**The E**ffi**cacy and Safety of Doripenem in the Treatment of Acute Bacterial Infections—A Systemic Review and Meta-Analysis of Randomized Controlled Trials**

### **Chih-Cheng Lai 1, I-Ling Cheng 2, Yu-Hung Chen <sup>2</sup> and Hung-Jen Tang 3,\***


Received: 9 May 2019; Accepted: 1 July 2019; Published: 2 July 2019

**Abstract:** This study aims to assess the efficacy and safety of doripenem on treating patients with acute bacterial infections. The Pubmed, Embase, and Cochrane databases were searched up to April 2019. Only randomized clinical trials comparing doripenem and other comparators for the treatment of acute bacterial infection were included. The primary outcome was the clinical success rate and the secondary outcomes were microbiological eradication rate and risk of adverse events. Eight randomized controlled trials (RCTs) were included. Overall, doripenem had a similar clinical success rate with comparators (odds ratio [OR], 1.15; 95% CI, 0.79–1.66, I2 = 58%). Similar clinical success rates were noted between doripenem and comparators for pneumonia (OR, 0.84; 95% CI, 0.46–1.53, *I* <sup>2</sup> = 72%) and for intra-abdominal infections (OR, 1.00; 95% CI, 0.57–1.72). For complicated urinary tract infection, doripenem was associated with higher success rate than comparators (OR, 1.89, 95% CI, 1.13–3.17, *I* <sup>2</sup> = 0%). The pool analysis comparing doripenem and other carbapenems showed no significant differences between each other (OR, 0.96, 95% CI, 0.59–1.58, *I* <sup>2</sup> = 63%). Doripenem also had a similar microbiological eradication rate with comparators (OR, 1.08; 95% CI, 0.86–1.36, *I* <sup>2</sup> = 0%). Finally, doripenem had a similar risk of treatment-emergent adverse events as comparators (OR, 0.98; 95% CI, 0.83–1.17, *I* <sup>2</sup> = 33%). In conclusion, the clinical efficacy of doripenem is as high as that of the comparator drugs in the treatment of acute bacterial infection; furthermore, this antibiotic is as well tolerated as the comparators.

**Keywords:** doripenem; acute bacterial infection; pneumonia; intra-abdominal infection; complicated urinary tract infection

#### **1. Introduction**

Carbapenems, including imipenem and meropenem, remain the mainstay of treatment for hospital-acquired infections, especially for the multidrug-resistant organism associated infections [1]. Doripenem is another important carbapenem, and has excellent bactericidal activity against most nosocomial pathogens according to several in vitro studies [2–5]. A global surveillance showed that doripenem was at least two-fold more potent in in vitro activities than imipenem and meropenem against *Pseudomonas aeruginosa*—an important nosocomial pathogen [3]. For another notorious pathogen—*Acinetobacter baumannii*, doripenem displayed comparable in vitro activities to imipenem and meropenem [4]. Clinically, doripenem is approved for the treatment of patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) and pyelonephritis, and healthcare-associated pneumonia (HAP) including ventilator-associated pneumonia (VAP) in Europe and in other countries, other than United States. Although Qu et al. [6] conducted a meta-analysis of

doripenem for treating bacterial infections in 2015, only six clinical trials were enrolled and the number of patients was limited. Since then, two more studies investigating the efficacy of doripenem in comparison with other comparators were reported [7,8]. In Wagenlehner et al.'s study [7], 1033 randomized patients were enrolled, and they did the comparison between doripenem and ceftazidime-avibactam for the treatment of cUTI. In Oyake et al.'s study [8], they compared the empirical use of doripenem versus meropenem for febrile neutropenia in patients with acute leukemia. These two studies provided more patients and different types of infections compared to previse meta-analysis [6]. Therefore, we could conduct a comprehensive review and updated meta-analysis to assess the efficacy and safety of doripenem on treating patients with acute bacterial infections in comparison with other antibiotics, especially imipenem and meropenem.

#### **2. Methods**

#### *2.1. Study Search and Selection*

Studies were identified by a systematic review of the literature in the PubMed, Embase, and Cochrane databases until April 2019 using the following search terms—"doripenem," "infection," and "randomized" (Appendix A). Studies were considered eligible for inclusion if they directly compared the clinical effectiveness of doripenem with other antimicrobial agents in the treatment of adult patients with acute bacterial infections. Studies were excluded if they focused on in vitro activity, or pharmacokinetic-pharmacodynamic assessment. The articles of all languages of publication could be included. Two reviewers (I.-L.C. and Y.-H.C.) searched and examined publications independently. When they had disagreement, the third author (C.-C.L.) resolved the issue in time. The following data including year of publication, study design, type of infections, patients' demographic features, antimicrobial regimens, clinical and microbiological outcomes, and adverse events were extracted from every included study.

#### *2.2. Definitions and Outcomes*

The primary outcome was overall clinical success with resolution of clinical signs and symptoms of acute bacterial infection, or recovery to the pretreatment state at the end of treatment. Secondary outcomes included the microbiological eradication rate and adverse events. A microbiological eradication was defined as eradication (the baseline pathogen was absent) and presumed eradication (if an adequate source specimen was not available to culture, but the patient was assessed as clinically cured). Treatment-emergent adverse events were recorded, irrespective of causality. In addition, the risk of discontinuing due to adverse event and the incidence of serious adverse events, and some common events, including diarrhea, nausea, headache, constipation, and seizure were recorded.

#### *2.3. Data Analysis*

This study used the Cochrane risk of bias assessment tool to assess the quality of enrolled randomized controlled trials (RCTs) and the risk of bias [9]. The software Review Manager, version 5.3, was used to conduct the statistical analyses. The degree of heterogeneity was evaluated with the Q statistic generated from the χ<sup>2</sup> test. The proportion of statistical heterogeneity was assessed by the *I 2* measure. Heterogeneity was considered significant when the p-value was less than 0.10 or the *I <sup>2</sup>* was more than 50%. The random-effects model was used when the data were significantly heterogeneous, and the fixed-effect model was used when the data were homogenous. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated for outcome analyses. Sensitivity analysis was performed to ensure that the findings were not significantly affected by any individual study

#### **3. Results**

#### *3.1. Study Selection and Characteristics*

The search program yielded 499 references, including 263 from Pubmed, 170 from Embase, and 66 from Cochrane database. Then, 258 articles were screened after excluding 241 duplicated articles. Finally, a total of eight RCTs [7,8,10–15] fulfilling the inclusion criteria were included in this meta-analysis (Figure 1). All of studies were designed to compare the clinical efficacy and safety of doripenem with other antibiotics for patients with acute bacterial infection (Table 1) [7,8,10–15]. During the initial enrollment, doripenem and comparators were applied to 1736 and 1763 patients, respectively. Six studies [7,10–13,15] of them were multicenter studies. Three studies [10–12] focused on pneumonia, including two [12,16] on ventilator-associated pneumonia and one [10] on nosocomial pneumonia. Two studies focused on complicated urinary tract infections (cUTI) [7,13] and intra-abdominal infections (IAI) [14,15]. Only one study investigated febrile neutropenia [8]. Five studies [8,11,12,14,15] compared doripenem with other carbapenems including imipenem in three studies [11,12,14] and meropenem in two studies [8,15]. The regimen of doripenem was 1 g every eight hours in two studies [8,11] and 500 mg every eight hours in the other six studies [7,10,12–15]. For the two studies using double dose of doripenem (1 g every eight hour), the study drug (doripenem or meropenem) was used for at least five days in one study [8] and another one [11] compared seven-day doripenem versus 10-day imipenem-cilastatin. Figure 2 shows the analyses of risk of bias.

