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Introduction

Nephrotic syndrome (NS) is a chronic renal disorder characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and generalized edema. Beyond its primary manifestations, NS poses a substantial risk for complications such as infections, thromboembolic events, acute kidney injury, and long-term renal impairment.^1–3 These complications can significantly increase morbidity, prolong hospitalization, and elevate healthcare costs. Early recognition and proactive management are critical to improving patient prognosis, reducing hospital readmissions, and preventing irreversible organ damage.^4,5

In clinical settings, nurses are often the first healthcare providers to detect early warning signs of NS-related complications. Their roles encompass not only routine care and medication administration but also active patient education, risk screening, and lifestyle counseling. Through continuous monitoring and close patient contact, nurses are well positioned to intervene promptly and implement complication-preventive strategies.^6,7 However, their ability to do so effectively is largely influenced by their level of knowledge, clinical attitude, and behavioral practice. Despite the rising burden of NS in China and other aging populations, there remains a lack of empirical data on how well-prepared nurses are to manage the potential complications of this condition. Existing literature has primarily focused on general nephrology knowledge or patient-level education, while the specific contribution and preparedness of nursing personnel in complication prevention have been underexplored. This study aims to fill this gap by assessing the KAP levels of nurses in preventing NS complications and identifying the factors influencing their practices.^8–10 Moreover, discrepancies in clinical training, lack of targeted protocols, and variable exposure to nephrology-specific content during education further contribute to practice inconsistencies. A recent systematic review highlights differences in perspectives between nurses and clinicians regarding NS complications.¹¹ This comparison underlines the need for further exploration of the role nurses play in complication prevention, which has been insufficiently addressed in current research.

Understanding nurses’ knowledge, attitudes, and practices (KAP) regarding complication prevention in NS is crucial for identifying systemic gaps and designing effective interventions. Studies in similar domains have shown that higher levels of professional knowledge and proactive attitudes are associated with improved clinical behaviors and better patient outcomes.^12–14 However, no comprehensive KAP assessment has yet been conducted among Chinese nurses in the context of nephrotic syndrome.

This study seeks to address this gap by systematically evaluating the KAP levels of nurses involved in NS patient care across Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Shanghai Baoshan Medical Emergency Center. By identifying key influencing factors and barriers, we aim to provide evidence to support the development of structured education programs, nursing protocols, and practice guidelines to improve the quality of nephrotic syndrome management and reduce preventable complications.

Methods

Study Design and Participants

This descriptive cross-sectional study was conducted between January and December 2023 in the nephrology and internal medicine departments of Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Shanghai Baoshan Medical Emergency Center in China. A total of 246 registered nurses working in nephrology, general medicine, or related inpatient units were invited to participate. Nurses were eligible if they: 1) had direct clinical responsibilities involving patients diagnosed with nephrotic syndrome; 2) were able and willing to complete the questionnaire independently; and 3) had no barriers to communication. Exclusion criteria included: 1) incomplete survey responses exceeding 5% of items; 2) known psychiatric or neurological disorders that could impair judgment; and 3) inability to complete the follow-up validation step for test-retest reliability.

The study employed a purposive sampling method, where 246 registered nurses working in nephrology, general medicine, and related inpatient units at Ruijin Hospital and Shanghai Baoshan Medical Emergency Center were invited to participate. This method ensured that the sample was representative of nurses who had direct clinical responsibilities involving nephrotic syndrome patients. Participants were selected based on their involvement in the care of nephrotic syndrome patients, ensuring that their experience and practice were relevant to the study’s focus. This purposive approach allows for a focused evaluation of nurses who are specifically engaged in the prevention and management of complications in nephrotic syndrome. Surveys with more than 5% of missing responses were excluded to ensure the integrity of the data used for analysis. This threshold was selected based on standard practices in survey research, where 5% missing data is generally considered an acceptable limit that does not introduce significant bias into the results. Only complete responses were considered valid for statistical analysis to maintain the reliability of the study findings.

The study was conducted in full compliance with ethical guidelines, and in accordance with the Declaration of Helsinki. All participants provided written informed consent before participation. The study protocol was reviewed and approved by the institutional ethics committees of Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Shanghai Baoshan Medical Emergency Center. Ethical procedures, including maintaining participant confidentiality and anonymity, were strictly followed throughout the study. Despite the large sample size of 246 participants, ethical standards were rigorously upheld, and no concerns regarding the violation of ethical procedures were identified.

Data Collection Procedures

Data were collected using a structured, self-administered questionnaire specifically designed to evaluate knowledge, attitude, and practice (KAP) regarding the prevention of complications in nephrotic syndrome. The questionnaire was adapted from previously validated instruments used in nephrology nursing and chronic disease prevention research, with modifications made for relevance to nephrotic syndrome care. The final tool consisted of 31 items across three domains: 10 knowledge items, 8 attitude items, and 13 practice items. Each knowledge item was scored as either correct (1) or incorrect/unclear (0), producing a total possible score ranging from 0 to 10. Knowledge levels were categorized into low (0–3), moderate (4–6), and high (7–10). Attitude items were assessed on a 5-point Likert scale from 0 (strongly disagree) to 4 (strongly agree), resulting in a score range of 0 to 32. Scores less than 8 indicated a negative attitude, 8 to 16 were considered moderate, and scores above 16 were deemed positive. Practice items were rated from 0 (never) to 4 (always), with a total possible score from 0 to 52, categorized as poor (0–13), general (14–26), good (27–38), and excellent (39–52).

