278) were indeterminate, and 7% (20/278) neutral. In the studies where authors stated positive conclusions of NIV, 59% (119/203) authors performed statistical analysis to test for significant differences for at least one of their outcomes, with 30% of the studies (60/203) supporting their positive conclusions with descriptive data only and the remaining 7% (14/203) reporting narrative outcome data (Pearson Chi-Square 17.089, p<0.04).
DISCUSSION
This is the first systematic overview of the literature on long-term NIV in children. The topic of this scoping review was intentionally broad with the goal of identifying the nature and extent of the literature relevant to long-term use of NIV in children. The results highlight the diversity of medical conditions for which long-term NIV has been reported and the variability of the information available to support its use across medical conditions. We also identified that the evidence for long-term NIV use differs by age group, with some medical conditions studied predominantly or exclusively in certain age groups. There is a paucity of multicenter, randomized, and interventional studies with predominantly descriptive results. While there are a range of outcome measurements studied to determine the benefits of NIV in children populations, there is less emphasis on other aspects of the NIV therapies such as treatment burden and most research available does not seem to be patient-prioritized. The results of this scoping review provide a detailed analysis of the existing evidence supporting the use of long-term NIV in children.
We identified a variety of terms referring to the description of NIV therapies. Differences in terms appear to relate to the definition of the technology (e.g. positive airway pressure), the specific NIV modality (e.g. CPAP, bi-level, auto-PAP), the time of the day for NIV use (e.g. nocturnal ventilation), the type of interface used (e.g. nasal ventilation), or simply the author's preference. The meaning of certain terms was not always clear, presenting a challenge for identification of the relevant literature. For example, terms referring to the use of ventilatory support technology at home (e.g. home mechanical ventilation, long-term ventilation, domiciliary ventilation) often included both children on NIV and IMV or did not clearly define the type of interface. Based on our results, we would recommend the use of the term 'non-invasive ventilation' (abbreviated as NIV) to denote the use of methods of ventilatory support delivered with an interface outside the airway. Using this definition, CPAP, bi-level, auto-PAP and other modalities of delivering ventilatory support with an interface outside the airway are included as sub-types of NIV. This definition is consistent with the medical subject heading for NIV, used for indexing articles in PubMed which defines NIV as 'techniques for administering artificial respiration without the need of intratracheal intubation' (http://www.ncbi.nlm.nih.gov/mesh/D063087). We recognize that CPAP is not considered by many to provide ventilation support; CPAP is, however, included under the MeSH term 'positive pressure ventilation' defined as 'a method of mechanical ventilation in which pressure is maintained to increase the volume of gas remaining in the lungs at the end of expiration, thus reducing the shunting of blood through the lungs and improving gas exchange', supporting our recommendation that CPAP is a method of ventilatory support. In addition, CPAP can be used both with an invasive and non-invasive interface so it is important to distinguish these
treatment modalities. Our results show that other authors have reported trends and outcomes combining children using both CPAP and bilevel [25, 31, 32, 69]. This makes sense given children using CPAP and bilevel therapies share common challenges related to adherence and complications with the non-invasive interface, similar methods of monitoring therapy and overlap in the outcome measures. Lastly, there is overlap in the medical conditions of children using CPAP and bilevel. While certain medical conditions are exclusively treated with bilevel therapy (e.g. congenital central hypoventilation syndrome), many others have pathophysiology that can be treated with CPAP or bilevel (e.g. upper airway obstruction, obesity). Other methods of NIV such as auto-PAP and negative pressure ventilation have been less well described in the literature. The use of the term NIV to refer to any ventilatory support administered through a non-invasive interface will simplify the literature search and allow clear differentiation from invasive methods of ventilation.