**Figure 1.** Flowchart of the study selection process.



MDS, myelodysplastic syndrome; UTI, urinary tract infection; RCT, randomized controlled

#### *J. Clin. Med.* **2019**, *8*, 958

**Figure 2.** Risk of bias per study and domain.

#### *3.2. Clinical Success*

Overall, doripenem had a similar clinical success rate with comparators (OR, 1.15; 95% CI, 0.79–1.66, *I <sup>2</sup>* = 58%, Figure 3). Sensitivity analysis after randomly deleting an individual study each time to reflect the influence of the single data set to the pooled OR showed similar findings in most occasions. There was only one exception, when we deleted Kollef et al.'s study [11], doripenem showed better clinical success rate than other comparators in the pool analysis of the remaining seven studies [7,8,10,12–15] (OR, 1.33; 95% CI, 1.03–1.72, *I <sup>2</sup>* = 0%). In the different subgroup of patients with pneumonia, cUTI, and intra-abdominal infection, similar clinical success rates were noted between two different regimens for pneumonia (OR, 0.84; 95% CI, 0.46–1.53, *I <sup>2</sup>* = 72%) and for IAI (OR, 1.00; 95% CI, 0.57–1.72). For cUTI, doripenem was associated with a higher success rate than comparators (OR, 1.89, 95% CI, 1.13–3.17, *I <sup>2</sup>* = 0%). Three studies [11,12,14] compared the effect of doripenem and imipenem, and there was no difference in terms of clinical success rate between these two regimens (OR, 0.76; 95% CI, 0.38–1.55, *I <sup>2</sup>* = 66%). Two studies [8,15] compared doripenem and meropenem, their clinical success rates were similar (OR, 1.31, 95% CI, 0.75–2.28, *I <sup>2</sup>* = 34%). The pool analysis of these

five studies comparing doripenem and other carbapenems showed no significant differences between each other (OR, 0.96, 95% CI, 0.59–1.58, *I <sup>2</sup>* = 63%).


**Figure 3.** Overall clinical success rates of doripenem and comparators in the treatment of acute bacterial infections.

#### *3.3. Microbiological Eradication*

Only six studies [7,10,12–15] reported the data of microbiological eradication rate, and the pool analysis showed that doripenem had a similar microbiological eradication rate with comparators (OR, 1.08; 95% CI, 0.86–1.36, *I <sup>2</sup>* = 0%, Figure 4). Sensitivity analysis showed similar results. In the different subgroup of patients with pneumonia and IAI, similar microbiological eradication rates were found for both regimens (for pneumonia, OR, 1.25; 95% CI, 0.79–1.97, *I <sup>2</sup>* = 0%; for IAI, OR, 1.04; 95% CI, 0.49–2.17, *I <sup>2</sup>* = 54%). While comparing doripenem and other carbapenems in the pool analysis of four studies [7,12,14,15], the microbiological eradication rates were similar between these two regimens (OR, 1.13; 95% CI, 0.85–1.51, *I <sup>2</sup>* = 0%).


**Figure 4.** Overall microbiological eradication rates of doripenem and comparators in the treatment of acute bacterial infections.

#### *3.4. Adverse Events*

Six studies [7,8,11,13–15] reported the incidence of treatment-emergent adverse events, the doripenem had a similar risk with other antibiotics (OR, 0.98; 95% CI, 0.83–1.17, *I <sup>2</sup>* = 33%, Figure 5). Serious adverse events were reported in six studies [7,10,12–15], the overall incidence was similar between doripenem and other antibiotics (OR, 1.06; 95% CI, 0.85–1.31, *I* <sup>2</sup> = 43%). Six studies [7,10,12–15] reported the risk of discontinuing drug due to adverse event, the risk was similar between doripenem and comparators (OR, 0.75, 95% CI, 0.35–1.61, *I <sup>2</sup>* = 61%). Regarding some common adverse events, doripenem was associated with the similar risk as comparators in terms of diarrhea (OR, 0.91, 95% CI, 0.64–1.28, *I <sup>2</sup>* = 0%) in the pool analysis of eight studies [7,8,10–15], nausea (OR, 0.93, 95% CI, 0.45–1.93, *I <sup>2</sup>* = 62%) among five studies [11–15], headache (OR, 1.10, 95% CI, 0.82–1.48, *I <sup>2</sup>* = 0%) among three studies [13–15], and constipation (OR, 0.96, 95% CI, 0.61–1.52, *I <sup>2</sup>* = 0%) among three studies [11,13,14]. In the pooled analysis of four studies [10,12,13,15] that reported the risk of seizure, doripenem was

associated with a similar lower risk as comparators (OR, 0.37, 95% CI, 0.15–0.92, *I <sup>2</sup>* = 0%). Moreover, no seizure attack was reported to be related to doripenem in these four studies [10,12,13,15].


**Figure 5.** Risk of treatment-emergent adverse events of doripenem and comparators in the treatment of acute bacterial infections.

#### **4. Discussion**

This meta-analysis based on eight RCTs found that doripenem had a similar clinical success rate of treating acute bacterial infections with other comparators. The similar efficacy in terms of clinical response and microbiological eradication was found between doripenem and other carbapenems, including meropenem and imipenem. In addition, this result was not affected by the different types of infections—pneumonia, cUTI, or IAIs. Even for several specific types of infection—cholangitis, cholecystitis, appendicitis, lower urinary tract infection, and acute pyelonephritis—no statistical differences in terms of clinical efficacy was found between doripenem and comparators in the included studies [13–15]. In fact, in addition to Kollef et al.'s study [11], that showed doripenem was found to have non-significant higher rates of clinical failure and mortality compared to imipenem [7,10,12–15]. The difference between Kollef et al.'s study [11] and the other seven studies [7,10,12–15] may be explained by the fact that Kollef et al. compared a fixed seven-day course of doripenem with a fixed 10-day course of imipenem-cilastatin for treating VAP. Seven days of antibiotic treatment may have been too short for the patients with VAP, so the clinical outcome of VAP treated with a seven-day course of doripenem was worse than with a 10-day course of imipenem-cilastatin. In this meta-analysis, while we did sensitivity analysis after deleting this negative study [11] for doripenem, we found that the pooled analysis of the other seven studies [7,8,10,12–15] showed that doripenem was associated with better clinical outcome than comparators. Although this finding hints that the effect of doripenem may be better, or at least as good as, other antimicrobial agents in the treatment of acute bacterial infections, if doripenem can be used as long as the comparators, we still need further study to confirm this issue. Before that, the findings of this meta-analysis indicate that the clinical efficacy of doripenem is not inferior to other antimicrobial agents in the treatment of acute bacterial infections. Finally, several studies [16–18] demonstrated that doripenem was associated with lower medical resource utilization and hospital cost in the treatment of HAP and VAP versus comparators, including imipenem. Overall, doripenem could be both a life- and cost-saving antibiotic and could be recommended as the appropriate antibiotic in the treatment of acute bacterial infections, including pneumonia, cUTI, and cIAI.

In this meta-analysis, we also compared the microbiological response of doripenem with other antibiotics for acute bacterial infection. Overall, we found the microbiological eradication rates were similar between doripenem and comparators. Moreover, a similar trend was noted in the sensitivity analysis and subgroup analysis of pneumonia and IAIs. Finally, doripenem was comparable to other carbapenems, including imipenem and meropenem, in terms of microbiological eradication rate in the subgroup analysis. All these findings may be well explained by previous in vitro studies [3,4,19–21] that showed doripenem had a greater or similar in vitro activity against bacteria, including multi-drug resistant organisms. In this meta-analysis, we did not assess we did not evaluate the association between

in vitro activity and the in vivo response of different organisms, especially for antibiotic-resistant pathogens, because the associated information was limited. However, this meta-analysis demonstrates that doripenem is comparable to other antimicrobial agents in both the clinical and microbiological responses of treating acute bacterial infections.