Translation and Validation

The questionnaire was initially developed in English and translated into Chinese following WHO guidelines for cross-cultural adaptation. Two independent bilingual nephrology professionals translated the items into Mandarin, and a separate linguist conducted back-translation into English. Discrepancies between the versions were reconciled through group discussion and expert consensus. The final Chinese version was reviewed by three senior nurse educators to ensure linguistic clarity and clinical applicability for the target population.

Pretest Evaluation and Reliability Assessment

A pilot test was conducted with 50 nurses to evaluate the clarity, relevance, and difficulty of each item. Items that received more than 20% negative feedback in terms of clarity or relevance were revised before the formal survey distribution. For reliability testing, a subgroup of 30 participants completed the questionnaire a second time after a two-week interval. Test-retest reliability was evaluated using Pearson’s correlation coefficient. Internal consistency across the knowledge, attitude, and practice domains was assessed using Cronbach’s alpha. The difficulty index for knowledge items was calculated using the formula: Difficulty Index (%) = (Number of correct responses / Total responses) × 100. Items with difficulty values outside the 30–70% range were flagged for review and refinement.

Sample Size Calculation

According to psychometric standards, a sample size of 5–10 participants per questionnaire item is recommended for validation and factor analysis. With 31 items, the minimum required sample size was between 155 and 310. A final sample of 246 participants exceeded this threshold, ensuring adequate statistical power and representativeness for subsequent analyses.

Statistical Analysis

Data analysis was performed using SPSS version 26.0. Descriptive statistics (means, standard deviations, frequencies, and percentages) were used to summarize demographic data and KAP scores. The Shapiro–Wilk test was employed to assess normality. Between-group comparisons were conducted using independent-sample t-tests and one-way ANOVA. Pearson correlation coefficients were calculated to assess relationships between knowledge, attitude, and practice scores. Multivariate logistic regression was used to identify predictors of good practice, with results expressed as odds ratios (OR) and 95% confidence intervals (CI). Model fit was assessed with the Hosmer-Lemeshow goodness-of-fit test, and a p-value < 0.05 was considered statistically significant throughout the analyses.

Results

Participant Characteristics

A total of 246 nurses from Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Shanghai Baoshan Medical Emergency Center completed the survey. Among them, 91.9% were female and 8.1% male. The average age of participants was 35.25 ± 7.55 years. Regarding residence, 39.8% were from rural regions, 48.6% from urban areas, and 11.4% from suburban settings. The education level varied: 14.2% had primary school or below, 22.0% middle school, 22.0% high school or technical training, 35.8% junior college or bachelor’s degree, and 6.1% had a master’s degree or above. Over half (64.2%) had less than 5 years of experience. In terms of professional status, 50.8% were employed, 40.7% self-employed, and 8.5% classified as other. Monthly income levels were nearly evenly split between those earning <700 USD (50.8%) and ≥700 USD (49.2%). The majority were married (64.2%), with 30.9% unmarried and 4.9% divorced or widowed. Most respondents (88.6%) held a nurse title, while 11.4% were associate or full professors. Regarding health background, 14.2% had a history of chronic illness, including hypertension, diabetes, or cardiovascular disease. Additionally, 28.5% reported having sleep problems. Concerning work patterns, 45.5% worked more than 40 hours per week, and 64.2% regularly worked night shifts. Only 26.8% held clinical teaching roles, and 41.5% had experienced promotion. Self-rated clinical competence was high in 37.0% of participants, moderate in 50.8%, and low in 12.2%. Comprehensive demographic and KAP score distributions are summarized in Table 1. The average knowledge score was 4.53 ± 2.88 (out of 10). Based on score classification, 34.7% of nurses were in the low knowledge group (0–3), 38.9% had moderate knowledge (4–6), and only 26.4% achieved high scores (≥7). Nurses with postgraduate education and clinical teaching roles tended to score higher. Attitude scores averaged 17.84 ± 4.64 (range 0–32). Most participants (71.5%) exhibited a positive attitude toward complication prevention, 22.9% demonstrated a moderate attitude, and 5.6% expressed negative attitudes. Positive attitudes were more common among nurses with higher education, better self-rated competence, and promotion experience. Practice scores averaged 31.25 ± 11.10 (range 0–52). Overall, 21.7% of respondents demonstrated excellent practices (score ≥39), 30.8% were in the good range (27–38), 29.1% fell into the general category (14–26), and 18.4% showed poor practice (<14). Nurses who had been promoted, had teaching duties, or rated themselves as highly competent tended to practice more effectively. Distribution across KAP dimensions is presented in Table 1.

Item-Level Performance Analysis

Among the ten knowledge items, the highest correct response rate (62.60%) was seen for infection prevention in nephrotic syndrome patients. The lowest accuracy was found in the question concerning routine anticoagulation in hypoalbuminemic patients (23.58%), indicating considerable confusion about thromboembolism prophylaxis. Multiple items, particularly K4, K7, and K10, fell below the 50% accuracy threshold, reflecting persistent knowledge gaps in complication monitoring, anticoagulation, and alternative therapies. Full item-level performance is detailed in Table 2.

