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Address correspondence to: David Hui, MD, MSc, Department of Palliative Care and Rehabilitation Medicine, Unit 1414, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Dyspnea is one of the most distressing symptoms for cancer patients. The role of high-flow oxygen (HFO) and bilevel positive airway pressure (BiPAP) in the palliation of dyspnea has not been well characterized.
Objectives
To determine the feasibility of conducting a randomized trial of HFO and BiPAP in cancer patients and examine the changes in dyspnea, physiologic parameters, and adverse effects with these modalities.
Methods
In this randomized study (ClinicalTrials.gov Identifier: NCT01518140), we assigned hospitalized patients with advanced cancer and persistent dyspnea to either HFO or BiPAP for two hours. We assessed dyspnea with a numeric rating scale (NRS) and modified Borg scale (MBS) before and after the intervention. We also documented vital signs, transcutaneous carbon dioxide, and adverse effects.
Results
Thirty patients were enrolled (1:1 ratio) and 23 (77%) completed the assigned intervention. HFO was associated with improvements in both NRS (mean 1.9; 95% CI 0.4–3.4; P = 0.02) and MBS (mean 2.1; 95% CI 0.6–3.5; P = 0.007). BiPAP also was associated with improvements in NRS (mean 3.2; 95% CI 1.3–5.1; P = 0.004) and MBS (mean 1.5; 95% CI −0.3, 3.2; P = 0.13). There were no significant differences between HFO and BiPAP in dyspnea NRS (P = 0.14) and MBS (P = 0.47). Oxygen saturation improved with HFO (93% vs. 99%; P = 0.003), and respiratory rate had a nonstatistically significant decrease with both interventions (HFO −3, P = 0.11; BiPAP −2, P = 0.11). No significant adverse effects were observed.
Conclusion
HFO and BiPAP alleviated dyspnea, improved physiologic parameters, and were safe. Our results justify larger randomized controlled trials to confirm these findings.
Prognostic factors in advanced cancer patients: evidence-based clinical recommendations—a study by the Steering Committee of the European Association for Palliative Care.
Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind randomised controlled trial.
Many patients experience persistent dyspnea despite these interventions.
High-flow oxygen (HFO) and bilevel positive airway pressure (BiPAP) represent two oxygen delivery modalities that may offer significant advantages compared with traditional low-flow oxygen. HFO delivers up to 40 L/minute of humidified heated oxygen through a nasal cannula. In addition to high-flow oxygenation, it also provides nasopharyngeal washout and positive distending pressure and decreases airway resistance and the metabolic cost of breathing, all of which may alleviate dyspnea.
Although both HFO and BiPAP significantly improve oxygenation, neither has an established role in the palliation of persistent dyspnea in patients with advanced cancer. Evidence to support their efficacy may allow us to improve patients' quality of life. In this Phase II “pick the winner” trial, we determined the feasibility of conducting a randomized trial of HFO and BiPAP in patients with advanced cancer and persistent dyspnea despite standard supplemental oxygen therapy. We also examined the effects of these interventions on the intensity of dyspnea, physiologic changes, and side effects as compared with baseline and with each other.
Methods
Patients
Eligible patients were recruited between February 5, 2007 and April 16, 2011. Hospitalized patients at M.D. Anderson Cancer Center, aged 18 years or older, and with a diagnosis of advanced cancer (i.e., locally advanced, recurrent, or metastatic disease) were eligible if they had an average intensity of dyspnea at rest over the past week ≥3/10 on a numeric rating scale (NRS) despite supplemental oxygen, the dyspnea was judged clinically to be predominantly the result of underlying malignancy, had a life expectancy of more than one week, and were English-speaking. Patients were excluded if they had hemodynamic instability, acute respiratory distress with impending intubation, delirium (Memorial Delirium Assessment Scale >13/30),
Glasgow coma scale score <8/15, contraindications to BiPAP, or non-cancer-related dyspnea requiring supplemental home oxygen before hospitalization. The Institutional Review Board at M.D. Anderson Cancer Center approved this study. All patients provided written informed consent.