In addition to the assessment of clinical efficacy and microbiological eradication, the safety issue is another important concern in the treatment of acute bacterial infection by doripenem. In this analysis, the risks of overall treatment-emergent adverse effects, common adverse effects (diarrhea, nausea, headache and constipation), serious adverse effects, and the risk of discontinuing the drug due to adverse effects were similar between doripenem and comparators. Seizure is another important concern for patients using carbapenems. In this meta-analysis, four studies [10,12,13,15] reported the incidence of seizure, and the doripenem group had a lower risk of seizure than comparators. Moreover, although six seizure events were reported in this meta-analysis, all these events occurred in patients with underlying risk factors and were not clearly related to doripenem. Therefore, all these findings indicate that doripenem may be as safe as conventional regimens in the treatment of acute bacterial infections.

This meta-analysis has several limitations. First, we did not evaluate the effect of doripenem and comparators against specific organisms in each type of bacterial infection and the confounding effect of the antibiotic resistance of these pathogens. Besides, the immune status and the age effect were not assessed in this meta-analysis due to limited information. Second, the use of doripenem for treating pneumonia remains a serious concern due to the negative findings of Kolleff et al.'s study [11] that showed a shorter course (seven days) of doripenem was associated with a worse outcome than a longer course (10 days) of imipenem for patients with VAP. However, doripenem was commonly used for treating pneumonia in many countries [22], and several studies [10,12,23–25] showed the clinical outcomes of pneumonia treated by doripenem were favorable. In the subgroup analysis of this meta-analysis, we found the clinical and microbiological responses of doripenem for treating pneumonia were as good as comparators. But, as only three RCTs [10–12] focusing on pneumonia were enrolled in this meta-analysis, the number of studies is limited, thus further study is warranted to clarify this issue.

In conclusion, based on the analysis of eight RCTs, no differences in terms of clinical success and microbiological eradication rates were found between doripenem and comparators in the treatment of acute bacterial infections. Moreover, doripenem was well tolerated and had comparable safety profiles to other antimicrobial agents.

**Author Contributions:** Conceptualization, I.-L.C., Y.-H.C. and C.-C.L.; formal analysis, I.-L.C. and Y.-H.C.; writing—original draft, C.-C.L.; writing—review and editing, H.-J.T.

**Conflicts of Interest:** The authors declare no conflicts of interest.

#### **Appendix A : List of Terms of the Search Strategy**

Pubmed 1. "doripenem" [MeSH Terms] 2. "doripenem" [All Fields] 3. 1 OR 2 4. "infection" [MeSH Terms] 5. "infection" [All Fields] 6. 4 OR 5 7. "randomized" [All Fields] 8. "randomised" [All Fields] 9. 7 OR 8 10. 3 AND 6 AND 9 Embase


#### **References**


© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Review* **A Scoping Review of The E**ffi**cacy of Virtual Reality and Exergaming on Patients of Musculoskeletal System Disorder**

### **Hui-Ting Lin 1, Yen-I Li 1, Wen-Pin Hu 2, Chun-Cheng Huang <sup>3</sup> and Yi-Chun Du 4,\***


Received: 3 April 2019; Accepted: 24 May 2019; Published: 4 June 2019

**Abstract:** To assess the effects of virtual reality on patients with musculoskeletal disorders by means of a scoping review of randomized controlled trials (RCTs). The databases included PubMed, IEEE, and the MEDLINE database. Articles involving RCTs with higher than five points on the Physiotherapy Evidence Database (PEDro) scale were reviewed for suitability and inclusion. The methodological quality of the included RCT was evaluated using the PEDro scale. The three reviewers extracted relevant information from the included studies. Fourteen RCT articles were included. When compared with simple usual care or other forms of treatment, there was significant pain relief, increased functional capacity, reduced symptoms of the disorder, and increased joint angles for the virtual reality treatment of chronic musculoskeletal disorders. Furthermore, burn patients with acute pain were able to experience a significant therapeutic effect on pain relief. However, virtual reality treatment of patients with non-chronic pain such as total knee replacement, ankle sprains, as well as those who went through very short virtual reality treatments, did not show a significant difference in parameters, as compared with simple usual care and other forms of treatment. Current evidence supports VR treatment as having a significant effect on pain relief, increased joint mobility, or motor function of patients with chronic musculoskeletal disorders. VR seems quite effective in relieving the pain of patients with acute burns as well.

**Keywords:** virtual reality; musculoskeletal disorders; randomized controlled tria

#### **1. Introduction**

Virtual reality (VR) of players using body movement to interact with a computer is a new form of treatment in rehabilitation settings. It generates a virtual world in three-dimensional space through a computer simulation that stimulates user senses, such as sight and hearing, making users feel as if they are immersed in it. VR has three elements: Interaction, Immersion, and Imagination [1]. It can be used in the teaching of human anatomy, online navigation of museums, 3D game teaching, flight training, and rehabilitation [2]. VR has become a therapeutic tool in many medical and rehabilitation fields. Due to the cost decline and ease of use of this technology, it has become an effective tool and trend in various fields.

However, its greatest obstacles lie in the lack of space, time, support staff, appropriate customer and customer incentives, therapist knowledge, and management support. The clinical use of VR often depends on the motivation and attitude of the therapist [3,4].

In the clinical investigations on the VR experience and perception of physical therapists (PTs) and occupational therapists (OTs) in Canada conducted by Levac et al., it was found that VR treatment is most commonly used for stroke (25.8%), brain injury (15.3%), musculoskeletal disorder (14.9%), cerebral palsy (10.5%), and neurodevelopmental disorders (6.3%) [3]. Most of the clinical applications of VR are for neurological problems. Moreover, numerous literature shows that VR is used to treat patients with stroke, cerebral palsy, Parkinson's disease, etc. [5–10]. Most researches in VR medical applications are used to the upper limb movement rehabilitation for stroke patients. The upper limb virtual reality rehabilitation systems were developed for the stroke group. The patient grasped and released the characteristic objects in the virtual environment, and finger movement control of the stroke patients after 4–6 weeks of VR intervention was improved [6,10]. Some scholars used Kinect and customized games to train the children with cerebral palsy (CP). The evidence appears to support the use of VR as a promising tool to be incorporated into the rehabilitation process of CP [7,11,12].

According to the World Heath Organization (WHO), musculoskeletal conditions affect muscles, bones, joints and associated tissues such as tendons and ligaments. To patients, musculoskeletal conditions are typically characterized by pain and limitations in mobility or functional ability.... Pain and restricted mobility are the consistent features of the range of musculoskeletal conditions. Musculoskeletal conditions are the second largest contributor to disability worldwide [13]. However, at present, there is less evidence on the therapeutic effect of VR on patients with musculoskeletal system disorder [14–18]. In addition, studies have shown that VR is beneficial in pain management, for example, in pain relief during dressing changes of burn patients [19]. VR can also reduce anxiety, distract from the fear of pain, and alleviate stress [20]. It can divert the attention of patients who are afraid of moving because of pain.

So far, there are no integrated and first-rate studies that explore which musculoskeletal disorders are suitable for VR treatment. The comparison of the effects of VR games and other treatments (e.g., traditional treatment, instrumental therapy, exercise) on patients with musculoskeletal disorder is inconclusive. Therefore, this article integrates the results of studies made in recent years into a scoping review to: (1) Compare the effectiveness of VR and other treatment interventions for patients with musculoskeletal disorder; (2) further explore whether there is any consistency in the VR treatment of patients with musculoskeletal system disorder, so as to give recommendations based on the highest level of evidence. This review only contains RCT articles with a PEDro Scale score ≥5 points.

#### **2. Materials and Methods**

#### *2.1. Determination and Selection of Articles*

The methodology of this scoping review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines because the main aim of this work is mapping all the available literature in the musculoskeletal field [21]. The use of the checklists based on PRISMA statement improve the quality and transparency of the scoping reviews [17]. Search was made in the PubMed, IEEE, and the MEDLINE library for reference literature using keywords and synonyms of "virtual reality", "pain", and "musculoskeletal". After performing a journal search, RCT (randomized controlled trial) journals that were written in English within the last 10 years (January 2008 to August 2018) were selected, and non-musculoskeletal diseases such as "stroke", "neurological", and "cognitive" were excluded using the Physiotherapy Evidence Database (PEDro) scale (http://www.pedro.org.au/). When reference materials could not be found on the PEDro website, scores were independently made by two authors who have completed the PEDro Scale training tutorial on the Physiotherapy Evidence Database.

