Definition of Episodic Dyspnea in Cancer Patients: A Delphi-Based Consensus among Spanish Experts: The INSPIRA Study

Abstract

Background:

Episodic dyspnea is an increasingly recognized phenomenon that occurs frequently in patients with cancer. Although numerous definitions have been proposed to describe episodic dyspnea, to date, no common widely accepted definition in Spanish has yet emerged. Without a clear well-accepted definition, it is difficult to design rigorous clinical trials to evaluate candidate treatments for this emerging entity and to compare outcomes among studies.

Objective:

The aim of the study was to reach a consensus definition of episodic dyspnea in the Spanish language based on professional criteria in cancer patients.

Design:

A two-round Delphi study.

Setting/Subjects:

Sixty-one Spanish specialists in medical oncology, radiation oncology, pneumology, palliative care, and pain management participated in the study.

Measurements:

Sixteen different questions on dyspnea-related terminology, including the definition of episodic dyspnea, were assessed.

Results:

The panel of experts reached a consensus on 75% of the 16 assessments proposed: 56.25% in agreement and 18.75% in disagreement. The term that most panelists considered most appropriate to define dyspnea exacerbation was dyspnea crisis. The panelists disagreed that dyspnea exacerbation is equivalent to dyspnea at effort and that the presence of dyspnea at rest is required for exacerbation to occur. However, there was wide agreement that exacerbation may or may not be predictable and can be triggered by comorbidities as well as emotional, environmental, or effort factors.

Conclusions:

The broad consensus reached in this study is a necessary first step to design high-quality methodological studies to better understand episodic dyspnea and improve treatment.

Introduction

Dyspnea, a common and highly distressing symptom in cancer patients,¹ is defined by the American Thoracic Society as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity; the experience of dyspnea derives from interactions among multiple physiological, psychological, social, and environmental factors and may induce secondary physiological and behavioral responses.² The reported prevalence rate of dyspnea in patients with advanced cancer ranges from 29% to 74%.³ Patients frequently report that this condition negatively affects quality of life and can even give rise to thoughts of impending death.⁴

Patients describe various types of dyspnea: continuous over time, intense flare-ups over background dyspnea, and solely episodic or intermittent dyspnea.⁵ Studies suggest that in advanced cancer patients, episodic dyspnea may be more prevalent than background dyspnea, with a rate of up to 80%.^6,7 Exacerbation of dyspnea, in fact, is designated using different terms, including acute,⁸ episodic,⁹ intermittent,¹⁰ and breakthrough.¹¹

However, despite efforts to reach a consensus definition for episodic dyspnea, for instance, by Simon et al.,¹² an operative definition of episodic dyspnea in Spanish is lacking, which would allow Spanish-speaking health care professionals to properly identify patients with this condition to enroll them in international well-designed studies. Furthermore, some terms used in English, for example, breathlessness, breakthrough, and episodic, do not have an unambiguous translation to Spanish. Note that no Spanish speakers participated in the study by Simon et al.¹²

In this context, the main aim of this Delphi study involving Spanish physicians was to reach a consensus definition of episodic dyspnea in cancer patients with a view to recruiting patients in future trials of candidate pharmacological treatments for episodic dyspnea. Additional aims were to determine the terminology to denote exacerbation and to define the characteristics of episodic dyspnea.

Materials and Methods

Study design

The study was conducted from March to June 2017 using a modified, two-round Delphi method. The Delphi method has been described in detail elsewhere¹³; briefly, it is a structured communication technique that allows a group of experts to compare opinions on complex or controversial topics for which the currently available scientific evidence is considered inadequate.

The process is structured in rounds in which participants indicate their level of agreement with specific statements related to the topic of interest. Participants provide their opinion and can also, if so desired, justify their opinions. When a round is completed, any statements that have not received sufficient consensus are submitted to another round in an attempt to achieve a broader consensus after revision. The present study was conducted in five stages as follows: establishment of a nominal group; survey development; participant selection; Delphi rounds; and data collection and analysis.