Study Design
This randomized, open-label study was initially designed as a crossover trial and later amended to a parallel design with an optional second intervention because four of seven patients who completed BiPAP and two of ten patients who completed HFO experienced significant improvement for greater than one hour after the first intervention.
Patients were screened and approached for this study while admitted at M.D. Anderson Cancer Center. Enrolled patients were assigned by our study coordinator using a computer-generated simple randomization scheme created by our biostatistician in a 1:1 ratio to receive either 1) two hours of HFO followed by a variable washout period and then two hours of BiPAP or 2) two hours of BiPAP followed by a variable washout period and then two hours of HFO. The two-hour duration was chosen because other studies have shown that oxygenation and physiologic parameters improved within 30 minutes to two hours, and we wanted to ensure participants had the opportunity to benefit from the study interventions.
We introduced a variable washout/follow-up period after the first intervention to determine the optimal duration required for patients to return to baseline dyspnea level, which has not been examined previously. Patients were asked about their level of dyspnea every 10 minutes after they had completed the first intervention for up to one hour. They were able to proceed to the second intervention if 1) their dyspnea level was greater than or equal to the baseline dyspnea level minus 1 or 2) their dyspnea level was ≥3/10 after one hour. In this study, we defined “extended relief” as dyspnea ≤2/10 at the end of one hour off study intervention.
Study Interventions
All study interventions were delivered in acute care units outside of the intensive care setting. Our respiratory therapists worked with patients to titrate the device settings to minimize dyspnea while maximizing comfort. Fraction of inspired oxygen (FiO2) was set at 100% throughout the intervention period for both devices.
Patients on HFO received high-flow, heated and humidified oxygen via nasal prongs using the Vapotherm® 2000i Respiratory Therapy Device (Vapotherm, Stevensville, MD). The level of heat (35–37°C) and oxygen flow (10–40 L/minute) were titrated to comfort.
Noninvasive ventilation was delivered using the BiPAP Vision® Ventilatory Support System (Respironics Inc., Murrysville, PA) in pressure support mode (S/T). Patients received BiPAP through a leak-tolerant ResMed Latex Free Hospital Full Face Mask R143-340/5 (ResMed Ltd., Bella Vista, NSW, Australia). The level of support was started at an inspiratory pressure of 8 cm of H2O and expiratory pressure of 5 cm of H2O; then, the settings were titrated, with a target inspiratory pressure between 8 and 18 cm of H2O and target expiratory pressure of 3–10 cm of H2O.
Study Assessments and Endpoints
At baseline, we collected information on patient characteristics (age, sex, cancer diagnosis, comorbidities, and medication use) and the Cancer Dyspnea Scale, a validated 12-item questionnaire that assesses the quality of dyspnea over the past few days.
Each item has a score between 1 and 5, with a total score of up to 60 and subscores for sense of effort, anxiety, and discomfort.
Our primary outcome was retention rate, defined as the percentage of subjects able to complete the first phase of this study. Secondary outcomes included changes in dyspnea, physiologic changes, and adverse effects immediately before starting and stopping each intervention. The intensity of dyspnea “now” was examined using both the NRS and the modified Borg scale (MBS). The NRS is a validated 11-point scale ranging from 0 (“no shortness of breath”) to 10 (“worst possible shortness of breath”).
We used two different measures to assess the convergent validity of dyspnea outcome. The NRS also was used to assess dyspnea every 10 minutes during the washout period.
We also examined physiologic variables such as heart rate, respiratory rate, blood pressure, transcutaneous carbon dioxide level (Sentec Digital Monitoring System TCO2M® Transcutaneous Monitor; Novametrix Medical Systems Inc., Wallingford, CT), and oxygen saturation (Alaris® SpO2 module-8200 series oximeter; Alaris Medical Systems, San Diego, CA) immediately before starting and stopping each intervention. Adverse effects related to the study interventions were assessed using an 11-point NRS, with 0 being absent and 10 denoting worst possible.
After completion of each intervention, we asked patients about their change in dyspnea (better/same/worse) using the Global Symptom Evaluation.