When the scores were different, the clinical physiotherapist with more than five years of experience, and who completed the PEDro assessment training, was asked to conduct another assessment. When issues such as disagreement or ambiguity arose, they were resolved through discussions. Finally, literature with very low PEDro scores (<5/10) was excluded. The search process is shown in Figure 1. Since there are few studies on VR for musculoskeletal disorders, we do not explore the virtual reality (VR) outcomes for any specific pathology in our study, but explore the VR treatment effects, such as pain relief, joint mobility, function, range of motion (ROM), muscle strength, angular velocity and self-satisfaction for all musculoskeletal disorders.

**Figure 1.** Flow chart displaying the screening process for studies included in this systematic review.

#### *2.2. Data Extraction and Quality Assessment*

Initially, the two authors completed the abstract review independently. When it was not possible to know whether an article could be included in the scoping review from its abstract, an assessment of the full article was made. All of the articles that had been included were reviewed in full. After sorting, the following were investigated: (1) Whether VR treatment improved the musculoskeletal system as compared with other treatments; (2) whether there was any consistency in the musculoskeletal disorder of patients that received VR treatment. The selected articles were summarized and analyzed with descriptive statistics. The author, publication year, subject, intervention, outcome measures, and mean between-group differences (95% confidence interval) were extracted from the references by the two authors of this study. A consensus was reached through discussion when the authors had different opinions.

#### **3. Result**

A database search was made to exclude articles with a PEDro score of less than 5 and non-English publications. A total of 14 articles were included. These 14 articles were included in this scoping review (Figure 1).

#### *3.1. Quality of the Included Studies*

The quality of included studies was presented in Table 1. The mean PEDro score of the included articles was 6.14 (range, 5–7). All studies were randomized (100%). 8 studies carry out concealed allocation (57.14%), and all studies baseline comparability (100%). All studies were analyzed between-group comparison (100%) and 13 studies reported point estimates and variability (92.86%). All studies didn't carry out blind therapist. One study carried out blind subjects (7.14%) and 7 studies carried out blind assessors (50%). 10 studies have adequate outcome measurement (71.43%), and 5 studies have an intension-to-treat analysis (35.71%).

#### *3.2. Description of Included Studies*

Each article abstract (including author, musculoskeletal disorder, design, participants, intervention, comparison, and outcome measure) is organized in Table 2. In terms of age, a study about frozen shoulder investigated subjects older than 20 years of age [15]; a research about subacromial impingement syndrome (SAIS) studied subjects between 18–60 years old [22]; subjects of two articles discussing chronic cervical pain were older than 18 years old [17,18]; three studies that explored low back pain (LBP) had subjects between 18–50 years old [23], and those between 40–55 years old [24,25]; an investigation on pelvic floor muscle had subjects older than 50 years of age [26]; two researches discussed the treatment of acute burn wounds in adolescents aged 10–18 years [27,28]; three studies discussed the treatment for patients with TKR aged in the sixties [14,16,29]; an article discussing ankle sprains had subjects aged 18–64, belonging to the working-age group [30]. In terms of experimental intervention, most of the study regarding VR intervention lasted 15 to 30 min, 2 to 4 times per week for 2 to 6 weeks. One research conducted VR intervention for 3 weeks [16]; 3 articles discussed 4 weeks of VR intervention [15,17,24]; 2 studies described 5 weeks of VR intervention [18,26]; and another 2 articles discussed 6 weeks of VR intervention [22,30]. One study conducted VR treatment beginning the second day after TKA until 6 months [29]. There were 5 studies that compared VR intervention and no intervention at all [17,23,27,28,30]. The rest made comparisons between VR and other treatments.

#### *3.3. Virtual Reality Resources Choosing*

Virtual Reality was applied using several resources. In the 14 studies, one study used Kinect [15]; 5 studies used Wii [14,22,24,26,30]; 5 studies used VR glasses (one of the studies used headphones and joysticks) [17,18,25,27,28]; two studies used 3-D TV and 3-D shutter glasses [23,29]; and one study used enhanced reality with VR and mirror therapy [16].

#### *3.4. Heterogeneity of Included RCT*

The outcome could not be pooled into meta-analysis due to the following reasons. Clinical heterogeneity (Table 2) can be clearly observed from the participant, intervention, exercise mode, and outcome measures of the included studies. Diversity is seen in patient conditions, frequency and duration of VR intervention, whether or not the patient does home exercise, received patient health education, whether the experiment conducted was pure VR (only VR) or VR mixed with traditional physical therapy or with exercise therapy, whether the outcome measure contains follow-up, and whether different estimate measures were inconsistent at different times.

#### *3.5. E*ff*ect of Virtual Reality versus Other Interventions*

In the articles included, a total of twelve studies compared the effects of VR treatment and other intervention on orthopedic conditions (Table 3). The research on patients suffering from frozen shoulder for more than three months shows that four weeks of VR plus modalities (hot pack and ultrasound) produced a significant 8% increase in their shoulder range of motion (ROM) when compared to traditional exercise training, plus modalities [15]. Another research showed that after 6 months of short-term training and one-month of follow-up, the subacromial impingement syndrome (SAIS) patients without a rotator cuff problem on the VR group and home exercise group (scapular muscles training), were able to significantly reduce their disability and improve their quality of life. Furthermore, the VR group showed significant improvement of SAIS and scapular dyskinesis symptoms when compared with the home exercise group [22]. Another article showed that patients with chronic cervical pain who went through 5 weeks of VR and cervical kinematic training (KT) had a big difference in the global perceived change (variations in different areas of patient self-assessment, such as satisfaction, self-reported pain differences), which could last for three months when compared to those in the KT group [18]. A study also showed that after four weeks of training, the VR group of patients with chronic cervical pain displayed a significant difference in terms of pain, physical condition, fear of moving the

neck, as well as in the mean and peak velocity from those in the laser beam projected group. However, there is no significant difference in cervical ROM during follow-up between the VR treatment group and the laser beam projected group [17]. Patients with chronic low back pain in another study were able to significantly improve pain, pressure algometry, disability, and the fear of low back pain after four weeks of VR training [24]. Another research proposed that VR with the supplementary traditional physical therapy can significantly reduce pain, fear, and increase functions for patients with subacute or chronic non-specific lower back pain [25]. Although a study comparing five weeks of pelvic floor muscle training via VR and traditional gym ball training, showed no significant difference in muscle strength, but a statistically significant difference in endurance was observed [26]. One study supported the idea that VR therapy during burn wound care can reduce adolescent pain [25]. Three included studies examined the effects of VR on patients with TKR [14,29]. The results of these two articles showed that VR treatment (physical therapy plus VR) did not produce a significant difference in terms of pain, ROM, walking speed, balance, and walking test for patients with total knee replacement (TKR), when compared with conventional therapy [14,16]. The other demonstrated that VAS scales were significantly lower in the experimental group than the control group during acute phase (at 3, 5, and 7 days after TKR) (*p* < 0.05) [29]. However, it did not reach the minimal clinically important difference (MCID) [31]. In the previously described study, VR intervention (one month, three months, six months after TKR) in the chronic phase can improve the functional recovery of the patients with TKR [29]. A study on the treatment of ankle sprains suggested that there is no significant difference in all parameters between VR treatment and traditional treatment [30].