Table 2 Knowledge Dimension in KAP Distribution of Responses Among Participants

Attitude Item Distribution

Nurses generally acknowledged the importance of early detection and multidisciplinary intervention in NS complications. Over 80% either agreed or strongly agreed that nurses play a key role in complication prevention. However, when asked whether nurses should lead complication management teams, responses were more divided, with nearly 20% disagreeing or expressing uncertainty. Notably, 75.2% agreed that time constraints limited their ability to apply preventive strategies, highlighting an operational barrier. Detailed response patterns are shown in Table 3.

Table 3 Attitude Dimension in KAP Distribution of Responses Among Participants

Practice Behavior Frequency

Clinical practices varied. The most consistently performed behaviors were regular monitoring of edema, urine output, and infection signs, with over 42% reporting “always”. Patient education, particularly on thrombosis warning signs and follow-up care, was less frequently performed; 41.2% reported “seldom” or “never” educating patients on thromboembolism. Only 25.6% of nurses reported always updating their knowledge via training or guidelines. These findings underscore a disconnection between positive attitudes and real-world implementation. Practice frequency by item is listed in Table 4.

Table 4 Practices Dimension in KAP Distribution of Responses Among Participants

Correlation Among Knowledge, Attitude, and Practice

Pearson correlation analysis demonstrated significant positive relationships among knowledge, attitudes, and practices. The strongest correlation was between knowledge and practice (r = 0.421, p < 0.001, 95% CI [0.303, 0.540]), followed by knowledge and attitude (r = 0.351, p < 0.001, 95% CI [0.219, 0.632]), and attitude and practice (r = 0.336, p = 0.015, 95% CI [0.061, 0.611]). These results support the interdependence of cognitive, affective, and behavioral domains in complication prevention (Table 5).

Table 5 Correlation Analysis Between Knowledge, Attitudes, and Practices

Predictors of Higher Practice Levels

Univariate logistic regression identified knowledge and attitude scores, education level, self-rated competence, clinical teaching role, and promotion experience as significant predictors of high practice levels. In multivariate regression, knowledge (OR = 1.14; 95% CI: 1.05–1.26; p = 0.007) and attitude scores (OR = 1.08; 95% CI: 1.03–1.20; p = 0.010) remained significant.

In addition, having a master’s degree or higher was independently associated with better practice (OR = 3.51; 95% CI: 1.31–5.66; p = 0.005). Self-rated high competence (OR = 1.75; 95% CI: 1.08–3.01; p = 0.036) and promotion experience (OR = 1.53; 95% CI: 1.07–2.74; p = 0.041) were also positively associated. Variables such as age, gender, income, and night shift status were not statistically significant predictors. Full regression details are provided in Table 6.

Table 6 Univariate and Multivariate Logistic Regression Analysis for Practice Levels

Discussions

This study sheds light on the current state of nursing knowledge, attitudes, and practices related to the prevention of complications in patients with nephrotic syndrome.^15–17 As frontline healthcare providers, nurses play an indispensable role in identifying early warning signs, delivering patient education, and coordinating multidisciplinary interventions aimed at minimizing adverse outcomes. The results demonstrate that while nurses generally maintain a positive attitude and engage in preventive behaviors, their foundational knowledge of nephrotic syndrome complications remains limited. This disconnect between attitude and knowledge suggests an underlying gap in both formal training and clinical exposure. Recent studies have explored the role of nurses in managing chronic kidney disease and nephrotic syndrome, highlighting the need for continued professional development and education.^18,19 This aligns with our findings, which emphasize the importance of targeted training to improve nursing practices in complication prevention. By incorporating these recent studies, our work provides a more comprehensive understanding of the current state of nephrotic syndrome care from a nursing perspective.

The moderate knowledge levels observed among the participants are consistent with previous studies in chronic disease nursing, where practical experience often outpaces theoretical understanding. In this context, limited familiarity with thromboembolic risk, hypoalbuminemia-associated complications, and long-term renal monitoring emerged as key deficiencies. These areas are crucial for early intervention and patient safety, yet they appear underrepresented in the knowledge profile of general ward nurses. This indicates a pressing need for nephrology-specific content to be more prominently integrated into continuing nursing education and certification programs. Notably, nurses with higher levels of knowledge were significantly more likely to demonstrate effective clinical practices and maintain positive attitudes toward complication prevention.²⁰ This finding supports the conceptual framework of health behavior change, which posits that knowledge acts as a catalyst for both motivation and action. The correlation between knowledge and practice also highlights the critical role of institutional support in fostering evidence-based care. Without access to updated guidelines, structured training, and supervisory feedback, even well-intentioned nurses may struggle to apply best practices consistently.

In line with other studies across nursing specialties, this research confirmed that higher educational attainment and prior nephrology training are strong predictors of better clinical practice. Nurses with postgraduate education exhibited superior performance in applying preventive strategies, suggesting that advanced academic preparation not only deepens knowledge but also enhances critical thinking and interdisciplinary coordination.^21,22 These findings underscore the value of postgraduate nursing education, not just for personal development but also for improving clinical outcomes in high-risk patient populations.