Nominal group

The need for this study emerged from informal conversations among authors of this article who form the nominal group. This nominal group agreed to focus the Delphi method on a specific condition, namely cancer and, more specifically, lung cancer. The reason was to avoid introducing confounding factors in responders' minds that could distract them in their answers. It was understood that the agreed definition would need to be validated for other conditions (e.g., chronic obstructive pulmonary disease).

To ensure input from the wide range of clinical disciplines commonly involved in treating patients with lung cancer in Spain, experts from the following specialties were included: medical oncology, radiation oncology, pneumology, palliative care, and pain management. All nominal group members had extensive clinical experience (greater than five years) in treating dyspnea in patients with lung cancer. The nominal group was responsible for developing the study methodology, preparing the survey and study protocol, performing the statistical analysis, and interpreting results.

Questionnaire

The online questionnaire included a total of 16 items: 15 statements (Tables 1 and 2) plus a proposed definition of episodic dyspnea (Table 4). The items were divided into three categories: terminology to denominate dyspnea exacerbation, characteristics of dyspnea exacerbation, and definition of episodic dyspnea. The statements reflected controversial issues in episodic dyspnea and were developed as a result of a nonsystematic, but in-depth, review of the literature and, in particular, from the analysis of another Delphi study on this topic.¹²

Table 1.

Terminology to Denominate Dyspnea Exacerbation

Item	Round	Mean	SD	Median	% in ^a	IQR	Result
1	The most appropriate term to denominate dyspnea exacerbation is breakthrough dyspnea
	Para la denominación de las exacerbaciones de disnea el término más apropiado es el de disnea irruptiva
	1	5.13	2.2	5	37.68	4	Indeterminate
	2	5.08	2.1	5	37.70	4	Indeterminate
2	The most appropriate term to denominate dyspnea exacerbation is episodic dyspnea
	Para la denominación de las exacerbaciones de disnea el término más apropiado es el de disnea episódica
	1	5.26	2.2	5	46.38	3	Indeterminate
	2	4.93	2.2	5	40.98	4	Indeterminate
3	The most appropriate term to denominate dyspnea exacerbation is crisis of dyspnea
	Para la denominación de las exacerbaciones de disnea el término más apropiado es el de crisis de disnea
	1	6.59	1.9	7	60.87	3	Indeterminate
	2	7	2.3	8	72.13	2	Agreement
4	The most appropriate term to denominate dyspnea exacerbation is intermittent dyspnea
	Para la denominación de las exacerbaciones de disnea el término más apropiado es el de disnea intermitente
	1	3.12	1.5	3	62.32	2	Indeterminate
	2	2.51	1.1	2	86.89	1	Disagreement
5	The term episodic dyspnea is appropriate for all dyspnea exacerbation events
	El término disnea episódica es adecuado para todas las exacerbaciones de disnea
	1	4.49	2.4	4	34.78	4	Indeterminate
	2	4.18	2.3	5	36.07	3	Indeterminate
6	The term basal dyspnea is equivalent to dyspnea at rest
	El término disnea basal equivale a disnea de reposo
	1	5.68	2.9	7	53.62	5	Indeterminate
	2	5.59	3.1	7	54.10	5	Indeterminate
7	The term dyspnea exacerbation is equivalent to dyspnea at effort
	El término exacerbación de disnea equivale a disnea de esfuerzo
	1	2.93	2.2	2	73.91	3	Disagreement

The original Spanish language statement is given below the English language statement.

Percentage of answers in the 3-point region that includes the median.

IQR, interquartile range; SD, standard deviation.

Table 2.