#### *3.6. E*ff*ect of Virtual Reality Versus No Intervention*

In the included articles, four articles discussed the therapeutic effects of VR and no intervention on chronic cervical pain, burn wound, low back pain, and ankle sprains (Table 4). When applied to chronic cervical pain and burn wound, a statistically significant difference was present in some parameters, as described in the following section. Bohat et al. (2017) [17] studied patients with chronic cervical pain after four weeks of training and found that the VR group had significantly different results from the control group in disability, cervical angular velocity, time to peak velocity, and head follow-up task accuracy. However, in cervical ROM, physical health, and fear of moving the neck, no significant difference was observed [17]. Another study compared the results of a 3-day VR training of low-back pain patients with the results of the non-invasive group, and found no statistically significant difference in lumbar spine flexion ROM and pain improvement [23].

During the dressing application of patients with burn wounds, patients undergoing VR treatment received significantly lower doses of Entonox (analgesic) compared with those in the standard distraction group. However, there is no significant reduction in patient pain [28]. For patients with ankle sprains, no statistically significant difference was observed between the VR treatment and the control group [30].


**Table 1.** Physiotherapy Evidence Database (PEDro) Score for Included Studies (*<sup>n</sup>* = 14).


#### *J. Clin. Med.* **2019**, *8*, 791

**Table 2.**

Description

 of Included studies.


**Table 2.** *Cont.*



TIP% (Time to peak velocity percentage); GPE (Global perceived effect); sway SD (standard deviation of the static head sway); EQ-5D(EQ-5D ™, http://www.euroqol.org); NVP (Number of velocity peaks); ODI (Oswestry low-back pain disability index); RMDQ (Roland Morris disability questionnaire); FBQ (fear avoidance beliefs questionnaire); NPRS (Numeric Pain Rating Scale); LEFS (Lower Extremity Functional Scale); ABCS (Activity-specific Balance Confidence Scale); WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index); FAAM (Foot and Ankle Ability Measure); ADL (activities of daily living); RICE (rest, ice, compression and elevation); FLACC (Faces, legs, activity, cry, consolability scale); Hospital for Special Surgery knee score (HSS); TKS (TAMPA Kinesiophobia Scale), TUG (timed-up and go test); 6MWT (6-Minute Walk Test); RCT (randomized controlled trial); LBP (low back pain); TKR (Total Knee Replacement).

#### *J. Clin. Med.* **2019**, *8*, 791





Abbreviations: VR (Virtual reality); ROM (range of motion); CMS (Constant-Murley score); VAS (Visual Analog Scale); SPADI (Shoulder Pain and Disability Index); SRT (Scapular Retraction Test); SAT (Scapular Assistance Test); LSST (Lateral Scapular Slide Test); NDI (Neck Disability Index); TSK (Tampa scale of kinesiophobia); TIP% (Time to peak velocity percentage); GPE (Global perceived effect); sway SD (standard deviation of the static head sway); EQ-5D(EQ-5D™, http://www.euroqol.org); NVP (Number of velocity peaks); ODI (Oswestry low-back pain disability index); RMDQ (Roland Morris disability questionnaire); FBQ (fear avoidance beliefs questionnaire); NPRS (Numeric Pain Rating Scale); LEFS (Lower Extremity Functional Scale); ABCS (Activity-specific Balance Confidence Scale); WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index); FAAM (Foot and Ankle Ability Measure); ADL (activities of daily living); vmean (Mean velocity); Vpeak (Peak velocity); F (Flexion), E (Extension), LR (Left rotation), RR (Right rotation); the-marked mean *p* > 0.05; NA (not available); Hospital for Special Surgery knee score (HSS); TKS (TAMPA Kinesiophobia Scale), TUG (timed-up and go test); 6 MWT (6-Minute Walk Test).


#### **Table 4.** Effect of VR versus no intervention.

Abbreviations: VR (Virtual reality); NDI (Neck Disability Index); TIP% (Time to peak velocity percentage); ROM (range of motion); EQ-5D (EQ-5D™, http://www.euroqol.org); TSK (Tampa scale of kinesiophobia); NVP (Number of velocity peaks); VAS (Visual Analog Scale); FLACC (Faces, legs, activity, cry, consolability scale); FAAM (Foot and Ankle Ability Measure); ADL (activities of daily living); the-marked mean *p* > 0.05; NA (not available).

#### *3.7. E*ff*ect of Virtual Reality on Acute and Chronic Musculoskeletal Pain*

Although associated pain is not itself part of the root disorder, managing the pain of musculoskeletal disorders is a major part of general practice. Of the 14 musculoskeletal studies included, six were for acute pain, including the dressing of the burn wound [27,28], three were for TKR patients [14,16,29], one for patients with ankle sprain [30], and the rest of the eight articles were for chronic musculoskeletal pain patients, including patients with frozen shoulder, SAIS, Neck pain, LBP, and pelvic floor muscle training [15,17,18,22,24–26]. VR treatment seems to reduce the pain of burn patients, or it could reduce the use of analgesics [27,28]. No significant difference in all parameters was observed when TKR and ankle sprain patients received VR treatment as compared to conventional treatment [14,16,29,30]. And there is no MCID for VAS pain in its acute phase [29]. In the included articles, a significant difference in the main outcome was observed for all patients with chronic pain aside from the research conducted by Tomas et al. [23].

#### **4. Discussion**

Most virtual reality treatment research applications still focus on the VR treatment of central nervous system problems, such as stroke and cerebral palsy, while only a little research explores the therapeutic effect of VR treatment on patients with musculoskeletal disorders. At present, there is no research on the integration of virtual reality for patients with various musculoskeletal disorders and an analysis of its effects. Therefore, this scoping review searched and integrated multiple musculoskeletal disorders in VR applications. Analysis showed which patients with musculoskeletal disorders had better results after VR treatment.

In general, chronic pain usually lasts for more than 12 weeks, while acute pain usually lasts for 4 to 6 weeks [32]. Therefore, patients in the articles included in this study are those who experience chronic pain due to frozen shoulder (symptoms lasting more than 3 months), SAIS (symptoms lasting at least 2 months), neck pain (symptoms appear for more than 3 months), and LBP (symptoms persist for 2 or 3 months) [15,17,18,22–25]. The study on burn wound care included patients with acute pain due to burns. Fung et al. (2012) included TKR patients in their study under the condition of being able to apply a full load on the lower limbs after 2 weeks of physical therapy post-surgery. Another research made by Koo et al. studied TKR patients after 2 weeks of physical therapy post-surgery followed by VR treatment. In the preceding two TKR studies, patients belonged to the sub-acute and acute phase, and the pain that they felt was an acute pain [14,16]. As for another study, VR intervention was applied from one days to 6 months after TKR (longitudinal study). In the early postoperative period (3–7 days), VR intervention did not achieve any clinically better analgesic effect than traditional treatment [29]. The study on ankle sprains mentioned that patients with non-repetitive sprains can undergo emergency treatment for 4 weeks without pain followed by VR treatment; therefore, this does not belong to the category of chronic pain. From this systematic review, it was found that subjects that experienced more effective VR intervention tend to be patients with chronic orthopedic pain, or those with acute pain due to burn wounds. Patients with TKR and ankle sprains are not chronic pain patients, and results show that VR treatment is not more effective than other treatments.