Despite the generally favorable attitudes observed, several inconsistencies were noted in actual practice behaviors. For example, many nurses infrequently provided education on thromboembolism or individualized preventive counseling to patients, despite acknowledging their importance. Such discrepancies may be attributed to systemic barriers, including insufficient staffing, high workload, lack of formal nephrology protocols, or limited collaboration with physicians. This echoes findings from studies in other domains such as diabetes, osteoporosis, and heart failure, where fragmented care environments often hinder effective knowledge translation.^23,24

This study provides valuable insights into the role of nurses in preventing complications associated with NS. While clinicians play a key role in the medical management of NS, nurses contribute significantly to the early detection of complications and the implementation of preventive strategies. Nurses, who are often the first to observe changes in patients’ conditions, have the unique opportunity to identify early warning signs of complications such as infections, thromboembolism, and acute kidney injury. Their proactive engagement in patient education, lifestyle counseling, and routine monitoring can complement clinicians’ efforts, ensuring a more holistic and comprehensive approach to patient care. From a nursing perspective, this study highlights the importance of continuous education and training to enhance the knowledge, attitudes, and practices of nursing staff in nephrotic syndrome management. By strengthening the competencies of nurses, we can improve not only the prevention of complications in adult patients but also in pediatric patients, where early intervention is crucial for minimizing long-term renal damage. The findings underscore the importance of collaboration between nurses and clinicians to ensure optimal management of nephrotic syndrome complications across diverse patient populations.

This study has several limitations. First, the cross-sectional design restricts the ability to draw causal inferences from the data. While the study provides valuable insights into the current state of nurses’ KAP regarding nephrotic syndrome complication prevention, the inability to track changes over time limits the understanding of how these factors evolve. Second, the study relied on self-reported data, which may introduce response bias or inaccuracies in reporting knowledge and practices. Third, while our sample of 246 nurses was representative of those working in nephrology-related units in two major hospitals, the findings may not be generalizable to other regions or healthcare systems, especially in rural areas or lower-resource settings. Additionally, the study was conducted in a single country, China, and the findings may not fully capture the diversity of practices and perspectives across different countries or cultural contexts. These limitations suggest the need for further research using longitudinal designs, objective measures, and more geographically diverse samples.

This study adds to a growing body of evidence advocating for the development of structured, nurse-centered models of chronic disease management. In the case of nephrotic syndrome, where complications are frequent and potentially life-threatening, empowering nurses with accurate knowledge and institutional support is vital. Improving clinical education, clarifying role responsibilities, and fostering interdisciplinary communication are key to enhancing the quality and consistency of care.

Conclusion

This study provides a comprehensive evaluation of nurses’ knowledge, attitudes, and practices in preventing complications associated with nephrotic syndrome. Although the majority of nurses expressed positive attitudes and demonstrated reasonable levels of preventive behavior, significant knowledge gaps persist, especially in areas critical to patient safety. The alignment among KAP domains and the influence of educational level and specialized training emphasize the need for systematic investment in nephrology-focused education and structured clinical support. By equipping nurses with both the knowledge and the operational tools to act effectively, healthcare systems can improve early detection, reduce preventable complications, and optimize outcomes for patients with nephrotic syndrome.

Data Sharing Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Informed Consent and Ethical Approval

This cross-sectional study was approved by the ethics committees of Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Shanghai Baoshan Medical Emergency Center. All patients provided written informed consent.

Consent for Publication

The patient provided written informed consent for publication of this research and the associated images.

Author Contributions

Nannan Wang and Xueqin Deng contributed equally to this work and share the first authorship. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors have no conflicts of interest to declare.

References

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Introduction

Asthma is a highly prevalent chronic respiratory disease, affecting approximately 340 million individuals globally.¹ It is characterized by bronchial hyperreactivity, resulting in symptoms such as wheezing, shortness of breath, chest tightness, breathlessness, and coughing, along with variable expiratory airflow limitation. As an inflammatory condition, asthma is treated using inhaled corticosteroids (ICS), with fluticasone propionate (FP) and ciclesonide (CIC) being among the most frequently used options. Globally, most ICSs are administered with pressurized metered-dose inhalers (pMDI).

pMDI containing FP is available as a suspension, a heterogeneous mixture where solid particles are dispersed within a liquid. These particles, typically larger than 1 µm, do not dissolve in the solvent. Suspensions are inherently unstable, with the dispersed particles prone to settling under gravity, a process that can be reversed by shaking. In contrast, pMDI containing CIC is prepared as a stable solution, with drug particles evenly distributed and resistant to settling over time.² The mass median aerodynamic diameter (MMAD) of an FP pMDI is significantly larger (2.6 μm) compared to a CIC pMDI (1.0 μm).³

Particle size plays a pivotal role in the aerodynamic behavior of aerosols and is a key factor in determining how deep inhaled medications travel in the respiratory tract. Particles within the 1–5 µm range, commonly referred to as the respirable range, are considered optimal for traversing the mouth, pharynx, and larynx to reach the lower airways. It is commonly thought that larger particles, exceeding 5 µm, are more likely to deposit in the upper airways or be swallowed, while smaller particles, below 1 µm, are generally exhaled.⁴ However, the notion that sub-1 µm particles do not achieve effective lung deposition has been called into question.⁵ Nevertheless, correct aerodynamic particle size distribution (APSD) of an aerosol medication is crucial for ensuring effective drug delivery and therapeutic efficacy.