Characteristics of Dyspnea Exacerbation

Item	Round	Mean	SD	Median	% in ^a	IQR	Result
8	Dyspnea at rest is a necessary precondition to have dyspnea at effort
	Es necesario que exista disnea de reposo para que haya exacerbación de disnea
	1	4.14	2.9	3	57.97	5	Indeterminate
	2	3.07	2.6	2	77.05	2	Disagreement
9	Dyspnea exacerbation may not be predictable
	La exacerbación de disnea puede ser no predecible
	1	8.12	1.1	8	92.75	1	Agreement
10	Dyspnea exacerbation may be predictable
	La exacerbación de disnea puede ser predecible
	1	7.45	1.7	8	81.16	2	Agreement
11	Dyspnea exacerbation can be triggered by emotional factors
	La exacerbación de disnea puede desencadenarse por factores emocionales
	1	8.07	1	8	94.20	1	Agreement
12	Dyspnea exacerbation can be triggered by effort
	La exacerbación de disnea puede desencadenarse por esfuerzo
	1	8.26	1	18	95.65	1	Agreement
13	Dyspnea exacerbation can be triggered by environmental factors
	La exacerbación de disnea puede desencadenarse por factores ambientales
	1	7.84	1.3	8	92.75	2	Agreement
14	Dyspnea exacerbation can be triggered by comorbidities
	La exacerbación de disnea puede desencadenarse por factores intercurrentes como las comorbilidades
	1	8.13	1	8	97.1	1	Agreement
15	The differentiation of dyspnea exacerbation with dyspnea of physiological effort lies in the disproportion in the intensity of dyspnea with respect to the effort made
	La diferenciación de la exacerbación de disnea con la disnea de esfuerzo fisiológico radica en la desproporción en la intensidad de la disnea respecto al esfuerzo realizado
	1	6.94	1.8	8	71.01	2	Agreement

The original Spanish language statement is given below the English language statement.

Percentage of answers in the 3-point region that includes the median.

The degree of agreement was assessed on a 9-point Likert scale ranging from 1 (complete disagreement) to 9 (complete agreement). Scores from 1 to 3 were considered to indicate disagreement with the statement, scores from 4 to 6 indicated neither agreement nor disagreement, and scores from 7 to 9 were considered to indicate agreement. Respondents were allowed to make free-text comments on any of the items analyzed by the nominal group.

Participants

Specialists from the fields of medical oncology, radiation oncology, palliative medicine, and pain management with at least five years' experience in treating cancer patients were invited to participate. Note that since the Delphi method is a systematic forecasting method that uses a panel of experts, there is no requirement to ensure the proportionality of participants in terms of affiliation or specialty.¹⁴ Candidate specialists, recruited from all 17 autonomous regions of Spain, were identified as follows: (1) using a literature search to identify Spanish authors of cancer-related dyspnea studies, (2) by proposal by the steering committees of the relevant Spanish medical societies, and (3) as proposed by the nominal group as having their well-known expertise in this area. Pain specialists were included because, beyond the treatment of pain, they are closely involved in the care of patients with advanced cancer in several Spanish regions. Twenty experts from each discipline were invited to participate. If the response rate was below 20% in a specific discipline, up to 10 additional experts were invited. Participants were contacted through an e-mail that explained the study aims and design. Ten participants were asked to complete the questionnaire in an initial pilot study, after which no further changes were made to the questionnaire. The responses from those 10 participants were included in the final analysis.

Ethical considerations

Participation was voluntary and no remuneration was provided. The survey instructions explicitly stated that the act of returning the completed survey was considered consent to participate. Although no patient data were collected, the study was approved by an ethics committee (ref. PR032/17).

Statistical analysis

In accordance with the RAND/UCLA Appropriateness Method User's Manual (ref. 15), we tested the hypothesis that 80% of the hypothetical population of repeated ratings were within the same region (values from 1 to 3, from 4 to 6, and from 7 to 9) as the observed median. If we were unable to reject that hypothesis in a binominal test at the 0.33 level, the indication was rated with agreement. According to that definition, therefore, the cutoff we used for consensus was 66%.

A statement was therefore considered to have achieved agreement when >66% of the specialists had indicated a level of agreement >7 on the 9-point Likert scale. Similarly, disagreement with the statement was considered when >66% of respondents indicated a level of agreement <3 on the scale.¹⁵ Agreement was considered indeterminate (neither agreement nor disagreement) for scores between 4 and 6. Statements with a high dispersion of opinions (interquartile range [IQR] >4) were also considered to be indeterminate. Statements for which no consensus was reached (either for or against) in the first round were evaluated again in the second Delphi round.