Generally, patients suffering from chronic pain have lower levels of fitness than healthy people. This is because pain can affect the motor control strategies of people. Individuals tend to move in the least painful way; however, the least painful way is usually to refrain from moving. This causes a decrease in muscle size and strength; it repeatedly increases pain and stress, eventually producing to a vicious circle [33]. In the included research articles, the motions designed for patients with chronic orthopedic disorders are suitable for the joint movements of patients of this type. For example, in the virtual reality games for patients with frozen shoulder, the actions designed include shoulder elevation, shoulder IR/ER, and a shoulder abduction action, and suitable WII games are selected for shoulder impingement patients (such as the tennis game which involves shoulder capsule stretch, pectoral muscle stretch and shoulder elevation). For patients with other chronic orthopedic disorders, through somatosensory interactive games with larger movements, patients could try actions which they could not achieve. Furthermore, people usually focus on pain or impending pain; therefore, the use of VR is effective in distracting the attention of patients from pain. The distraction produced by VR reduces pain, induces movement, and promotes exercise. It also motivates patients to move. Most users describe that their experience of VR was pleasant, and it can relieve pain as well as reduce anxiety [20,34–36]. Nevertheless, VR treatment done under inadequate supervision may result in less than expected results [17,30]. VR intervention under supervision can increase the motivation or induce patients to receive movement training and boost their concentration. This systematic review found that VR treatment for patients with chronic pain, such as 4 weeks of VR plus modalities (hot pack and ultrasound) on patients with frozen shoulders produced a significant 8% increase in shoulder ROM when compared to traditional exercise training plus modalities [15]. Subacromial impingement syndrome (SAIS) patients underwent 6 weeks of VR training for 45 min/day, twice a week, and showed a significant improvement of SAIS and scapular dyskinesis symptoms than those in the home exercise group.

In addition, this result lasted for one month [22]. Another article that studied chronic cervical pain patients after 5 weeks of VR plus cervical kinematic training (KT) recounted a significant difference in global perceived change (patient self-reported changes in different areas, such as satisfaction, self-reported pain differences) when compared to the only KT group. The experienced outcome lasted for 3 months [18]. One research on low back pain showed that 4 weeks of VR training can alleviate pain, deep tissue pressure algometry, disability, and fear of low back pain. For the TKR patients, after one month to six months of VR intervention, the knee function is better than for those who received the traditional treatment [29]. One of the articles included in this study showed no significant difference in pain and lumbar spine flexion ROM after comparing 3 days of VR treatment for patients with lower back pain, and patients without VR treatment [23]. This scoping review shows that chronic patients may receive at least four weeks of VR treatment in order to experience a significant therapeutic effect. In addition, VR training seems to have a short-term effect for patients with chronic pain in the musculoskeletal system [17,18,22,25]. This is consistent with past research [36–38].

The results of this study show that VR treatment with a hand joystick significantly reduces the pain score of patients when removing dressings from patients with acute burns, or it will reduce the use of analgesics [27,28]. This is consistent with previous research [39–42]. Hoffman, et al. [40] showed that the use of VR for patients under severe pain can effectively reduce pain by 41%. It is speculated that VR can also be used to distract patients from severe acute pain during dressing change. Therefore, VR can be used to divert attention, thus reducing the use of analgesics.

In summary, VR treatment can reduce pain in acute burn wound care and chronic musculoskeletal disorders. It can effectively distract patients with chronic pain, and allow them to ignore the cumbersome rehabilitation training, consequently improving treatment motivation. In addition, VR treatment may be helpful in the psychological level and the establishment of confidence. For example, patients with burns or chronic disability may have a tendency to fall into depression because of the long course of the disorder. The use of VR can release psychological stress and reduce their fear of pain [19].

Virtual reality is also helpful in the control and perception of muscle movements. This systematic review includes the hard to control PFM, as well as waist and neck movements. The PFM training research included in this article [26] recommended the simple contraction of the lower abdominal muscles in the VR group. Previous studies pointed out that the lower abdominal muscles have a synergistic effect with PFM. Therefore, some scholars have suggested that if the patient does not know how to apply force during PFM contraction, training on abdominal transverse muscle contraction can be done to attain the same purpose [43]. Patients in the VR group interacted with the game screen and performed pelvic movements such as pelvic forward, backward, lateral tilt, and go around motions according to the easy-to-understand motion instructions provided by the Wii game screen. This made it possible for patients to understand how to control their pelvic motion, and at the same time, increased the control and perception of the PFM. The LBP patients included in this article used games that combined Wii and yoga for their training [24]. LBP patients usually have weak deep core muscles [44]. Yoga promotes the strengthening and relaxation of the waist muscles and ligaments. Through yoga, the body can be continuously aligned correctly. At the same time, the patients can clearly see their posture on the screen. The Wii board senses the weight and center of gravity of the body and trains LBP patients according to the steps in the game screen. For rehabilitation that needs repeated feedback and learning of exercises, VR can provide enthusiasm. Patients with neck pain can also use VR glasses to perform target tracking according to the instructions given by the game, and flex, stretch, and rotate the neck. Patients can adjust neck motion through the instant feedback given by the VR glasses [17,18]. The preceding discussions show that VR can be used to increase the control and training of PFM as well as the consciousness of waist and neck motion. Moreover, posture can be adjusted through VR instant feedback.

Depending on the different facilities which possess different visual perception methods, Virtual Reality can be divided into four types: (a) Desktop VR: Mouse, trackball, and joystick are the main computer transmission devices and a common PC screen was used as its output; (b) Simulator VR: In a specific environment, machines and equipment, added to an image screen, provided the Users simulation results; (c) Projection VR: With a large projection screen, several projectors, and stereo sound output devices, simulation scenes were projected around the user; (d) Immersion VR: Specific Input and output devices, such as helmet display, etc., were used in this type of simulation [1]. The result of the five included articles in the current study seemed to show some effectiveness of the immersion VR. VR glasses or VR TV output, 3D shuttle glasses or helmet display were used to allow the user to become fully immersed in the system, and computers were used to provide image or sound feedbacks (five out of five); Three of the five articles showed Wii (belong to the VR type (a) described as above ) had achieved some effectiveness. Some patients may have nausea and dizziness due to the problems of the VR device, such as mismatched motion, motion parallax, viewing angle, limited reproduction of a real environment, and the imperfect simulation of human–world interactions. This condition occurring may affect its treatment effectiveness [45]. Facing the current economic development and the increase of the need of clinical care, we believe that it is necessary to explore the clinical effectiveness and applicability of the VR system. This highlights the importance of the ongoing discussions of the MCID on pain relief or on function increase in this article. The challenges in using the truly immersive

VR system include nausea or dizziness caused by immersing in the virtual world and investment costs (facilities, cost, personnel training) [35,45]. All of these also affect whether VR treatment is appropriate in clinical environment implementation.

#### *Limitations*

Because this system review includes first-rate RCT studies, fewer articles that compare the effects of VR therapy with other interventions on patients with musculoskeletal disorders are available. In some articles, the lack of raw numeric data makes it impossible to calculate the mean difference between the experimental and control groups. During the article retrieval process, language was also restricted; therefore, some language bias might exist. In addition, very few articles contain the minimal clinically important difference (MCID) on various parameters; hence, further discussion was not made.

#### **5. Conclusions**

VR treatment appears to have a significant effect upon pain relief, increased joint mobility, or the motor functions of patients with chronic painful musculoskeletal disorders. VR seems quite effective in relieving the pain of patients with acute burns as well. However, there is insufficient evidence in the current literature; hence, more research is needed to explore the therapeutic effects of VR treatment on musculoskeletal disorders. In the future, VR games maybe used for more patients with chronic musculoskeletal injuries. As to whether different types of VR would affect the effectiveness for rehabilitation results in musculoskeletal disorder patients, this should also be further investigated.

**Acknowledgments:** This study was partially funded by E-DA Hospital (EDAHT107029) and the Allied Advanced Intelligent Biomedical Research Center (A2IBRC) under the Higher Education Sprout Project of Ministry of Education.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Review* **Patient Experience in Home Respiratory Therapies: Where We Are and Where to Go**

#### **Cátia Caneiras 1,2,**†**, \*, Cristina Jácome 3,4,**†**, Sagrario Mayoralas-Alises 5,6, José Ramon Calvo 6, João Almeida Fonseca 3,7,8, Joan Escarrabill 9,10,11 and João Carlos Winck <sup>12</sup>**


Received: 5 March 2019; Accepted: 23 April 2019; Published: 24 April 2019

**Abstract:** The increasing number of patients receiving home respiratory therapy (HRT) is imposing a major impact on routine clinical care and healthcare system sustainability. The current challenge is to continue to guarantee access to HRT while maintaining the quality of care. The patient experience is a cornerstone of high-quality healthcare and an emergent area of clinical research. This review approaches the assessment of the patient experience in the context of HRT while highlighting the European contribution to this body of knowledge. This review demonstrates that research in this area is still limited, with no example of a prescription model that incorporates the patient experience as an outcome and no specific patient-reported experience measures (PREMs) available. This work also shows that Europe is leading the research on HRT provision. The development of a specific PREM and the integration of PREMs into the assessment of prescription models should be clinical research priorities in the next several years.