Our primary objective was to determine the feasibility of conducting a randomized trial of HFO and BIPAP based on the retention rate for the first intervention. We hypothesized that more than 65% of the enrolled patients would complete the process of randomization, the first intervention, and the dyspnea NRS measurement.
We initially planned to enroll 25 patients per arm, which was powered to detect an effect size difference between the two study arms of 0.60 SD units, with a two-tailed α of 0.05 and an 80% power assuming 35% attrition. As a result of funding limitations, this study was terminated after 30 patients. Fifteen patients per arm provided us with an 80% power to detect an effect size difference between the two study arms of 0.80 SD units, with a two-tailed α of 0.05.
Statistical Analysis
We summarized the baseline demographics using descriptive statistics, including medians, means, SDs, ranges, interquartile ranges, and frequencies. This study was analyzed as a parallel study. We conducted a before-after analysis for the first intervention using the sign test and the signed-rank test for all continuous variables (e.g., dyspnea, physiologic changes, adverse effects). Intention-to-treat analysis was conducted to compare the change between the two interventions using the Wilcoxon rank sum test for continuous variables, and Fisher's exact test for categorical variables. A two-sided P-value of <0.05 was considered to be statistically significant. The Statistical Analysis System (SAS version 9.2; SAS Institute, Cary, NC) was used for statistical analysis.
Results
Patient Characteristics
The two study arms had similar baseline characteristics (Table 1). Thirteen (43%) patients had lung cancer. All patients had poor performance status. The average intensity of dyspnea was high, despite concurrent use of opioids (93%) and steroids (59%). A vast majority of participants (93%) were on supplemental oxygen at the time of enrollment, with a median of 3 L/minute (interquartile range 2.4–5 L/min) and an average oxygen saturation of 95% (SD 4%).
One patient assigned to BiPAP as the first intervention was erroneously given HFO instead. This individual was analyzed as not having completed in the assigned intervention in our retention rate calculation, received BiPAP in intention-to-treat comparison between the two interventions, and received HFO in the before-and-after comparison.
Study Feasibility
Among the 1933 patients screened, 282 (15%) were eligible and 30 (11%) participated (Fig. 1). Thirteen of 15 (87%) patients assigned to HFO and 10 of 15 (67%) patients assigned to BiPAP completed the study intervention, for a total retention rate of 23 of 30 (77%) and no statistical difference between the two interventions (P = 0.39).
Fig. 2 shows that dyspnea improved with both devices in a before-and-after comparison. Specifically, BiPAP was associated with an average dyspnea improvement of 3.2 by NRS and 1.5 by MBS, whereas HFO was associated with an average improvement of 1.9 by NRS and 2.1 by MBS (Table 2). No significant differences in dyspnea relief were detected between the two devices (Table 2).
Fig. 2Change in dyspnea scores with high-flow oxygen and BiPAP. As compared with baseline, BiPAP was associated with an average improvement in (a) the dyspnea numeric rating scale of 3.2 (P = 0.004) and (b) the modified Borg scale of 1.5 (P = 0.13). High-flow oxygen also was associated with an average improvement in (c) the numeric rating scale of 1.9 (P = 0.02) and (d) the modified Borg scale of 2.1 (P = 0.007). Intention-to-treat analysis revealed no significant differences between the two devices with the dyspnea numeric rating scale (P = 0.32) and the modified Borg scale (P = 0.29). BiPAP = bilevel positive airway pressure.
One patient assigned to receive BiPAP was erroneously started on high-flow oxygen and completed the first intervention. This individual was analyzed as having received BiPAP in the comparison between the two interventions and analyzed as having received high-flow oxygen in the before-and-after comparison.
The Wilcoxon rank sum test was used to compare the change in values between high-flow oxygen and BiPAP.