While pMDIs may be used without a valved holding chamber (VHC), the use of a VHC is recommended for ICS delivery to reduce oropharyngeal deposition and minimize the risk of local side effects, such as dysphonia and oral candidiasis.^6–8 VHCs differ significantly in properties such as material composition, aerodynamic characteristics, valve mechanisms, shape, electrostatic properties, and volume, all of which can impact APSD.^9–11

The effectiveness of ICS administration relies on proper inhaler technique and incorrect use has been associated with poor asthma outcomes.¹² Nevertheless, errors in inhaler technique are common.^13,14 To optimize the delivery of active substances to the lower airways, patients are advised to begin with a slow, steady inhalation and actuate the inhaler immediately after starting to inhale. However, patients may activate the inhaler simultaneously with or even before beginning inhalation, preventing the adequate flow rate from being achieved before actuation. As many as a quarter of patients have been observed making this mistake.¹⁴

Earlier in vitro investigations have demonstrated that the interval between pMDI actuation and subsequent inhalation can markedly influence the amount of aerosolised medication delivered when used with VHCs.^15,16 Initiating inhalation at the time of actuation may hinder efficient ICS delivery if a VHC is not used, as there is no space for the plume to disperse, unlike when a VHC is used. To the best of our knowledge, the protective effect of VHCs during inhalation delay has not been sufficiently quantified. This in vitro study aimed to assess how initiating inhalation before actuation affects APSD of FP and CIC, compared to when inhalation is started at actuation. We also sought to determine how the use of a VHC influences APSD of FP and CIC when inhalation is initiated at actuation.

Methods

Data Collection

Instrumentation, Drugs, Sample Collection and Analyses

This study was performed in vitro. The VHCs were connected to an anatomical adult throat model (Adult Alberta Idealised Throat, Copley Scientific Limited, Nottingham, UK) with a silicone adapter. The throat model was followed by the mixing inlet (Copley Scientific Limited, Nottingham, UK) and the cascade impactor system Next Generation Impactor (NGI, Copley Scientific Limited, Nottingham, UK).

The pharmaceutical products studied were FP pMDI (Flixotide Evohaler 125 µg/dos, GlaxoSmithKline Inc., Evreux, France) and CIC pMDI (Alvesco 160 µg/dos, AstraZeneca AB, Södertälje, Sweden). The FP pMDI canister was vigorously shaken prior to each actuation. In each test setup, two doses of the drugs were delivered – each puff actuated individually in coordination with inhalation – and the resulting samples were subsequently collected.

The preparation of the test system included coating the cups of the NGI stages with a fixation solution (40 g glycerol + 10 mL of 15% Brij35 in ethanol) to minimize particle bounce and re-entrainment. The samples were collected from the throat model and all eight stages of the NGI. At NGI flow rate of 45 L/min, the particle diameter cut-off values of various stages were as follows: 9.4 µm, 5.2 µm, 3.3 µm, 1.9 µm, 1.1 µm, 0.7 µm, 0.4 µm, and 0.1 µm (Micro-Orifice Collector, MOC). The NGI stage cut-off diameters were calculated based on the constant flow rate within the NGI with interpolation performed between adjacent stages.

To collect the samples, 30 mL of solvent, 50% ethanol (v/v), was added to the throat model and 15 mL to the NGI cups. The outlets of the throat model were covered, solvent added, and the model was then shaken. The cups were shaken with a gentle rocker (Copley Scientific Limited, Nottingham, UK) after adding the solvent for 15 minutes. After adequate mixing, 1.5 mL of each sample was collected to a vial. The NGI samples were analyzed by high-performance liquid chromatography carried out by Emmace Consulting AB (Lund, Sweden) with the following setup: mobile phase: 96% ethanol/0.1% ammonium acetate 43/57 (vol/vol), pump flow rate: 1.5 mL/min, injection volume: 100 µL, detection wavelength: 226 nm, column: Waters XTerra RP18 3.5 µm, 50×4.6 mm. Validation showed linearity 0.03–32 µg/mL. The limit of quantitation (LOQ) was 0.03 µg/mL.

Inhalation Simulations, Timing of Actuation and Valved Holding Chamber

The APSD of FP and CIC was examined using three different setups: 1) inhalation initiated before actuation without a VHC; 2) inhalation started at actuation without a VHC; and 3) inhalation started at actuation with a VHC. Each test setup was repeated four times. To assess how a VHC affects deposition of a suspension and a solution pMDI (FP and CIC, respectively), the reusable plastic (acrylonitrile butadiene styrene) EasyChamber (TriOn Pharma, Hampshire, United Kingdom) with a chamber volume of 175 mL was used. Three separate VHCs from different manufacturing lots were used to ensure reliability of data. Before and in between the experiments the components of the VHCs were washed and dried according to the manufacturer’s instructions. To simulate inhalation initiated before actuation, a constant flow of 30 L/min was used. To simulate delayed inhalation, actuation was initiated at the exact start of inspiration using a breathing simulator (Breathing Simulator BRS 3100, Copley Scientific Limited, Nottingham, UK), which was programmed to represent an adult-type single inhalation. The flow rate reached 30 L/min within 0.5 seconds, followed by a steady flow maintained at 30 L/min for 3.5 seconds.¹⁷ The flow then ceased over the subsequent 0.5 seconds, resulting in a total inhalation duration of 4.5 seconds with a total inhalation volume of 2030 mL.