Starting in the 1980's, when the first case reports on long-term NIV use in children were published [70-72], there is substantial literature documenting the long-term use of NIV in children with a large variety of underlying conditions. Over the subsequent two decades, there has been a steady increase in the number of publications investigating the use of long-term NIV in children, with the greatest increase in the last 5 years. This pattern confirms the reported trends of increased use of long-term NIV worldwide [23-34]. The drivers of this increase in use are likely multi-factorial and include improvements in the technology for children using NIV, greater awareness of the potential use of NIV, as well as changes in funding for NIV. While there is an extensive literature on long-term NIV use in children, there are clearly gaps in our
understanding of the use of this technology, and a pressing need to fill these gaps in this growing field.
Our results highlight the low methodological quality of the literature in long-term NIV use in children. The majority of the available data comes from descriptive studies, with small sample sizes and a paucity of randomized controlled clinical trials. We identified many singlecenter descriptive studies with similar methodology where the combination of data would enable larger sample size to allow subgroup analysis. This could facilitate the identification of common characteristics of those children that benefit most from long-term NIV and improve the power to detect between group differences. Randomized trials may be challenging given that NIV is an accepted therapy for many medical conditions, hence calling into question the ethics of randomizing subjects to alternative therapies or placebo. However, before-after comparisons within the same subjects provide an assessment of risks and benefits despite lower rigor than randomization.
Despite evidence of long-term NIV use in a large number of medical conditions, the majority of the current literature is focused on a small number of diseases including OSA and NMD. While these conditions are likely the most common ones leading to NIV use, this focus limits the extrapolation of this information to children with other medical conditions. Efforts to apply further systematic review methods to summarize data examining studies addressing specific outcomes for these more common conditions or broader outcomes for less prevalent conditions would be of value. For example, prior systematic reviews on OSA have included aspects of diagnosis, comorbidities, and surgical treatment options [1, 57, 60, 62]; a similar systematic review focused on adherence to NIV in OSA would be informative. Systematic
review or meta-analysis of long-term NIV outcomes for children with NMD such as SMA, or DMD would also provide stronger evidence than individual study results. While there has been a previous systematic review on nocturnal mechanical ventilation in patients with neuromuscular and chest wall disorders of all ages, data were not separated into IMV and NIV [63]. Other medical conditions where long-term NIV use has been described, such as congenital central hypoventilation syndrome, cystic fibrosis, obesity, trisomy 21, or craniofacial abnormalities, present different challenges for NIV where a systematic review could help clarify what is known and not known about specific outcomes related to NIV use in these conditions. Future research efforts focused on multi-centre studies or the development of national or multi-national patient registries may be the best means of developing robust data to support NIV use for less common medical conditions.
Few studies focus exclusively on infant populations. Infancy represents a time when both breathing and sleep control mechanisms are evolving and, therefore, is a unique physiological period distinct from older children [73]. Studies on long-term NIV use for medical conditions with significant respiratory morbidity during the neonatal period, such as craniofacial disorders, laryngomalacia, SMA type 1, or congenital central hypoventilation syndrome, are almost exclusively descriptive [74-77]. Long-term NIV use may be an alternative to IMV as many of these infants improve with time, allowing discontinuation of ventilatory support and preventing complications related to tracheostomy and IMV [74, 78]. Future studies exclusive to infants or including infants as a distinct group should assess outcomes that emphasize the unique sleep and respiratory physiology of infancy and take into account normal developmental changes across infancy when considering the impact of long-term NIV use.
Specific gaps in the literature include some negative aspects of long-term NIV therapies. While approximately 20% of the studies identified report on adverse events and adherence rates, other relevant outcomes such as treatment burden or barriers to adherence for children and caregivers were included in only 3% of included studies. This means there is limited data on the impact of long-term NIV on children and their families. No studies examining funding or community supports for long-term NIV were identified. The paucity of studies exploring the experience of NIV from the child, family and community viewpoints is an important gap. As the use of long-term NIV requires a significant investment, both with respect to the work involved in using NIV and in some cases the financial cost, the lack of information on the child, family and community experience with long-term NIV may limit our ability to provide the best possible care.