Invitation to the study, design of the online survey, and statistical analyses were performed by a contract research organization.

Results

A total of 151 experts in treating dyspnea in cancer patients were invited to participate in the study. In the first and second rounds, 68 and 61 participants, respectively, completed the questionnaire. The response rate was 40.4% (Table 3). Consensus was reached on nine statements (eight in agreement and one in disagreement) in the first round. The remaining seven statements passed to the second round where consensus was obtained for three statements (one in agreement and two in disagreement); the experts failed to reach consensus on the remaining four statements. After two rounds, therefore, consensus was reached on 12 of the 16 statements (75.9%): 9 in agreement (9/16; 56.3%) and 3 in disagreement (3/16; 18.8%). Mean and IQR values for the results for each category reported below are provided in brackets.

Table 3.

Number and Response Rate of Participants by Specialty

Specialty	Invited, n (%)	Round 1, n (%)	Round 2, n (%)	Response rate (%)
Palliative medicine	30 (19.9)	24 (35.3)	23 (37.7)	76
Medical oncology	30 (19.9)	20 (29.4)	20 (29.4)	66
Radiation oncology	30 (19.9)	15 (22.0)	11 (18.0)	36
Pneumology	22 (14.6)	5 (7.4)	4 (6.6)	18
Pain management	39 (25.7)	4 (5.9)	3 (4.9)	7
Total	151 (100)	68 (100)	61 (100)	40

Terminology to denominate dyspnea exacerbation

The experts reached a consensus that the most appropriate term for dyspnea exacerbation was “crisis de disnea” (dyspnea crisis) (7; 2). There was consensus disagreement regarding the use of “disnea intermitente” (intermittent dyspnea) (2.51; 1) (Table 1). Neither agreement nor disagreement was found for “disnea irruptiva” (breakthrough dyspnea) and “disnea episódica” (episodic dyspnea). The panelists were unable to reach agreement regarding the use of episodic dyspnea for all dyspnea exacerbation events (4.18; 3). Agreement was also indeterminate regarding “disnea basal” (baseline dyspnea) as equivalent to dyspnea at rest (5.59; 5). Panelists disagreed that “exacerbación de disnea” (dyspnea exacerbation) was equivalent to dyspnea on effort (2.93; 3).

Characteristics of dyspnea exacerbation

The experts disagreed that the presence of dyspnea at rest was required for dyspnea on effort to occur (3.07; 2) (Table 2). However, they strongly agreed that dyspnea exacerbation may be unpredictable (8.12; 1) or predictable (7.45; 2). Likewise, the experts also reached a consensus that dyspnea exacerbation can be triggered by emotional factors (7.84; 2), effort (8.26; 1), environmental factors (7.84; 2), or comorbidities (8.13; 1). They also agreed that differentiation of the dyspnea exacerbation from physiological effort lay in the imbalance between dyspnea intensity and exertion.

Definition of episodic dyspnea

The experts agreed with the proposed definition of episodic dyspnea as “aparición o incremento, en un paciente oncológico, de una dificultad respiratoria transitoria y desproporcionada, ocasionada por un desencadenante conocido (esfuerzo, factores emocinales, ambientales o comorbilidades) o desconocido, con la presencia o no de disnea de reposo” (the appearance or increase, in a cancer patient, of transitory and disproportionate breathing discomfort, caused by an unknown or known trigger (i.e., effort, emotional or environmental factors, or comorbidities), in the presence or absence of dyspnea at rest) (7.49; 1) (Table 4).

Table 4.

Assessment of Proposed Definition of Episodic Dyspnea

Round	Mean	SD	Median	% in ^a	IQR	Result
Episodic dyspnea is defined as the appearance or increase, in an oncological patient, of a transitory and disproportionate breathing discomfort, caused by a known (i.e., effort, emotional or environmental factors, or comorbidities) or unknown trigger, with or without the presence of dyspnea at rest.
Se define disnea episódica como la aparición o incremento, en un paciente oncológico, de una dificultad respiratoria transitoria y desproporcionada, ocasionada por un desencadenante conocido (esfuerzo, factores emocionales o ambientales o comorbilidades) o desconocido, con la presencia o no de disnea en reposo.
1	7.49	1.6	8	80.88	1	Agreement

The original Spanish language statement is given below the English language statement.