Statistics

The software IBM SPSS Statistics for Windows, version 27 (IBM Corp, NY, USA), was used for the data analysis. Proportions of the label claim of FP and CIC deposited in the throat model and as particles 1–5 µm and under 1 µm in diameter, delivered with inhalation initiated before actuation without a VHC as well as with inhalation started at actuation both without and with a VHC, were compared using the mean. Confidence intervals of 95% were established. To compare APSD of FP and CIC delivered with inhalation initiated before actuation without a VHC as well as with inhalation started at actuation both without and with a VHC, a general linear model of repeated measures was utilized.

Ethical Statement

Due to the in vitro setting of the study, no ethical approval was required.

Results

Figure 1 illustrates the APSD of FP delivered with inhalation initiated before actuation without a VHC as well as with inhalation started at actuation both without and with a VHC. When inhalation began at actuation, the APSD profiles beyond the throat model had a similar shape. However, without a VHC, overall drug delivery was significantly lower than with a VHC. When inhalation was initiated before actuation (without the VHC), particle deposition was slightly more skewed toward smaller particles (Figure 1).

Figure 2 illustrates the APSD of CIC delivered with inhalation initiated before actuation without a VHC as well as with inhalation started at actuation both without and with a VHC. Without considering throat deposition, APSD profile of CIC was almost identical when inhalation started before actuation without a VHC and when a VHC was used with inhalation starting at actuation. However, when no VHC was used and inhalation started at actuation, the APSD changed in both shape and magnitude, leading to a much lower delivered dose and a slight shift toward smaller particles (Figure 2).

Figure 2 The aerodynamic particle size distribution of ciclesonide (320 µg) delivered using three different setups: inhalation initiated before actuation without a valved holding chamber (VHC), inhalation started at actuation without a VHC, and inhalation started at actuation with a VHC. Error bars indicate 95% confidence interval. Abbreviation: MOC, Micro-Orifice Collector.

Table 1 presents the percentage of the label claim deposited in the throat model and as particles in the 1–5 µm and under 1 µm diameter ranges, delivered with inhalation initiated before actuation without a VHC as well as with inhalation started at actuation both without and with a VHC. The timing of inhalation relative to pMDI actuation did not affect throat deposition of FP or CIC; however, with the VHC, throat deposition was reduced to only a few percent of the label claim for both. Deposition of particles 1–5 µm was lowest for both medications when inhalation was initiated concurrently with actuation without a VHC. The VHC markedly improved the deposition of particles 1–5 µm for both medications, with the effect being especially pronounced for CIC. The proportion of particles under 1 µm for FP was only a few percent of the label claim and increased only slightly with the use of a VHC while remaining unaffected by inhalation timing. In contrast, for CIC, deposition of particles under 1 µm was lower when inhalation was initiated concurrently with actuation and no VHC was used but markedly improved when a VHC was utilized and when inhalation was initiated before actuation (Table 1).

Table 1 Proportions of the Label Claim Deposited in the Throat Model and in the Next Generation Impactor as Particles 1–5 µm and Under 1 µm in Diameter, Delivered Using Three Different Setups: Inhalation Initiated Before Actuation without a Valved Holding Chamber (VHC), Inhalation Started at Actuation without a VHC, and Inhalation Started at Actuation with a VHC

The mass MMAD and geometric standard deviation (GSD), representing the measures of central tendency and spread, respectively, are presented in Table 2.

Table 2 Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) of Fluticasone Propionate and Ciclesonide Obtained from the Next Generation Impactor Using Three Different Setups: Inhalation Initiated Before Actuation without a Valved Holding Chamber (VHC), Inhalation Started at Actuation without a VHC, and Inhalation Started at Actuation with a VHC. Values are Mean ± Standard Deviation (SD)

Discussion

In this in vitro investigation, we found that when inhalation is initiated simultaneously with actuation, the effective dose delivered decreased markedly for both FP and CIC compared to when inhalation was begun correctly, ie, before actuation. However, when a VHC was used and inhalation was started at actuation, delivered dose improved substantially for both medications. This protective effect of the VHC was especially pronounced for CIC, with both the fraction of particles in the 1–5 µm range and those under 1 µm returning to the same levels as when inhalation was initiated correctly.

We hypothesize that when the pMDI is actuated at 0 seconds, or before inhalation, corresponding to a flow rate of 0 L/min at the inlet, the emitted dose lacks sufficient airflow to transport it through the inlet, causing it to stagnate or rebound. This results in a loss of formulation into the surrounding air, which can sometimes be observed as a visible cloud of formulation escaping from the top of the device. In contrast, when the pMDI is actuated into a spacer at 0 L/min flow, the aerosol is captured within the spacer chamber. As airflow increases, this dose is subsequently delivered into the NGI, improving mass balance and dose delivery efficiency.