This scoping review provides a comprehensive and exhaustive examination of the literature on long-term NIV use in children. However, there are several limitations that must be acknowledged. As with any systematic review methodologies, a publication bias towards studies conducted in English-speaking countries is likely due to limited resources for translation. In our case, research done in certain geographical areas of Europe and Asia may be underrepresented. However, no articles from Africa or South America were excluded for that reason. We did not contact authors for clarification of information. While contacting authors would have filled gaps in our data extraction, this scoping review is intended to represent the information that is most easily accessible and, therefore, available to parents, clinicians, and policy makers to support decision making relevant to long-term NIV use in children. Our inclusive approach was deliberate and allows us to define the scope of the literature relevant to
our topic. However, it also limits our ability to summarize details of diverse methods and outcomes. As such, our results represent the first step in describing the literature relevant to long-term NIV use in children with work underway for further analysis of this important data in more detail.
CONCLUSIONS
This scoping review has mapped the existing literature on the long-term use of NIV in children. Long-term NIV use has been documented in a great diversity of pediatric patient groups and NIV modalities. However, most of the studies to date have been observational and descriptive in nature. While more robust information exists for some conditions, there is a paucity of data relevant to many pediatric populations currently using NIV. In addition, outcomes studied may not be those of highest priority for children using NIV and their families. The results of this scoping review provide a rigorous overview of the existing literature and a context on which to build a research agenda aimed at improving the lives of children using long-term NIV.
Practice Points
1. The term non-invasive ventilation better describes the techniques for administering ventilatory support through an interface outside the airway.
2. Long-term use of non-invasive ventilation is a therapeutic option in a variety of pediatric groups although the available data is not evenly distributed across medical conditions or age groups.
3. The majority of studies of long-term NIV use in children are observational and predominantly descriptive in nature.
Research Agenda
1. Identify populations for whom sufficient data is available for systematic review or metaanalysis to provide comprehensive summary of the data currently available for specific childhood populations.
2. Establish multicenter or multinational studies or patient registries to enable larger sample size and studies of more robust study design including clinical trials of long-term NIV use in children.
3. Design patient-oriented studies with a focus on the experience and impact of long-term NIV use on the children that use this therapy, their families and their communities.
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LEGENDS
Figure 1: Flow diagram of screened and included studies (adaption from PRISMA-P 2015).
* Each conference proceeding included is counted as a single record. T Individual abstracts from conference proceedings have been added manually and duplicate data removed.
Figure 2: Number of publications by year of publication. The most noticeable increase in publications began in 2011. Publications for 2016 include only those published before 2 May 2016.
Figure 3: Geographical distribution of contributing authors. Publications with authors from multiple continents were counted in each contributing nation resulting in a higher total number than publications included.
Figure 4: Word cloud created with tagxedo software (www.tagxedo.com) summarizing 76 terms used to describe long-term non-invasive ventilation in children. The size of the words represents the frequency of the use of each term; larger words correspond to the terms that are used more frequently. Share under creative copyright under a Creative Commons Attribution-Noncommercial-ShareAlike License 3.0 (https://creativecommons.org/licenses/by-nc-sa/3.0/us/)
Figure 5: Word cloud with tagxedo software (www.tagxedo.com) summarizing 73 medical conditions for which the use long-term NIV in children has been reported. The size of the words represents the frequency of the use of each medical condition; larger words correspond to the medical conditions with more reports of long-term NIV use in children. Share under creative copyright under a Creative Commons Attribution-
Noncommercial-ShareAlike License 3.0 (https://creativecommons.org/licenses/by-nc-sa/3.0/us/)
Figure 6: Age range included in studies. Vertical axis markers at 2 year of age to indicate infancy, 12 years of age to indicate childhood, and 18 years to indicate adolescence. Each line represents one article.
Table 2: Subject characteristics and NIV interventions reported in 289 included studies. Numbers represent the number of studies with percentage in parentheses unless otherwise indicated.