Dry eyes
1.5 (0.0, 4.0)
0.0 (0.0, 4.0)
0.0 (−1.0, 0.0)
0.63
3.0 (0.0, 4.0)
0.0 (0.0, 3.0)
0.0 (−3.0, 0.0)
0.22
0.10
Eye irritation
1.0 (0.0, 3.0)
0.0 (0.0, 3.0)
0.0 (−1.0, 0.0)
0.22
3.0 (0.0, 4.0)
0.0 (0.0, 1.0)
0.0 (−3.0, 0.0)
0.13
0.47
Feel anxious
2.0 (1.5, 4.0)
2.0 (0.0, 5.0)
0.0 (−1.0, 0.0)
0.69
1.0 (0.0, 5.0)
1.0 (0.0, 2.0)
0.0 (−4.0, 0.0)
0.69
0.12
Mask painful
0.0 (0.0, 2.0)
1.0 (0.0, 3.0)
1.5 (0.0, 3.0)
>0.99
NA
NA
NA
NA
0.30
Moist nose
2.0 (1.5, 2.0)
0.0 (0.0, 2.0)
−1.5 (−2.0, 0.0)
0.13
2.0 (0.0, 5.0)
5.0 (1.0, 7.0)
0.0 (−1.0, 2.0)
0.73
0.32
Prong uncomfortable
2.0 (0.0, 5.0)
0.0 (0.0, 0.0)
−2.5 (−5.0, 0.0)
>0.99
2.0 (0.0, 5.5)
2.0 (0.0, 4.0)
0.0 (−1.0, 2.0)
0.73
0.12
Stomach bloating
1.0 (0.0, 3.0)
0.0 (0.0, 1.0)
−1.0 (−2.0, 0.0)
0.13
3.0 (0.0, 6.0)
2.0 (0.0, 4.0)
−0.5 (−1.0, 0.0)
0.22
0.82
Suffocating
1.5 (0.0, 5.0)
0.0 (0.0, 3.0)
−1.0 (−3.0, 0.0)
0.22
1.5 (0.0, 7.0)
1.5 (0.0, 4.0)
0.0 (−1.0, 0.0)
>0.99
0.58
Trouble drinking
1.5 (0.0, 2.5)
3.0 (0.0, 7.0)
1.0 (−2.0, 5.0)
0.51
0.0 (0.0, 5.0)
0.0 (0.0, 3.0)
0.0 (0.0, 1.0)
>0.99
0.46
Trouble eating
2.5 (1.0, 5.5)
3.0 (0.0, 5.0)
−1.0 (−3.0, 3.0)
0.75
5.0 (0.0, 7.0)
2.0 (0.0, 6.0)
0.0 (−1.0, 0.0)
0.69
0.87
Trouble sleeping
2.0 (0.5, 4.5)
2.0 (0.0, 7.0)
0.0 (−1.0, 3.0)
>0.99
7.0 (6.0, 8.0)
1.0 (0.0, 6.0)
−6.0 (−8.0, 0.0)
0.04
0.02
Trouble talking
2.0 (0.5, 3.5)
5.0 (2.0, 7.0)
0.0 (0.0, 5.0)
0.45
6.0 (2.0, 8.0)
2.0 (0.0, 6.0)
0.0 (−6.0, 2.0)
0.73
0.004
BiPAP = bilevel positive airway pressure; IQR = interquartile range; NA = not applicable.
a One patient assigned to receive BiPAP was erroneously started on high-flow oxygen and completed the first intervention. This individual was analyzed as having received BiPAP in the comparison between the two interventions and analyzed as having received high-flow oxygen in the before-and-after comparison.
b Before measurements were done while patients were on baseline oxygen; after measurements were conducted after two hours of study intervention.
c The signed-rank test was used for before-after comparison.
d The Wilcoxon rank sum test was used to compare the change in values between high-flow oxygen and BiPAP.
The average level of oxygen flow on HFO was 21 L/minute (SD 7). The average BiPAP inspiratory pressure was 9 cm (SD 2.6) of H2O, and the expiratory pressure was set at 5 cm (SD 1) of H2O. We identified a nonstatistically significant decrease in respiratory rate with both HFO and BiPAP (Table 2). BiPAP was associated with a decrease in heart rate. HFO also was associated with a significant decrease in systolic blood pressure and improvement in oxygen saturation (Table 2).
Adverse Effects
We did not identify any significant adverse effects with BiPAP and HFO (Table 2). Patients reported less trouble sleeping (0–10 NRS) while on HFO as compared with BiPAP.