For FP, the use of a VHC significantly improved the deposition of 1–5 µm particles when the inhalation started at actuation, although still not reaching the level when inhalation was initiated before actuation. In contrast, for CIC, the VHC improved deposition of 1–5 µm particles to a level comparable to that achieved with correctly coordinated inhalation, as indicated by the overlapping 95% confidence intervals (Table 1). A comparison of Figures 1 and 2 reveals that within the 1–5 µm range, the mass of CIC particles was on average more concentrated toward smaller particles compared to FP. This difference in particle size may explain why the VHC provided greater protection for CIC against inhalation and actuation discoordination. This is further supported by previous findings showing that the MMAD of FP pMDI is larger than that of CIC pMDI.³

Only a few percent of the label claim for FP were deposited as particles smaller than 1 µm, and the inhalation delay appeared to have no clear effect on these. However, the 95% confidence interval for the mean of measurements with inhalation initiated before actuation was too wide to draw a definitive conclusion about its effect (Table 1). The use of a VHC slightly improved the deposition of FP particles under 1 µm. In contrast, for CIC, the deposition of sub-1 µm particles improved substantially with both the use of a VHC and the early initiation of inhalation. We believe that this is also related to the average particle size within the sub-1 µm particle range, which differed between FP and CIC. Specifically, within the sub-1 µm range, CIC particles were, on average, smaller than FP particles, as illustrated in Figures 1 and 2.

Previous studies have highlighted the impact of delayed inhalation on drug delivery efficiency when using pMDIs with VHCs. For example, Berlinski and Pennington reported that a 10-second delay following actuation led to a significant reduction (between 27% and 42%) in the fine particle fraction of albuterol across several VHC devices.¹⁵ Similarly, Chambers et al found that certain VHC designs, particularly those with smaller volumes or lacking valves, were more prone to dose loss when a delay was introduced during use of a budesonide–formoterol combination inhaler.¹⁶ Although these studies offer important evidence on the role of timing and chamber design, their methodologies differed from ours in several ways. Notably, they did not include physiologically realistic throat models or incorporate breathing profiles that reflect actual patient inhalation patterns. Furthermore, solution-based inhaled corticosteroids and direct comparisons between solution and suspension formulations were not examined, limiting their relevance to the full range of available ICS therapies.

Although recommendations state that ICS delivery from pMDIs should ideally be performed with a VHC, this guidance is often overlooked.⁶ It has also been suggested that the delivery of drugs with small MMADs, such as CIC pMDI, may be reliably achieved even without a VHC if the inhalation technique is correct.¹⁸ However, studies indicate that up to 25% of adults use incorrect inhalation timing.¹⁴ It is also important to note that the commonly recommended inhalation time of 3–5 seconds is already long and challenging, so asking patients to extend it further just to avoid using a VHC is not practical. If inhalation begins too early, there may not be enough time to fully inhale the medication, as the lungs will already be full. This could also introduce additional technique-related issues for certain patients, such as those with obstructive pulmonary disease, neuromuscular disorders and the elderly. Given these factors, can we truly claim that the use of a VHC is unnecessary?

We employed the NGI cascade impactor, a widely used pharmaceutical tool for characterising aerosol particle size distribution. The MMAD and GSD values obtained in our study align with previously reported data for both FP and CIC delivered by pMDI.^3,19 We noted that CIC’s GSD increased slightly in the setup where inhalation started at actuation without using a VHC (GSD = 2.11), suggesting a broader particle distribution under less optimal timing conditions. Importantly, the low standard deviations across all replicates reflect good reproducibility.

The use of an anatomical throat model enabled a more precise simulation of airway conditions, facilitating accurate throat deposition estimation. The integration of a breathing simulator further enhanced the realism of our setup by closely mimicking real inhalation conditions. The EasyChamber VHC was selected based on its reliable performance in our previous studies, which enabled us to accurately assess the effects of VHCs under ideal conditions. A significant advantage of our in vitro approach was the ability to control for variables that could confound results in in vivo studies, allowing us to focus solely on the variables of interest.

We used an adult throat model, which may not accurately reflect the conditions of a child’s throat. Likewise, the breathing pattern used in our experiments was representative of adult breathing and may not mirror pediatric breathing patterns. Therefore, our findings may not be directly applicable to children. Additionally, since we only tested one VHC and two medications, the results may not be fully generalizable to other devices or drugs. A broader limitation of in vitro studies is their inability to fully replicate the complexity of human organ systems and physiological environments.

In conclusion, initiating inhalation simultaneously with pMDI actuation, a common mistake in real life, reduces the delivered dose of FP and CIC compared to when inhalation is started before actuation. The use of a VHC effectively mitigates this issue, ensuring a higher and more consistent medication dose is delivered, even when actuation timing is suboptimal. This effect was especially pronounced for CIC pMDI, which has a smaller MMAD and may be more sensitive to variations in inhalation technique. Given that correct inhaler use is often challenging in everyday practice and only the medication that actually reaches the lungs can help, it is important to encourage the use of valved holding chambers (VHCs) not just for children but also for adults.

While our results provide mechanistic insight into how inhalation timing and device configuration influence aerosol delivery, they are based on laboratory simulations and do not directly reflect clinical outcomes. Therefore, larger real-world clinical studies are needed to confirm whether the improved drug delivery observed with VHC use in vitro translates into better asthma control, adherence, and health outcomes in diverse patient populations.

Abbreviations

APSD, Aerodynamic Particle Size Distribution; CIC, Ciclesonide; FP, Fluticasone Propionate; ICS, Inhaled Corticosteroid; MMAD, Mass Median Aerodynamic Diameter; NGI, Next Generation Impactor; pMDI, Pressurized Meter-Dosed Inhaler; VHC, Valved Holding Chamber.

