Relief of Incident Dyspnea in Palliative Cancer Patients: A Pilot, Randomized, Controlled Trial Comparing Nebulized Hydromorphone, Systemic Hydromorphone, and Nebulized Saline
Article Outline
Abstract
Acute episodic breathlessness in patients receiving palliative care is a distressing symptom with little evidence-base to inform management. This pilot, double-blind, controlled, crossover study compared the effects of nebulized hydromorphone, systemic hydromorphone and nebulized saline for the relief of episodic breathlessness in advanced cancer patients. On three occasions of acute breathlessness, patients randomly received either nebulized hydromorphone, a systemic breakthrough dose of hydromorphone or nebulized saline together with a blinding agent. Breathlessness was scored before and 10, 20, 30, and 60 minutes post-treatment completion using a 100 mm visual analog scale. Twenty patients completed the trial. Ratings did not differ significantly across pretest treatments. Change in ratings from pretest to 10 minutes after completion of nebulization (about 20 minutes after administration of systemic hydromorphone) indicated that each of the treatments resulted in statistically significant improvements in breathlessness, with no significant differences between treatments. Over time, breathlessness decreased significantly for all treatments, with no significant differences between treatments. Only nebulized hydromorphone produced a rapid improvement in breathlessness that reached a magnitude considered to be clinically important. Interpretation of these results is considered in relation to our definition of clinical significance, the dose of hydromorphone used and the possibility of a placebo effect. This study can serve to inform the design of future trials to investigate the management of incident breathlessness.
Key Words: Incident breathlessness, palliative cancer patients, nebulized opioids
Introduction
Acute episodic, or incident, breathlessness—either spontaneous or associated with minor exertion—is a devastating and common symptom for patients with advanced cancer.1, 2 Ideally, such breathlessness requires fast-acting interventions to avoid consequent feelings of impending doom, fear and panic attacks that frequently result in admissions to inpatient units for people who would otherwise prefer to remain at home. There is evidence that systemic opioids provide a small, though statistically significant, overall benefit for the symptomatic relief of background intractable dyspnea.3, 4 Opioids, nebulized with saline, also have been reported to be of value for breakthrough breathlessness, though there is little high-level evidence to support their use in the management of incident dyspnea.
Theoretically, the use of nebulized opioids for the relief of incident dyspnea is advantageous. The presence of opioid receptors in the respiratory tract, especially within the alveolar walls and lining the smooth muscle within the trachea, offers a possible local mechanism for the rapid relief of dyspnea.5, 6 Nebulized opioids have low systemic absorption, thus decreasing the likelihood of unwanted side effects, such as nausea, cognitive impairment, and constipation.7, 8
Based on case studies and retrospective chart reviews, clinicians have reported that some patients get dramatic relief from breathlessness with the use of nebulized opioids. Nonetheless, clinicians have difficulty defining the characteristics of that subpopulation and there is marked variability in the dose and type of opioid recommended.9, 10, 11, 12, 13 Results from laboratory-based trials concerning the efficacy of nebulized opioids for improving exercise function in dyspneic patients, usually with chronic obstructive airway disease, or for the improvement of background dyspnea at rest, are scant and inconclusive.14, 15, 16 Further, it is difficult to determine whether such findings can be generalized to a population that is rapidly deteriorating and has little capability for exercise. A Cochrane review, based on a meta-analysis with only three randomized controlled trials comparing nebulized morphine against placebo, concluded there is no evidence to support the use of nebulized opioids for the treatment of breathlessness.3 Given the small number of studies, it is probably premature to assume that this absence of evidence equates to evidence of no treatment effect.
A recent study with advanced cancer patients, which postdates the review, indicated that both nebulized and subcutaneous morphine significantly decreased background dyspnea; these results were not compared against a saline treatment arm.17 The authors of this study, and others, have called for more trials to clarify any possible role for nebulized opioids in the treatment of dyspnea.18, 19 To be relevant to palliative clinical practice, such trials need to be based firmly within the clinical domain and to concentrate on the relief of the perception of breathlessness.