Percentage of answers in the 3-point region that includes the median.

Discussion

This Delphi study, participated in by a wide range of Spanish experts with experience in treating lung cancer patients, revealed several interesting findings with regard to the definition of episodic dyspnea in cancer patients. In particular, our definition highlights the imbalance between the patient's expected level of breathlessness in a particular situation and the actual degree of dyspnea experienced. This study provides a new perspective on the conceptualization of dyspnea, which could be useful in identifying patients with episodic dyspnea for inclusion in future epidemiological or clinical trials. This is the first time that a consensus definition of episodic dyspnea has been reached for the Spanish language.

Episodic dyspnea is an increasingly recognized entity and appears to be the term that best defines the experience of patients with dyspnea. However, several different terms have been used to refer to this phenomenon, including breakthrough dyspnea, dyspnea attack, intermittent dyspnea, and dyspnea crisis, among others.^5–8 Our definition of episodic dyspnea is the appearance or increase, in a cancer patient, of transitory and disproportionate breathing discomfort, caused by an unknown or known trigger (i.e., effort, emotional or environmental factors, or comorbidities), in the presence or absence of dyspnea at rest.

This definition, which is similar to those of Simon et al.¹² and Reddy et al.,⁶ includes a comprehensive evaluation of dyspnea linked to subjective experiences of patients, regardless of how it is managed or treated.^16,17 In the definition given by Simon et al.,¹² episodic dyspnea starts beyond usual fluctuations in the patient's perception [of dyspnea]. By contrast, our definition indicates that episodic dyspnea is present when there is an imbalance between the expected level of breathlessness in a given situation and the breathlessness actually experienced. This is consistent with the mismatch theory, which explains that the sensation of dyspnea at a pathophysiologic level reflects discordance between outgoing motor signals to the respiratory muscles and incoming afferent information to the brain.^18,19 There was strong agreement among our panelists in support of this definition.

Regarding the terms that best describe dyspnea exacerbation, the main differences between the terms proposed in our consensus were mainly semantic in nature. Although the term included in our definition was “disnea episódica” (episodic dyspnea), experts in our study agreed that the term “crisis de disnea” (dyspnea crisis) better defined this phenomenon.

This conflicting result merits some consideration. First, in the Spanish language, the preferred term among experts is “crisis de disnea” as it connotes an emergency; this is important as the presence of such a crisis in cancer patients is a real crisis, as described elsewhere.¹⁶ Second, the term “disnea episódica” (episodic dyspnea) denotes a time-limited phenomenon that occurs repeatedly over time, but that does not encompass all of the possibilities of dyspnea exacerbation as these may arise in an unpredictable manner without any specific pattern of onset or progression. Third, the preferred term in the English language literature is episodic dyspnea and not dyspnea crisis since (according to some experts) the term crisis is too widely used in many aspects of medicine and even in daily life.⁵ Consequently, our nominal group—strongly supported by the expert group—decided to maintain the proposed definition rather than alter it to include the term dyspnea crisis.

This decision was based on recognizing the strength of the definition as a whole rather than just a single word. It was assumed that the term “crisis de disnea” (dyspnea crisis) will be used in Spanish language settings, while the term “disnea episódica” (episodic dyspnea) may also be used as a direct translation from the English language. In a nonsystematic review, Doneski¹⁶ defined breathlessness crisis as sustained and severe resting breathing discomfort that occurs in patients with advanced, often life-limiting, illness and overwhelms the patient and caregivers' abilities to achieve symptom relief. In contrast, our definition does not consider the role of caregivers since the patient's experience is unrelated to the caregivers' abilities to cope with the situation, and it is clear that the crisis may or may not happen at rest.