Follow-up Period
Seventeen of 23 (74%) patients completed the follow-up period. Among these 17 patients, two of 10 patients who completed HFO and four of seven patients who completed BiPAP experienced improvement in dyspnea level for more than one hour while on baseline supplemental oxygen (Table 3) and were ineligible to continue to the next intervention.
Table 3Dyspnea Numeric Rating Scores at Baseline and During Washout Period in Six Patients Who Experienced Extended and Significant Improvement in Dyspnea
These patients experienced extended and significant improvement in their dyspnea (i.e., less than baseline dyspnea level minus 1 and ≤2/10 at the end of one hour) and thus did not continue onto the next study intervention.
a These patients experienced extended and significant improvement in their dyspnea (i.e., less than baseline dyspnea level minus 1 and ≤2/10 at the end of one hour) and thus did not continue onto the next study intervention.
A vast majority of patients reported that HFO (10 of 13; 77%) and BiPAP (nine of 10) improved their dyspnea (Fig. 3).
Fig. 3Global Symptom Evaluation for HFO and BiPAP. Patients were asked to provide their overall impression about the change in dyspnea level (“worse,” “about the same,” or “better”) using the Global Symptom Evaluation scale. Consistent with the dyspnea scores, a majority of patients reported that HFO and BiPAP were efficacious in relieving their dyspnea. HFO = high-flow oxygen; BiPAP = bilevel positive airway pressure.
Our study showed that it is feasible to conduct a parallel randomized study of HFO and BiPAP in hospitalized cancer patients with persistent dyspnea. This study also provided preliminary evidence that both devices are associated with significant and extended relief of dyspnea and enhanced physiologic parameters without significant adverse effects. Because this study was unblinded, placebo effect, clinician effect, and obsequiousness bias may have contributed to the observed improvement in the patient-reported outcomes. Our study justifies the need for larger, blinded, randomized, controlled trials to confirm the efficacy of these interventions.
We were able to enroll acutely ill hospitalized patients with advanced cancer into this clinical trial and assess a multitude of patient-reported outcomes. This is a technically challenging clinical trial for multiple reasons. First, our patients had a poor performance status and were often in severe distress. This is in contrast to a majority of other dyspnea studies that enrolled ambulatory patients who are generally more functional and able to engage in studies of longer duration.
Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind randomised controlled trial.
Third, our study was interrupted by clinical investigations and sometimes abrupt discharges. Fourth, not all patients were able to tolerate BiPAP. Because of the difficulty in enrollment and retention, a majority of dyspnea clinical trials have small sample sizes.
we hypothesize that HFO and BiPAP could offer symptomatic benefit to a wider patient population because of their high oxygen delivery and varied mechanisms of action. Thus, our study did not specifically exclude non-hypoxemic patients. Rather, all patients had significant dyspnea despite having tried supplemental oxygen and a vast majority were already on opioids and steroids.
To our knowledge, this study is the first randomized trial to examine the role of HFO for dyspnea in patients with advanced cancer. This novel device is postulated to relieve dyspnea by 1) maintaining a high level of PaO2, 2) improving ventilation by nasopharyngeal washout, 3) decreasing the work of breathing, and 4) increasing airway compliance and positive distending pressure.
However, the effect of HFO on dyspnea in cancer patients has not been examined. Only one retrospective case series reported the usage pattern of HFO in cancer patients.
In our study, HFO offered significant improvement in dyspnea assessed by the NRS, MBS, and Global Symptom Evaluation. This was accompanied by an improvement in oxygen saturation, a nonsignificant decrease in respiratory rate, and no detectable adverse effects. Interestingly, a majority of patients in our study did not require the maximal oxygen flow. Further studies are needed to confirm our findings and determine the optimal duration, settings, and population for this device.
BiPAP represents another attractive option for relief of dyspnea.
We found significant improvement in the dyspnea level after two hours of BiPAP. Our results are consistent with the only other study examining dyspnea in cancer patients, in which the MBS decreased from 5.5 to 2.3 after one hour of BiPAP.