This pilot study compares the efficacy of a nebulized opioid, a systemic opioid and nebulized saline to provide rapid relief for incident dyspnea in patients with advanced cancer. Hydromorphone was the opioid chosen because it has been reported to have a faster onset of analgesic action and to be somewhat shorter acting compared with equivalent doses of morphine.20, 21 The study was designed to reflect a real clinical scenario common to many patients with advanced cancer, that is, patients who are opioid tolerant, with a degree of irreversible dyspnea at rest and who become so distressed with incident, or breakthrough, breathlessness that they request pharmacological interventions.
Methods
Approval for this study was obtained from an institutional Human Research Ethics Committee and all participants signed informed consents.
Study Design
The pilot was a double-blind, randomized, crossover, controlled trial. On three different occasions, when patients requested treatment for incident breathlessness, they randomly received one of the following: 5
mg of nebulized hydromorphone (NH), a systemic breakthrough dose of hydromorphone (SH), or 3mL of nebulized saline (NS), plus an agent to maintain double blinding. If a patient felt that a treatment was ineffective, they could ask for additional pharmaceutical interventions. Cointerventions were recorded. Patients were required to score their breathlessness at the following times: pretreatment and 10, 20, 30, and 60 minutes post-treatment completion. The primary outcome of interest was evidence of an improvement in rated breathlessness at 10 minutes post-treatment completion (rapid improvement). Other outcomes of interest included evidence of any differences between treatments in rapid improvement, evidence of possible ongoing treatment effects over time as well as any differences between these treatments plus any corresponding changes in objective indicators of respiratory status.
Sample
Inpatient and community-based patients from the Mt. Olivet Hospice Services, Brisbane, were recruited over a period of two years. To be eligible, patients needed to be able to provide informed consent in English, to be over 18 years of age, to have a primary diagnosis of cancer with a clinical prognosis of at least seven days and to obtain Mini-Mental State Examination scores of at least 24 out of 30, assessed 48 hourly. They needed to be experiencing incident dyspnea with no reversible components on a background of either irreversible dyspnea at rest or development of dyspnea when they spoke, and to be using a stable regular dose of an opioid.
Patients were given a test dose of 2mg of hydromorphone nebulized in 2mL of saline, administered under medical supervision. The purposes of the test dose were to ensure that the patient would tolerate the nebulizer and not experience bronchospasm. No patient was excluded after the test dose.
Protocol
After obtaining informed consent, a dyspnea history was taken. Once a day, between the hours of 0900 and 1700, when the patient requested treatment for incident breathlessness, they received one of the three following treatments:mg of hydromorphone (equivalent to 25 mg morphine) made up to a volume of 3mL with saline, immediately preceded by a blinding treatment of a volume of sterilized water (equivalent to that of the volume of the usual breakthrough pain medication) administered by the same route used for breakthroughs (oral or subcutaneous).mL of nebulized saline. For safety reasons, it was decided to use each patient's usual breakthrough dose hydromorphone equivalent because a systemic dose of 5mg of hydromorphone was often higher than the patient's usual equivalent breakthrough.mL of saline, immediately preceded by a blinding treatment of a systemic dose of sterilized water given by the usual route of administration for the patient's breakthrough opioid.
Treatment order was randomized using a random number generator. To ensure double blinding, treatments composed of medications (commercially obtained) and blinding agents were prepared by a nonclinical research doctor and checked with a nonclinical nurse, neither of whom was involved with the care of the patient. Pre-prepared and randomized treatments were administered subsequently by a research nurse, who was unaware of the order sequence and who was not involved with the clinical care of the patient. The nonclinical research doctor held a master plan of the randomizations so that treatments could be unblinded in an emergency. There were no such emergencies over the course of the study.
All nebulizations required between eight and nine minutes to deliver, using a facemask and a Ventalair Forte II Nebulizer pump (Allersearch, Granville, Australia). If a patient was receiving continuous oxygen, this was continued during treatments. Oral medications were prepared in 20mL of orange juice to disguise taste cues. Attempts were made to deliver treatments at the same time for three consecutive days, though actual times were determined by patients’ requests for treatment. Most requests were triggered by patient exertion, for example, after walking, eating, or washing.