The expert panel in our study was unable to reach consensus on the term “disnea irruptiva” (breakthrough dyspnea), mainly because of the widespread use of breakthrough pain, as it was felt that it could generate confusion given that breakthrough pain can only occur in the presence of background pain. By contrast, episodic dyspnea can occur in the presence or absence of background dyspnea.^7,20,21

The panelists agreed that episodic dyspnea can occur in a predictable or unpredictable manner. They also agreed that it can be triggered by emotional factors (such as anxiety or fear), environmental factors (such as moisture, dust, or heat), effort, and/or exacerbation of comorbidities. All of these findings coincide with the consensus reached by Simon et al.¹² and by other authors.^6,17,22 Some studies have described predictable episodic exacerbation related to environmental, psychosocial, or stress factors.²³ In addition, the interaction between certain factors—such as effort and anxiety—can aggravate the dyspnea experience.²⁴

The experts did not reach a consensus regarding equivalence between baseline dyspnea and dyspnea at rest. This may have occurred because some panelists consider baseline dyspnea to be continuous except in periods of exacerbation or crisis. By contrast, dyspnea at rest could be interpreted as dyspnea that occurs when the patient does not exercise, as opposed to dyspnea on effort. If dyspnea is classified according to its intensity, then baseline dyspnea would be interrupted by a crisis (similar to what occurs in the assessment of pain intensity).

However, a significant aggravation of dyspnea may occur in patients with or without background dyspnea.²⁵ If dyspnea is classified according to its relationship with exercise, then there must be a difference between dyspnea at rest (i.e., without exercise) and dyspnea on greater or lesser effort, as described by the New York Heart Association in its functional classification of heart failure. However, most of the panelists agreed that episodic dyspnea is not equivalent to dyspnea on effort. This is because patients can experience an increase in breathlessness that is unrelated to the amount of effort made. The experts also agreed that dyspnea at rest need not be present to experience episodic dyspnea since a dyspnea crisis can occur in some cases without background dyspnea.

Limitations and strengths

Limitations of this study are similar to those observed in other studies that used the Delphi methodology, primarily the moderate response rate. The response rates for specialties varied substantially, with higher rates for palliative care and medical oncology experts and lower rates for pneumologists and pain management experts. The higher participation rates for palliative care and medical oncology specialists thus meant that their opinions had a greater bearing on the final results. However, it is difficult to know what impact a more balanced participation rate would have had on the findings. Another issue was that the study concluded after two rounds, even though no consensus was reached for four of the statements, as the nominal group decided that performing additional rounds was unlikely to result in consensus.

Regarding the strengths of our study, one was the wide range of specialties of participants as this ensured a more comprehensive perspective on episodic dyspnea. Another was that the fact that most of the statements resulted in a high degree of agreement among the specialists, which increased the strength and validity of the proposed definition. Finally, unlike other studies, we did not define the clinical characteristics of episodic dyspnea, which can only be described in an epidemiological study.

Conclusions

The final consensus definition of episodic dyspnea was as follows “aparición o incremento, en un paciente oncológico, de una dificultad respiratoria transitoria y desproporcionada, ocasionada por un desencadenante conocido (esfuerzo, factores emocinales, ambientales o comorbilidades) o desconocido, con la presencia o no de disnea de reposo” (the appearance or increase, in a cancer patient, of transitory and disproportionate breathing discomfort, caused by an unknown or known trigger (i.e., effort, emotional or environmental factors, or comorbidities), in the presence or absence of dyspnea at rest).

The consensus reached in this study, by better defining its terminology and characteristics, represents an important step toward a better understanding of dyspnea and will allow researchers to conduct high-quality clinical trials that better characterize the clinical characteristics of episodic dyspnea and that identify optimal treatments aimed at improving the quality of life of cancer patients who experience episodic dyspnea.

Footnotes

Acknowledgments

Authors would like to thank all the specialists who participated in the study, the Research Unit of Luzán 5 (Madrid) for design and coordination of the work, and Dr. Fernando Sánchez Barrero and Bradley Londres for their help in preparation of the manuscript. Kyowa Kirin Farmacéutica S.L.U. financed the work without participating in design or data analysis or in writing of the article.

Author Disclosure Statement

No competing financial interests exist.

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