BiPAP not only assists ventilation but also corrects hypoventilation, increases the inspiratory flow rate, resets the central respiratory drive, and reduces the work of respiratory muscles.
This last mechanism is of particular interest for patients with advanced cancer who have dyspnea secondary to respiratory muscle weakness.
We were pleasantly surprised by the extended relief of dyspnea during the follow-up period for some patients. We found that many patients continued to report dyspnea relief after discontinuation of over one hour. This may be explained by the fact that BiPAP augments respiratory muscles, giving them time to rest. Another plausible explanation is that dramatic improvement in SaO2 has long-lasting effects on dyspnea. However, we could not rule out trial or placebo effect as contributing factors. If our findings were confirmed, BiPAP and HFO may be highly effective even if used intermittently. Further studies are needed to test this hypothesis, assess respiratory muscle function, and examine the optimal duration for use.
Importantly, only 30 of 282 eligible patients enrolled in the study, raising concerns about selection bias and generalizability. Many patients declined participation because they were not interested or in too much distress (Fig. 1). Specifically, BiPAP has multiple exclusion criteria and was not tolerated by some patients because of claustrophobia, anxiety, or distress. However, individuals who have persistent dyspnea despite standard treatments and are able to tolerate this device may derive significant symptom benefit. Further studies are needed to examine if newer interfaces (i.e., mouthpieces) and delivery devices designed for home use could increase BiPAP's applicability.
Our study has several limitations. First, this was an unblinded study. Future studies may compare different levels of FiO2 in a blinded design. Second, we had to screen a large number of patients to find eligible and willing participants. Multicenter studies may be helpful to maximize accrual. Third, we compared two active interventions and did not incorporate a control group. Non-rebreather mask delivering oxygen may be considered as a comparison group for future design. Fourth, the extended and unexpected improvement in dyspnea made it challenging to conduct a crossover study design. Fifth, we had to close the study early because of funding limitations, resulting in a reduction in statistical power. Even with the reduced sample size, we were able to demonstrate study feasibility and an improvement in dyspnea scores. Sixth, we have conducted multiple statistical comparisons. Although these were all preplanned secondary endpoints, readers should interpret the significance of the study findings with caution. Seventh, we did not conduct baseline arterial blood gas nor measure the oxygen saturation while on room air. Future studies would need to collect these baseline data routinely. Finally, this study was conducted in a single academic institution with a unique patient population and health professional team. Further studies are needed to determine the efficacy of these devices in other settings.
Based on the findings from this study, we propose that HFO and BiPAP be examined separately in the future because of their differential eligibility criteria, patient tolerance, and retention. We are in the process of developing a double-blind, randomized, controlled trial comparing HFO and high-flow air over multiple days in non-hypoxemic ambulatory patients with refractory dyspnea (i.e., dyspnea despite regular opioids). We also propose a separate double-blind, randomized, controlled trial examining as needed use of BiPAP compared with oxygen delivered with minimal positive end-expiratory pressure in hypoxemic cancer patients, with particular attention paid to the duration of dyspnea relief while off BiPAP. Importantly, future studies need to be adequately powered to examine dyspnea as the primary outcome, which means that multicenter involvement is essential.
Conclusions
We completed a randomized trial of HFO and BiPAP in hospitalized cancer patients with persistent dyspnea. Patients reported that these devices were safe and efficacious in relieving dyspnea. Our study supports the need for larger, randomized, controlled clinical trials to confirm the therapeutic role of these novel devices.
Disclosures and Acknowledgments
Dr. Bruera is supported in part by National Institutes of Health grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01. Dr. Hui is supported in part by an institutional startup grant (#18075582). This study also was supported by the M.D. Anderson Cancer Center Support Grant (CA 016672). The funding sources were not involved in the conduct of the study or development of the submission. The authors declare no conflicts of interest.
References
Tishelman C.
Petersson L.M.
Degner L.F.
Sprangers M.A.
Symptom prevalence, intensity, and distress in patients with inoperable lung cancer in relation to time of death.
Prognostic factors in advanced cancer patients: evidence-based clinical recommendations—a study by the Steering Committee of the European Association for Palliative Care.
Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind randomised controlled trial.
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