With each treatment, four variables were measured: perceived intensity of breathlessness, pulse rate, peripheral oxygen saturation, and respiratory rate. Measurement occurred immediately prior to a treatment and 10, 20, 30, and 60 minutes post-treatment completion. Post-treatment completion times equate to 10, 20, 30, and 60 minutes after finishing a nebulization but to 18–19, 28–29, 38—39, and 68–69 minutes after oral or subcutaneous treatment administration. The patient scored their breathlessness using a vertical 100 mm visual analog scale (VAS). The scale was anchored by two endpoints. The lower end of the scale (0) corresponded to “no breathlessness” and the upper end (10) to “worst possible breathlessness.” To stabilize ratings, each previous rating was made available to the patient. The other three variables were assessed by the research nurse, after the patient scored their breathlessness. Pulse rate and peripheral oxygen saturation were measured using a pulse oximeter. Respiratory rate was estimated by the research nurse counting total respirations over two 30-second intervals immediately after the pulse oximeter was removed.
After completion of the trial, patients were asked to nominate which treatment, if any, they felt was most effective for them.
Statistical Analysis
Primary outcome of interest was evidence of a rapid improvement in rated breathlessness at 10 minutes after completion of the nebulization. Based on the review of Jennings et al.22 and the findings of Abernethy et al.,4 we considered that a one centimeter decrease in rated breathlessness on the VAS would represent a clinically significant improvement in breathlessness. A one centimeter decrease on a 100 mm VAS represents at least a 10% improvement in the sensation of breathlessness, even for a patient who was experiencing the “worst possible breathlessness.”
Power analysis was based on the assumption that the standard deviation of change scores was 1.5, meaning that for the effect deemed clinically significant (1cm), the standardized mean difference, d, would be 0.67. This scale-free measure of effect size is the basis of power analysis,23 with rules of thumb suggesting that in the absence of objective criteria, 0.2 standard deviations difference between means is a small effect size, 0.5 is a medium effect size, and 0.8 is a large effect size.24 To detect the assumed medium–large effect, we calculated that for power of 80% at the 5% significance level in a paired t-test, a sample size of 20 was required to detect a change of one centimeter on the scale. Recruitment was continued until 20 patients had completed the trial. Analysis on an intention-to-treat basis was not considered feasible with such a small sample size. In this population, dropout rates are relatively high due to declining health. Continuing changes across time were assessed with contrasts for linear and quadratic trend.
Results
Figure 1 illustrates patient progress through the study. Twenty patients completed the study; reasons for study withdrawal included discharge from the service before any treatment (1), rapid deterioration in condition so that carers considered it burdensome for the patient to continue (2), and reduction in Mini-Mental State Examination score (2). Withdrawal was not systematically related to treatment or order of treatments.
Fig. 1
Flow of patients through the study. NH-nebulized hydromorphone; SH-systemic hydromorphone; NS-nebulized saline.
All patients had either primary lung disease or secondary lung pathology including lung metastases, pleural effusions, or pulmonary emboli. Only two patients reported a history of chronic obstructive pulmonary disease as a comorbidity. Table 1 summarizes characteristics of patients and lists frequencies of primary diagnoses. Nineteen patients received their breakthrough analgesic opioid doses orally. The range of breakthrough oral doses of opioid, expressed as hydromorphone equivalents, was 0.2–11mg of hydromorphone. One patient was receiving breakthrough analgesia subcutaneously, at a dose equivalent to 2mg of hydromorphone.
Table 1. Characteristics of Patients (n=20) Who Completed the Trial
| Characteristic | n |
|---|---|
| Sex (male/female) | 11/9 |
| Average age (range) | 69 (48–83) |
| Environment of care (inpatient/home) | 10/10 |
| Number of days to death post-trial—mean/ median (range) | 54/40 (2–198) |
| Number of patients already receiving nebulized medications (not narcotics) | 8 |
| Primary diagnosis | |
| Lung cancer | 14 |
| Breast cancer | 2 |
| Renal cancer | 2 |
| Mesothelioma | 1 |
| Prostate cancer | 1 |
| Number of patients using continuous oxygen | 13 |
| Route of administration for breakthrough medications (oral/subcutaneous) | 19/1 |
| Baseline daily opioid dose expressed as oral morphine equivalent in mg—mean/median (range) | 82/50 (10–540) |
Rapid Improvement in Rated Breathlessness
The primary outcome of interest was evidence of rapid improvement in rated breathlessness, measured at 10 minutes postnebulization completion, which was approximately 20 minutes after administration of systemic or oral opioids. Means at pretreatment, 10 minutes post-treatment, and mean change in the VAS scores are shown in Table 2. Repeated measures analysis of variance indicated that ratings of breathlessness did not differ significantly across treatments at pretest, F(2,38)=0.32, P=0.73. Change in scores from pretest to 10 minutes post-treatment completion was analyzed using paired t-tests. Improvement in breathlessness was statistically significant at 10 minutes postintervention completion in each of the treatment conditions. Only in the nebulized hydromorphone condition, however, did the results exceed the level (1cm) considered to be clinically significant at this time point. As seen in the standardized effect sizes reported in Table 2, the treatment outcomes ranged from medium (saline) to large (nebulized hydromorphone) effects. There was no evidence of period or sequence effects.
