a randomized, double-blind, crossover trial of the effect of oxygen on dyspnea in patients with...

Vol. 32 No. 6 December 2006 Journal of Pain and Symptom Management 541

Original Article

A Randomized, Double-Blind, Crossover Trialof the Effect of Oxygen on Dyspneain Patients with Advanced CancerJennifer Philip, MBBS, MMed, Dip Pall Med, FAChPM, Michelle Gold, MBBS,FRACP, FAChPM, Dip Pall Med, Alvin Milner, BSc, PhD, Juliana Di Iulio, BSc, PhD,Belinda Miller, MBBS, PhD, FRACP, and Odette Spruyt, MBChB, Dip Obs, FRACP,FRAChPMPalliative Care Service (J.P., M.G.) and AIRMed (B.M.), The Alfred Hospital, Melbourne; and Center

for Biostatistics & Clinical Trials (A.M., J.D.I.) and Department of Pain and Palliative Care (O.S.),

Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia

AbstractDyspnea is a common symptom in palliative care. Despite this, there is uncertainty regardingthe role of oxygen to treat the symptom in patients with advanced illness. This randomized,double-blind, crossover trial examined the effect of oxygen versus air on the relief of dyspneain patients with advanced cancer. Following the blinded administration of air and oxygenvia nasal prongs, 51 patients rated dyspnea and indicated preferences for the blindedtreatments. On average, patients improved symptomatically with both air and oxygen, andthere were no significant differences between the treatments. The subgroup of 17 hypoxicpatients overall did not demonstrate a significant difference between air and oxygen, despitehaving improved oxygen saturations when administered oxygen. Hypoxia was corrected in13 of 17 patients using the treatment dose of 4 L/min of oxygen. The experience of dyspnea isa complex, multifactorial phenomenon, with oxygen tension not correlating with thesubjective experience. The administration of either air or oxygen via nasal prongs on averageconfers improvement of the symptom. J Pain Symptom Manage 2006;32:541e550.� 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Key WordsDyspnea, cancer, oxygen, palliative care

This research was made possible through grantsfrom the Australian New Zealand Society of Pallia-tive Medicine and The Bethlehem Griffiths Re-search Foundation. The authors have no conflictsof interest to declare.

Address reprint requests to: Jennifer Philip, MBBS, Pal-liative Care Service, The Alfred Hospital, Commer-cial Road, Melbourne 3004, Victoria, Australia.E-mail: [email protected]

Accepted for publication: June 24, 2006.

� 2006 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

IntroductionDyspnea is a common symptom in patients

with advanced cancer, rated as a moderate orsevere problem in 46% of those admitted toa palliative care program, and affecting 70%of hospice inpatients.1,2 At the Peter MacCal-lum Cancer Center, the incidence of dyspneaamong all patients with a cancer diagnosis was33%.3 The presence of dyspnea indicatesa poor prognosis for patients with pancreatic

0885-3924/06/$esee front matterdoi:10.1016/j.jpainsymman.2006.06.009

mailto:[email protected]

542 Vol. 32 No. 6 December 2006Philip et al.

or lung cancer.4,5 In one study, this prognosticassociation was so strong for some patientswith a cancer diagnosis presenting to the emer-gency department of a North American center,the presence of dyspnea may have heraldeda shift in treatment focus from acute interven-tion to palliative measures.6

Dyspnea is one of the most distressing symp-toms experienced by patients. It is a combinationof a ‘‘sensation’’ (neural activation resulting fromstimulation of a receptor) and a ‘‘perception’’(reaction of the individual to that sensation).7

A consensus statement of the American ThoracicSociety has defined dyspnea as ‘‘a term used tocharacterize a subjective experience of breathingdiscomfort that is comprised of qualitatively dis-tinct sensations that vary in intensity. The experi-ence derives from interactions among multiplephysiological, psychological, social and environ-mental factors, and may induce secondary phys-iological and behavioral responses.’’7

The development of dyspnea is a complexphenomenon and is related to activation ofsensory systems involved with respiration. Themain mechanisms involve feedback from che-moreceptors, mechanoreceptors, and vagal af-ferents in the lung and chest wall, whichproject to higher brain centers to provide a di-rect review of the chemical state of the bodyand the mechanical state of the lungs. Efferentcopies of brainstem respiratory motor outputalso appear to be transmitted to higher braincenters and result in a conscious awarenessof the motor command.8 Behavioral style andemotional state influence the perception ofthe stimulus. These factors all play a role inshaping the perception of dyspnea, and, there-fore, this symptom, like pain, should be under-stood to be a multidimensional experience.