Characteristics
Age at NIV start (years) (mean ± SD) 8.06 ± 3.09
Disease category: N (%)
Upper airway obstruction 94 (33)
Neuromuscular/ Musculoskeletal 63 (22)
Pulmonary 16 (6)
Obesity 9 (3)
CNS 8 (3)
Multiple medical conditions 75 (26)
Other medical conditions (including cardiac, syndrome) 10 (3)
Not reported 14 (5)
Type of NIV: N (%)
CPAP 73 (25)
Bi-level 61 (21)
CPAP + bi-level 63 (22)
NIV not specified 27 (10)
NIV + IMV 57 (20)
Negative pressure ventilation 1 (1)
Auto-PAP 7 (2)
Time of NIV use: N (%)
Day and Night 45 (16)
Night only 112 (39)
Day Only 2 (1)
Not Reported 130 (45)
Interface type: N (%)
Nasal 69 (24)
Nasal + full face 27 (9)
Multiple 20 (7)
Other: Full face, mouth piece, negative pressure 6 (2)
Not reported 167 (58)
Author's conclusion: N (%)
Positive 203 (70)
Negative 10 (4)
Neutral/Indeterminate 65 (23)
Not reported 11 (4)
Auto-PAP, auto positive airway pressure; CNS, central nervous system; CPAP, continuous positive pressure; IMV, invasive mechanical ventilation; NIV: non-invasive ventilation; SD, standard deviation.
Table 1: Summary of publication type and study design for 289 included studies. Numbers represent the number of studies with percentage in parentheses unless otherwise indicated.
Description n (%)
Type of publication:
Journal 215 (74)
Abstract 63 (22)
Dissertation 1 (1)
Manufacturer Report 4 (1)
Unpublished Trial 6 (2)
Type of study:
Quantitative:
Observational (Cohort, Case series, Case-Control) 182 (63)
Cross Sectional/Survey 34 (12)
Controlled Before-After 28 (10)
Randomized/Non-Randomized Controlled Trial 19 (7)
Qualitative 5 (2)
Bench Study 17 (6)
Manufacturer reports 4 (1)
Single vs Multi-center:
Single-center 244 (84)
Multi-center 45 (16)
Prospective vs Retrospective:
Prospective 134 (46)
Retrospective 155 (54)
Control group:
Yes 66 (23)
No Treatment 29 (43)
Invasive Ventilation 13 (20)
Tonsillectomy and/or Adenoidectomy 5 (7)
Other 19 (31)
No 223 (77)
Number of study subjects using NIV (median, range) 14 (3-658)
Study duration (months; median range) 40 (1-552)
Duration of NIV intervention (months; median, range) 12 (0-180)
NIV, non-invasive ventilation.
Table 3: Summary of outcomes described in the 289 included studies. Numbers represent the number of studies with percentage in parentheses unless otherwise indicated.
Outcomes n (%)
Descriptive data
Number of patients initiated NIV 177 (61)
Patient characteristics 147 (51)
Discontinuation of NIV 20 (7)
Efficacy of NIV
Sleep studies (including PSG, PG, limited channel studies) 77 (27)
Respiratory gases 14 (5)
Other respiratory tests (pulmonary function test, airway pressures, chest X-ray) 7 (2)
Metabolic outcomes 4 (1)
Other (echocardiogram, EEG) 4 (1)
Benefit from NIV
Respiratory symptoms (airway obstruction, hypoventilation, postoperative
complications, tracheostomy avoidance or decannulation) 43 (15)
Reduction of health care encounters due to respiratory exacerbation 13 (5)
Sleep 14 (5)
Neurocognition 13 (5)
Quality of life 14 (5)
Mood/behavior 5 (2)
Growth and development 5 (2)
Increased survival 8 (3)
Other symptoms 2 (<1)
Mortality rate 18 (6)
Adverse events 59 (20)
Compliance/ adherence 74 (26)
NIV machine settings and interfaces 28 (10)
Healthcare providers knowledge/ practice 7 (2.5)
Other (optimal pressure requirements, predictors of NIV need...) 19 (6)
NIV, non-invasive ventilation. PG, polygraphy. PSG, polysomnography. EEG, electroencephalogram.
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