Table 2. Mean VAS Scores of Breathlessness Before and 10Minutes After Completion of Nebulization
| Treatment | Pretreatment; Mean (SD) | Post-treatment; Mean (SD) | Improvement; Mean (SD) | 95% CI | d |
|---|---|---|---|---|---|
| Nebulized hydromorphone | 5.29 (1.92) | 4.25 (2.01) | 1.04a (1.38) | 0.39–1.68 | 0.75 |
| Systemic hydromorphone | 5.28 (2.01) | 4.34 (1.87) | 0.94b (1.49) | 0.24–1.63 | 0.63 |
| Nebulized saline | 5.59 (2.34) | 4.81 (1.78) | 0.78b (1.54) | 0.05–1.50 | 0.50 |
aP |
bP |
Differences Between Treatments in Rapid Improvement
To compare for differences between treatments in improvement scores, paired t-tests were carried out comparing the change scores across treatments. There were no significant differences between treatments (NH vs. SH: t19=0.45, 95% confidence interval (CI) (−0.37, 0.57); NH vs. NS: t19=0.70, 95% CI (−0.51, 1.03); SH vs. NS: t19=0.55, 95% CI (−0.45, 0.77), all P>0.4). As seen in Table 2, there is considerable overlap in the CIs for the mean change scores.
Effects Over Time
A secondary outcome of interest was whether any improvements in breathlessness scores would be maintained or improved over time. This was tested by examining linear and quadratic trends across post-treatment occasions of assessment (10, 20, 30, and 60 minutes post-treatment completion). Decreasing linear trend would indicate continued reduction in rated breathlessness, and quadratic trend in conjunction with linear trend would indicate a change in rate of improvement. Mean VAS scores across all time points are shown in Fig. 2. Breathlessness scores decreased linearly from 10 to 60 minutes post-treatment completion and the contrast for linear trend was statistically significant, F(1,19)=10.04, P=0.005. There were no significant differences between treatments in the slope of the linear trend, nor was there evidence of a quadratic trend. Inspection of the lines in Fig. 2 reveals that the slopes of the lines are virtually parallel across conditions, and by 20 minutes postnebulization, the difference from baseline was greater than the level deemed clinically significant (1cm) in all conditions.
Fig. 2
Mean breathlessness with treatments: NH
=nebulized hydromorphone, SH=systemic hydromorphone, NS=nebulized saline.
No cointerventions were requested during the test period for any of the treatments. One patient requested a subcutaneous breakthrough at the completion (60 minutes) of the nebulized hydromorphone arm.
Six patients nominated nebulized hydromorphone as their treatment of choice, six chose systemic hydromorphone, six chose nebulized saline, and two were undecided.
Physiological Indices
Respiratory rate, pulse rate, and peripheral oxygen saturation were recorded at each time interval to investigate whether changes in subjective ratings of breathlessness were related to objective indicators of respiratory status. Mean levels for each index across treatments and times are shown in Fig. 3. Improvements in status would be reflected in a decrease in respiratory rate, pulse rate, and/or an increase in peripheral oxygen saturation. The data were initially analyzed following the same procedures applied for the dyspnea ratings.
Fig. 3
(a) Respiratory rate, (b) pulse rate, (c) peripheral oxygen saturation. Objective indicators of respiratory status across treatments and time periods. NH
=nebulized hydromorphone, SH=systemic hydromorphone, NS=nebulized saline.
There were no significant differences across treatments between means at baseline on any of the indices.