Data Sharing Statement

Data collected for the study, along with a data dictionary defining each field in the set, will be made available following publication, pending approval of a proposal and a signed data access agreement. All data requests should be submitted to the corresponding author for consideration.

Generative Artificial Intelligence

AI technology (ChatGTP) was utilized solely for grammar and language refinement in this submission. No AI was used for data analysis, content generation, or research interpretation. The purpose of AI involvement was to ensure clarity and grammatical accuracy while maintaining the original meaning and integrity of the work.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The study was supported by unrestricted grants from the following sources: Research Foundation of the Pulmonary Diseases (Hengityssairauksien tutkimussäätiö), Tampere Tuberculosis Foundation (Tampereen Tuberkuloosisäätiö), Finnish Medical Foundation (Suomen Lääketieteen säätiö), and Jalmari and Rauha Ahokkaan Foundation (Jalmari ja Rauha Ahokkaan säätiö). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Disclosure

Professor Lauri Lehtimäki reports personal fees from ALK, AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Orion, Sanofi, outside the submitted work. The authors declare no other competing interests related to the manuscript content.

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SINGAPORE – Active individuals will be able to get a faster diagnosis of potentially life-threatening or serious heart conditions with an imaging test introduced by the National Heart Centre Singapore (NCHS), a first in Asia.

Exercise Cardiac Magnetic Resonance (ExCMR) imaging combines magnetic resonance imaging (MRI) with real-time exercise to detect underlying heart conditions, distinguishing them from normal changes brought about by exercise, in just one session.

An MRI is a diagnostic test that uses magnetic fields and radio waves to create detailed images of the body’s internal structures, including organs.

Introduced by NHCS as a research project in 2017, ExCMR involves a specially designed stationary bike that is attached to an MRI scanner.

It costs about $200 more than a conventional MRI test for subsidised patients and about $500 more for private patients, said NHCS.

During the test on the stationary bike, patients pedal at set intervals while doctors observe how the heart performs during exercise, capturing detailed images of the heart’s structure, function and blood flow, NHCS said in a statement on Aug 27.

“Unlike conventional tests that often require weeks or even months of several separate assessments, ExCMR provides fast and accurate results in a single visit,” it said.

Each ExCMR session will take about 15 to 20 minutes longer than a conventional MRI, which takes about an hour to complete.

Faster diagnosis, cost savings for patients

Assistant Professor Michelle Kui, a consultant with the NHCS, said patients suspected of having an enlarged heart following an echocardiogram can be referred for additional tests to confirm if it is due to exercise or something more serious, such as a genetic disorder affecting the heart muscles.

She added that this would traditionally be followed by additional tests such as an MRI and a treadmill test. Patients can also be asked to restrict their activities for a few months, then undergo tests again before a diagnosis is confirmed.

With the ExCMR, doctors will be able to pinpoint the cause sooner.

“If it’s a healthy heart, the patient can continue to compete,” she said. “There is no need to restrict any activities and no need to repeat scans. If it’s a serious condition, he or she will get treatment early.”

NHCS said: “Research has shown that ExCMR significantly reduces the need for patients to undergo multiple tests by nearly 90 per cent, from 56.8 per cent to just 6.5 per cent.”

“This not only ensures timely diagnosis and earlier treatment for patients but also translates into significant cost savings for patients and healthcare systems in the long run.”

More than 600 participants were studied to refine and validate the test, said NHCS.

It was progressively rolled out in 2020 as an alternative stress MRI, and has since been used on about 400 patients.

One such patient is former national footballer Adam Swandi.

Adam, 28, experienced dizziness and chest tightness during a match in September 2024. He was referred for ExCMR after cardiac tests suggested he had cardiomyopathy, a form of heart muscle disease.

The test confirmed his diagnosis and revealed that he was at high risk of a fatal cardiac event if he continued to play football competitively.

“The ExCMR helped my doctors and me gain a clearer picture of my condition,” he said. “The detailed indicators pointed to the most effective next steps in my treatment journey.”

He was referred for treatment and subsequently retired from the sport.

Assistant Professor Le Thu Thao, who leads the ExCMR research programme, said a more accurate assessment will allow active individuals to “continue sports safely where appropriate, while those at risk are identified more quickly to receive timely intervention”.

Safety in sport has been much discussed in recent years following sudden deaths in football and endurance events.

In 2024 and 2025, there have been at least four instances of footballers collapsing on the pitch and dying as a result of a cardiac event. This includes a 27-year-old Uruguayan player during a Copa Libertadores game and two promising teenage players, a 14-year-old in France and a 13-year-old in Britain.

In Singapore, three people have died during or following the country’s premier distance running event – the Standard Chartered Singapore Marathon.

Two of them were due to cardiac causes. And several other endurance events have also had fatalities.

‘Game changer’

Associate Professor Calvin Chin, senior consultant and clinician scientist at NHCS, called the ExCMR a “game changer”.

The NHCS said it aims to expand its capacity to 100 patients a year. Active individuals can get referrals to take the test through cardiologists from both public and private healthcare institutions.

“Initially applied to distinguish between an athlete’s heart and dilated cardiomyopathy, ExCMR is now being extended to patients with suspected coronary artery disease and other heart conditions,” it said.

Source: The Straits Times © SPH Media Limited. Permission required for reproduction

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