**Keywords:** Long-term oxygen therapy; home mechanical ventilation; patient-reported experience measures; quality of care; healthcare; sustainability

#### **1. Introduction**

Long-term oxygen therapy (LTOT) and/or home mechanical ventilation (HMV) are well-established therapies for patients with chronic respiratory failure, such as those with chronic obstructive pulmonary disease (COPD), neuromuscular diseases, and obstructive sleep apnea (OSA), among others. These therapies represent key services in the home respiratory therapy (HRT) provided to these patients. Increasing numbers of patients receiving HRT are reported not only in Europe but also worldwide [1–5]. Thus, HRT is imposing a major impact on clinical care and healthcare systems. Over the next several years, the main challenge will be to ensure a sustainable healthcare system to continue to guarantee access to HRT while maintaining the quality of care.

According to the World Health Organization, quality of care is defined as "the extent to which health care services provided to individuals and patient populations improve desired health outcomes. In order to achieve this, health care must be safe, effective, timely, efficient, equitable and people-centered" [6]. A necessary step in the process of maintaining and improving quality is to monitor and evaluate the quality of healthcare in routine clinical practice. Based on the reactive, disease-focused, and biomedical model, the indicators of quality have been mainly restricted to traditional clinical metrics. A number of studies conducted over the last few decades have addressed the beneficial effects of HRT on morbidity, mortality, and adverse outcomes, as well as the variations in HRT provision among countries [5,7,8]. However, these metrics alone do not provide a complete picture of HRT quality.

The patient's experience of treatment is a cornerstone of high-quality healthcare [9]. Only by analyzing the relational and functional aspects of the patient experience is it possible to assess the extent to which patients are receiving care that is in line with their preferences, needs, and values. The integration of the patient experience with healthcare delivery and quality evaluation are key steps in moving toward patient-centered and personalized care [10]. As Doyle et al. suggested, the patient's experience is the third pillar of quality, along with clinical safety and effectiveness [11]. However, it is only in recent years that patients' perceptions of healthcare provision have started to receive attention.

This review approaches the assessment of the patient experience in the clinical context of HRT while highlighting the European contribution to this emerging body of knowledge.

#### **2. Patient Experience in the Context of HRT**

The patient experience in the context of HRT is reviewed with a focus on two main areas: (1) HRT prescription models and the inclusion of the patient experience as an outcome of these models and (2) methods used to assess the patient experience. To address these two aims, a narrative review was conducted. The search, although not systematic in nature, included searches in electronic databases (PubMed, Medline, ISI Web of Knowledge and Google Scholar), as well as hand searches (expert consultation and a review of the reference lists in the included papers). The databases were searched between July and December 2018 using topic-related terms, such as oxygen therapy, home mechanical ventilation, noninvasive mechanical ventilation, home respiratory therapy, home treatment, chronic respiratory insufficiency, chronic respiratory failure, epidemiology, prescription, quality control, outcomes, patient experience, patient perspective, carers, caregivers, patient-reported experience measure, questionnaires, interviews, and focus groups. There was no time restriction in the literature search, although it was limited to English, Portuguese, or Spanish.

#### *2.1. Prescription Models of HRT*

There are a number of studies that have assessed the prescription of HRT. Table 1 summarizes 15 relevant studies on this topic. The majority of the studies (*n* = 9) were conducted from 2009 onward and primarily assessed the prescription of HMV (*n* = 10) [4,5,12–19], followed by LTOT (*n* = 6) [19–24]. The estimated prevalence of HMV (from 2.5 to 23/100,000 population) and of LTOT (from 31.6 to 102/100,000 population) were variable among distinct regions or countries. The estimated prevalence of HMV in Europe was 6.6 per 100,000 people, and Portugal was one of the countries with the highest prevalence [5].

Three studies reported the assessment of HRT prescription at a regional level (Catalan, Spain; Hong Kong, China; Tasmania, Australia), eight at a national level (Sweden, Canada, Poland, Denmark, England, Australia, France, Spain), and four at an international level (two countries, seven countries, 13 European countries, 16 European countries).













36 (30%) had a median use < 15 hours/day.



syndrome (43, 17.2%); and Restrictive thoracic

disorders (85, 34.1%).









by a nurse and/or a doctor and equipment

maintenance by a technician.

#### *J. Clin. Med.* **2019**, *8*, 555

Most studies included both children and adult patients in their analysis. Only one of the studies specifically focused on a pediatric population [18]. Questionnaires, having been used in 10 studies, were the preferred method of data collection. In five studies, existing databases from HRT registries or health services were used. Irrespective of the data collection method used, data on users (age, sex, and diagnosis), type and duration of respiratory therapy, and equipment and interfaces were the most commonly recorded. None of the 15 studies reported the patient's experience with HRT.

#### *2.2. Assessment of Patient Experience*

Assessing the patient experience has become a common approach to describing healthcare from the patient's point of view, evaluating the process of care, and measuring the outcome of care [25–27]. Both quantitative and qualitative methods are being used to assess patients' perception. Self-reported questionnaires, individual interviews, and focus groups are among the most frequently used methods of collecting data.

#### 2.2.1. Patient-Reported Experience Measures

The development of self-reported questionnaires, namely, patient-reported experience measures (PREMs) and patient-reported outcome measures (PROMs), has exponentially increased in the last several years. These two types of questionnaires collect information about the patient's perspective but with distinct purposes. A PREM evaluates patients' perception of their personal experience of the healthcare received, while a PROM assesses the perception of their health status and health-related quality of life [10,28]. A combination of PROMs and PREMs is essential to fully understand the performance of healthcare systems. Moreover, both measures are useful to provide a patient-centered perspective of healthcare, but PREMs are more adequate to assess experience with healthcare.

Distinctinstruments to assess the patient's experience with healthcare are available. Table 2 summarizes 14 instruments designed to assess the patient's experience with the provision of care in different clinical settings [29–34], hospital [35–38], primary care [39,40], intermediate care [41], and community [33,41]. The majority of such instruments are generic and designed to be used for a diverse range of health conditions. However, two of the described questionnaires were specifically developed for patients with chronic diseases [29,34], and one was intended particularly for patients with COPD [30]. The majority of PREMs were developed to target adult patients and tested in patients who were at least 15 years old. Only two developed instruments were tested with the carers of children [31,39]. English is the most common language used, with some instruments also in Norwegian [31,38,39], Italian [35,41], and Spanish [29]. Most instruments already had some of their psychometric properties explored, namely, their reliability and validity.

None of the instruments above were specifically designed to assess the patient's experience with HRT. However, a recent European Respiratory Society (ERS)/European Lung Foundation (ELF) survey was conducted across 11 European countries and assessed the attitudes and preferences of 687 patients on HMV and those of 100 carers [42]. A questionnaire was specifically developed for this study in eight languages (English, German, Dutch, Spanish, Italian, Portuguese, Greek, and French) and explored four areas: (1) patients' demographic and clinical characteristics; (2) issues influencing compliance, such as interface comfort, abilities to travel, sleep, and socialize with a ventilator, type and technical functioning of the ventilator (e.g., alarms, ability to operate and change settings, on/off switches, and electricity consumption); (3) support, training, and education; and (4) requests for improved devices and support.

Today, it is possible to evaluate a patient's perception of the HRT received using one of the described PREMs. Nevertheless, in the near future, the aim should be to develop a specific PREM to assess patients' personal experience with HRT.