In terms of rapid change from baseline to 10minutes after treatment completion, there was a significant reduction in respiratory rate in each of the treatment conditions (see 95% CI in Table 3, and Fig. 3a), but no significant differences between treatments. Pulse rate decreased significantly with NH, but this reduction did not differ significantly from the nonsignificant SH and NS treatment conditions (Fig. 3b). Peripheral oxygen saturation increased significantly in the NS condition, but this increase did not differ significantly from the nonsignificant NH and SH treatment conditions (Fig. 3c).
Table 3. Objective Indicators of Respiratory Status at Baseline and 10Minutes Post-Treatment Completion, with Associated 95% CI for the Difference Between Baseline and 10 Minutes Post-Treatment Completion for Nebulized Hydromorphone, Systemic Hydromorphone, and Nebulized Saline
| Treatment | Respiratory Rate | Pulse Rate | Peripheral Oxygen Saturation | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline | 10 min | 95% CI | Baseline | 10 min | 95% CI | Baseline | 10 min | 95% CI | |
| NH | 25.9 | 22.2 | 1.34, 6.06a | 101.6 | 90.8 | 0.72, 20.78a | 89.8 | 91.7 | −5.48, 1.68 |
| SH | 26.4 | 21.7 | 1.86, 7.54a | 103.7 | 98.0 | −0.07, 11.47 | 91.4 | 91.9 | −4.01, 3.01 |
| NS | 26.1 | 21.9 | 2.08, 6.32a | 107.1 | 97.6 | −1.72, 20.62 | 89.7 | 91.8 | −4.10, −0.10a |
aP |
Continuing improvement in respiratory rate was found, with a significant linear trend from 10 to 60 minutes averaged over treatments, F(1,19)=14.60, P<0.05, and no significant difference between treatments. There was no evidence of systematic continuing change in pulse rate or peripheral oxygen saturation, or of quadratic effects over time.
Discussion
The clinical relevance of this pilot study is that it is the first adequately powered, randomized controlled trial targeting the debilitating symptom of incident, or breakthrough, dyspnea in cancer patients who are opioid tolerant, receiving palliative care, and experience a degree of background dyspnea. The primary outcome of interest was evidence of a rapid improvement in rated breathlessness. Results indicate that nebulized hydromorphone, systemic hydromorphone, and nebulized saline all produce rapid and statistically significant improvements in breathlessness, with only nebulized hydromorphone producing an improvement large enough to be considered clinically important. Other outcomes of interest included evidence of possible ongoing treatment effects over time, as well as any differences between these treatments. There were no statistically significant differences between treatments and continuing benefits from all treatments were observed. As they stand, these data add support for the findings of the Cochrane review that “patients may benefit from the use of nebulized opioids but they probably do not receive additional benefit from nebulized morphine over nebulized saline.”
As mentioned, only nebulized hydromorphone provided a rapid improvement in dyspnea rating that was both statistically significant and clinically important. There is ongoing discussion regarding the quantitative and qualitative aspects of clinical significance, or the minimal clinically important difference, in dyspnea ratings.25, 26 Following the lead of other researchers,4, 22 we defined clinical significance as an improvement of one centimeter or greater on the VAS. This criterion is arbitrary to the extent that there is no gold standard for how strong an effect might be considered clinically significant. However, the guidelines for interpreting the size of a standardized mean difference in the absence of more objective criteria offer support for the prespecified one centimeter criterion, corresponding to an effect that is in the medium to large range given the standard deviation of change scores.
Nonetheless, the differences between treatments, whether considered in terms of standardized mean differences, mean differences, or overlap in CIs, are so small as to suggest that there may be no important clinical differences between the treatments. Coupled with patients’ lack of clear preference for any one of the treatments, this further suggests that statistical power to detect differences between treatments would require sample sizes that are not achievable in practice with this vulnerable population. Clinical importance may need to be defined according to the individual patient's perception of relief. It may be appropriate to use “N of one” trials for dyspneic cancer patients experiencing breakthrough episodes of breathlessness, comparing individuals’ responses to nebulized and systemic opioids and nebulized saline alone.
There is the possibility that if the treatments are differentially effective in the direction suggested by the results, such differences may become more apparent with higher nebulized drug dosages. Indeed, in a previous study using nebulized morphine, Davis et al.27 observed that there was a trend toward greater improvement in breathlessness with higher doses of morphine. To tease out possible differences in treatments, nebulized hydromorphone dose ranging studies, particularly using higher doses, merit investigation.
Air-jet nebulization of aqueous solutions can be an inefficient way to deliver medications.28 Drug becomes absorbed onto equipment and the nebulizer used affects inhaled particle size and subsequent trajectory within the airway.29 It has been estimated that up to 50% of drug can be lost on expiration whereas some drug may be swallowed or deposited in the pharynx.30, 31 In this study, no attempt was made to determine the amount of hydromorphone deposited in the lower airway.
The findings that systemic (either oral or subcutaneous) breakthrough analgesic doses of hydromorphone provide rapid and significant relief for incident breathlessness are consistent with those reported elsewhere for the effects of opioids on baseline intractable dyspnea. In this study, the total time between the delivery of the systemic treatment dose and the first post-treatment completion rating of breathlessness was about 20 minutes, which is within the time range for the onset of analgesic effects of oral hydromorphone.20, 21 No attempt was made to measure or compare possible side effect differences, for example, drowsiness or nausea, between systemic and nebulized hydromorphone because it was expected that, as none of the patients were opioid naive, a larger sample size would be required to detect any significant differences.
The nebulized saline results from this pilot study are noteworthy. Davis et al.27 reported no significant effect from nebulized saline on ratings of resting breathlessness for patients with advanced cancer. Consequently, in the present study, a nebulized saline treatment was included to ensure blinding and to act as a comparator, controlling for nonspecific factors such as possible distraction effects due to activity associated with administering a nebulization. The results suggest, however, that nebulized saline provides significant relief of incident breathlessness, and that the effect is ongoing and does not differ significantly from the effects of opioid treatments. Such a finding allows for the possibility that nebulized saline has true therapeutic equivalence to nebulized and systemic hydromorphone for the relief of incident dyspnea. Interestingly, another randomized controlled trial, predominantly using patients with advanced chronic obstructive pulmonary disease, reported significant symptomatic relief of resting dyspnea with nebulized saline.32 Such results are encouraging, as there is little or no morbidity associated with the use of nebulized saline and it is a convenient intervention that may easily be used in the home setting. Further investigations into the use of nebulized saline for the relief of the sensation of dyspnea, both breakthrough and background, are justified.
In General, the relationship between intensity of subjective dyspnea and objective measures of respiratory function is poor. In this study, respiratory rates showed significant and continuing improvements over time, with no significant differences between treatments. This result may reflect either spontaneous recovery or a treatment effect, perhaps due to patients’ diminishing anxiety levels consequent to receiving an intervention. There was no evidence of systematic continuing changes in the other objective parameters. It is the opinion of the authors that the significant decrease in pulse rate with nebulized hydromorphone and the increased peripheral oxygen saturation with nebulized saline at ten minutes post-treatments likely reflect Type 1 errors as these patients had a background of irreversible baseline breathlessness.
There are various potential confounders to this study that may have impacted on the results. First, there is the possibility that elements of spontaneous recovery or an unknown placebo effect contributed to the decreasing breathlessness scores. The patient's need for symptom control is paramount in palliative care, and as the patients themselves requested an intervention, ethically it is not conscionable to explore this possibility further. Second, a therapeutic effect due to the presence of the research nurse cannot be excluded. The perception of breathlessness incorporates important emotional domains. The presence of the research nurse may have reassured patients and decreased their anxieties and fears, allowing them to cope more successfully with their dyspnea. A study in which patients self-administer their own medications would help quantify this possibility. It is reasonable to assume, however, that these possible confounders would have been equally represented across all treatments.
Overall, a strength, and simultaneous limitation, of this pilot study is its pragmatic attempt to apply a scientifically rigorous methodology to investigate the complex clinical reality of incident, or breakthrough, breathlessness. Episodes of breakthrough dyspnea may not represent the most reliable experimental model for treatment studies, but such episodes are so clinically distressing that they demand experimental attention. Although the findings reported in this study cannot be used to generate definite clinical recommendations, they may be used to inform the design of future trials.
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This study was funded by the Sisters of Charity, Mt. Olivet Community Hospice Services, Brisbane, Queensland, Australia. The authors have no conflicts of interest to declare.
PII: S0885-3924(08)00066-3
doi:10.1016/j.jpainsymman.2007.08.016
© 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