**2.**Instruments designed to assess patient's experience with the provision

 of care.

**Table** 



**Table 2.**

*Cont*.


**Table 2.***Cont*.



**Table 2.** *Cont*.

#### 2.2.2. Individual Interviews and Focus Groups

Qualitative studies that explore the experience of patients receiving HRT are still limited in the literature. Nevertheless, the literature review revealed some studies that explored the experience of patients living with COPD, pulmonary fibrosis, and OSA. These studies specifically focused on patients' needs and the adaptation process to respiratory therapies. Two studies explored the patient's experience with LTOT [45,46], and the others assessed the patient's experience with non-invasive ventilation [47–51]. These studies were conducted in the United States of America [45,47], New Zealand [48,49], the United Kingdom [50], Sweden [51], and Spain [46] and included both adult patients and carers. Two reviews were also found on the needs of patients with COPD and were also used in the present analysis [52,53].

From the analysis of these studies, it was possible to clearly identify education, training, support, and carer involvement as important key-points in facilitating a patient's treatment experience and subsequent adherence. Below, each one of these four key-points is described in detail.

Education: on the basis of the perspectives of patients, it is apparent that education is crucial for defining clear expectations about the treatment and motivating patient adherence. The main education topics raised by patients receiving respiratory therapies are related to disease self-management (e.g., COPD, OSA); physical effects and potential clinical benefits of the respiratory therapy; risks of not using the respiratory therapy; guidance on the use and function of equipment (e.g., continuous positive airway pressure (CPAP) devices, oxygen concentrators, how to use pulse oximeters and adjust flow with exertion); side effects and guidance on its management (skin protection, dry mouth, nasal congestion, irritated eyes); traveling with equipment; follow-up appointments; and assistance with financial elements (e.g., how to claim electricity costs) [45,46,49,50].

Training: formal training on appropriate equipment use has been suggested to be an important strategy for improving adherence [46–51]. Healthcare professionals need to introduce the device, explore possible practical problems, and give advice/help to solve these problems. In their initial experiences with respiratory therapy, patients should have a hands-on demonstration for setting up the device, trialing different masks/pressures, making mask adjustments, conquering different side-effects, and finding the best position for the tubing or machine (also considering the loudness of the device). Regular follow up visits or phone calls are important to assess practical problems being experienced (e.g., pressure from the mask, mask leakage, disturbing noise, and difficulties changing sleeping positions) and to discuss effective strategies to address them.

Support: establishing a trustworthy relationship with healthcare professionals after the initiation of respiratory therapy is perceived as helpful by patients, and these relationships positively influence their adherence [46]. Healthcare professionals need to foster a non-judgmental environment in which patients have opportunities to ask questions, share concerns and feelings, feel listened to, and feel understood. This is particularly important following the initiation of therapy [47], as questions or concerns are more likely to arise during the first days or weeks of treatment [49,52]. These opportunities can arise during regular follow-up visits, scheduled follow-up phone calls, and through access to a 24-h hotline [47].

Carer involvement: carers provide substantial care (emotional, physical) to the individual on a daily basis and, most of the time, live in the same house as the patient. On the basis of their important role in patients' lives, carer involvement has been found to be essential to patients receiving HRT [45–48,50–53]. Patients recognize that carers play a major role in their treatment by helping them manage the disease and adapt to the equipment (e.g., verbal reminders, encouragement, setting up the machine, making mask adjustments, reassurance of therapy benefits). Carers themselves recognize their need for information regarding aspects of the disease and benefits of the HRT [47]. Carer involvement is thus perceived by all stakeholders as an essential component of education and training from the beginning of treatment [45,47,48,50–53], and it is generally associated with positive results, namely, the patients' adoption and adherence to HRT [47,53].

#### **3. Discussion**

This comprehensive review is a first critical step toward the assessment of the patient experience in the clinical context of HRT. It demonstrates that research in this area is still limited, with no example of an HRT prescription model that incorporates the patient experience as an outcome and with no specific PREM available. This review also shows that European countries have been involved in HRT provision research from an early stage.

Most of the research on the assessment of HRT prescription models has been conducted within the last decade and mainly in European countries, highlighting the emergent interest and Europe's leading position in this area of health research. In addition, HMV has attracted more attention from the scientific community in comparison with LTOT. Questionnaires were found to be the preferred method for data collection, however, existing databases from HRT registries or health services have also been used. Databases in comparison with questionnaires have the advantage of generating more representative data and may be a method of choice in future studies. The patient experience has not been examined in the assessment of the prescription models presented. While this reality was expected from the oldest studies, it was quite a surprising result for those from the last decade. These results show that, until now, the assessment of patients' perceptions has not been seen as a priority in the assessment of prescription models. Unfortunately, this is also a reality in other health contexts and settings [10]. The Organisation for Economic Co-operation and Development (OECD) and Europe in "Health at a Glance: Europe 2018" reported critical gaps in the data on patient-reported experience, and they recommended collecting data on the patient experience from any doctor in ambulatory care settings [10]. Thus, future studies on the provision of HRT should address this important gap in the literature.

To address this gap, we need to be aware of the current methods being used to assess the patient experience. Different instruments used at distinct levels of healthcare are available and described in this review. These instruments were developed to be completed by adult patients and, in some cases, by carers of children. In our opinion, although the carers' perspective is, of course, incredibly valuable, it should do not replace the children's experience. The development of PREMs for pediatric populations is crucial to the collection of information on the experience and outcome of children's care. Additionally, as previously mentioned, none of the instruments have been specifically designed to assess the patient's experience with HRT. The development of a specific PREM for this health context should be a research priority in the upcoming years. The most commonly assessed domains in the described instruments, including the ERS/ELF survey, together with the key facilitators of the patient's treatment experience, can be used as important sources of data to inform the development of a comprehensive instrument. Access to information and support, implementation of effective and clear communication, active participation in shared decision making, enhanced accessibility and navigability across the healthcare system for patients and families, particularly across transitional care, and management of polypharmacy are known to influence the patient experience in other healthcare settings and could be topics of interest to be included in future PREMs for patients on HRT [54]. Future studies should explore which of these raised topics are indeed meaningful for patients and carers.

On the basis of qualitative studies, it was found that education, training, support, and carer involvement were important key-points in facilitating the patient's treatment experience and adherence. This knowledge comes mainly from the perspective of adult patients with COPD, pulmonary fibrosis, and OSA receiving CPAP and from their carers. These studies were conducted in five countries (three from Europe) [45–53]. Thus, this evidence may not completely apply to the experience of younger patients (including children) and that of their carers or to patients with other diseases and other treatment modalities (e.g., Bilevel Positive Pressure Airway, LTOT) and from other countries/continents. Considering these identified gaps, the experience of other patients receiving HRT could be explored in future studies. The identified key-points may inform the development process of semi-structured guides of focus groups or individual interviews to be used in these exploratory studies.

#### **4. Conclusions**

To the authors' best knowledge, this is the first published work to review the emerging topic of the patient experience in the clinical context of HRT and give important insights into the status of this clinical research area while also pointing out possible directions in which to move to realize patient-centered care. The assessment of the patient experience is in its early stages, and further research is needed to integrate these measures with routine healthcare delivery and the core set of healthcare quality indicators, as well as and to drive quality improvements in HRT.

**Author Contributions:** Conceptualization, C.C., C.J., J.A.F., J.E., and J.C.W.; writing—original draft preparation, C.C. and C.J.; writing-review and editing, S.M.A., J.R.C., J.A.F., J.E., and J.C.W.; project administration, C.C., S.M.A., J.R.C., and J.C.W.

**Funding:** C.J. has a post-doctoral grant (SFRH/BPD/115169/2016) funded by Fundação para a Ciência e a Tecnologia (FCT), co-financed by the European Social Fund (POCH) and Portuguese national funds from MCTES (Ministério da Ciência, Tecnologia e Ensino Superior).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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