The management of dyspnea involves atten-tion to the etiology of the symptom and wherepossible, correction of causative factors. Manage-ment of the symptom itself may include behav-ioral approaches, pharmacological agents, andthe use of airflow and oxygen. A number of smallstudies have demonstrated the benefit of behav-ioral techniques,9,10 while the body of literaturesupporting pharmacological management, prin-cipally opioids, is well established.11e17

Oxygen plays an important role in the man-agement of the hypoxic patient with chronicobstructive pulmonary disease (COPD), beingassociated with improvements in survival,

quality of life, and neuropsychologic func-tion.18 There have been few studies addressingthe role of oxygen in hypoxic and normoxicdyspneic patients with advanced cancer.Bruera et al. conducted a randomized, dou-ble-blind, crossover trial in 14 patients with ad-vanced cancer and hypoxemia, defined asoxygen saturation of less than 90% on pulseoximetry.19 These patients received oxygen orair at 5 L/min by mask and then were twicecrossed over to the other treatment. The aver-age dyspnea score, measured by visual ana-logue scale (VAS), was significantly less whenpatients received oxygen (P< 0.001), and 12of 14 patients consistently preferred oxygen(P< 0.001). The blinded investigator alsochose oxygen for 12 of 14 patients. Accordingto a global well-being scale, patients felt littleor no benefit with air but moderate to muchbenefit when receiving oxygen. The authorsconcluded that hypoxic patients with cancerreceive symptomatic benefit from oxygen ther-apy.19 In 1994, Booth et al. did not obtainthese findings when they conducted a single-blind, crossover trial of oxygen and air admin-istered in random order to 38 hospice patientswho reported dyspnea at rest.20 These patientscompleted a VAS for dyspnea, oxygen satura-tion measures, and limited lung function testsbefore and after 15 minutes on each gas. Onaverage, dyspnea improved significantly withboth treatments, with the air group having a re-duction of dyspnea from a mean of 59 to48 mm on a 100 mm scale (P< 0.001) andthe oxygen group having a reduction of dysp-nea from a mean of 59 to 45 mm (P< 0.001).While the average response to oxygen wasquantitatively better than the response to air,there was no statistically significant differencebetween the treatments.20 It is noteworthythat the analysis performed in this study didnot appear to make use of statistical methodsappropriate for crossover trials. The discrep-ancy between these two studies may, therefore,be explained by the different patient groups(hypoxic versus mixed hypoxic and normoxicpatients on no routine inhaled treatment) orthe analysis methodology, or may be a spuriousresult due to the small numbers in each study.

We proposed, therefore, to clarify the role ofoxygen when used to relieve dyspnea in pa-tients with advanced cancer, focusing on theclinically relevant group of patients who

Vol. 32 No. 6 December 2006 543Trial of Oxygen for Dyspnea in Advanced Cancer

present with the symptom and, therefore, in-cluding both hypoxic and normoxic patients.

MethodsThe primary aim of this randomized, dou-

ble-blind, crossover study was to determineblinded patient preference for oxygen or air,following 15-minute administration of both.Secondary aims were to compare the responseto oxygen and air in hypoxic and normoxic pa-tient groups, and to identify factors other thanhypoxia that may affect the experience of dys-pnea and the response to oxygen.

The study took place in two centers in Aus-tralia (The Alfred Hospital and the Peter Mac-Callum Cancer Center) and recruited bothinpatients and outpatients. Patients were eligi-ble if they had a diagnosis of cancer, were dys-pneic and had a main etiology for dyspnea thatwas clinically deemed to be related to cancer,had a dyspnea intensity score of at least30 mm on a 0e100 mm VAS, were on stablemedication doses (including opioids), hadnormal cognitive status defined according tothe Blessed Orientation Memory & Concentra-tion mental status examination, were over 18years of age, had no contraindications to oxy-gen, and signed a written informed consent.21

Patients were ineligible if they had evidence ofacute respiratory distress, were thought to beunable to complete the trial, or were oxygendependent.

Eligible patients completed a VAS for dys-pnea and the European Organization for Re-search and Treatment of Cancer (EORTC)QLQ-C30 dyspnea measurement, providingverbal ratings of intensity,22 and underwentoxygen saturation pulse oximetry. The investi-gator collected demographic data and deter-mined the most likely pathological causes ofthe symptom, to a maximum of three causes.Patients were then randomized to receive ei-ther air or oxygen at 4 L/min via nasal prongsfor 15 minutes, following which dyspnea inten-sity ratings and oximetry were repeated. Then,following a 30-minute interval without gas, re-peat measurements were taken with crossoverto the other gas for a further 15 minutes. Mea-surements of symptom intensity and oximetrywere then repeated, and the blinded patientand investigator nominated the preferred

gas. Patients were asked to select qualitativedescriptors of their experience of dyspneaaccording to the Dyspnea Assessment Ques-tionnaire.23 The results of these qualitativedata will be presented elsewhere.

Four-liters-per-minute of gas administrationis generally the maximum amount that is toler-ated for longer-term use when given via nasalprongs and is also the maximum amountthat can be achieved via standard home oxy-gen therapy delivery systems. Thus, 4 L/minwas chosen for practical reasons and becausethis most closely mimics the clinical situationfor patients at home. Since the trial wasattempting to answer the clinical problem ofimprovement of dyspnea, gas flows requiredto correct hypoxia were not conducted forpatients prior to trial enrollment.

Institutional ethics committee approval wasgranted at both centers. The trial was regis-tered with the Clinical Trials Registry. All datawere collected on study-specific case recordforms and entered into a Microsoft Access da-tabase. Data consistency checks were made atthe time of data entry and prior to statisticalanalysis.

Statistical MethodsA sample size of 50 was chosen based upon

the primary objective of the study, which wasto determine patient preference for oxygenor air. Given a two-sided significance level of0.05, the study had 90% power to detect a sig-nificant difference between the two gases if60% of patients preferred oxygen, 20% pre-ferred air, and 20% had no preference.

Descriptive statistics of baseline patient char-acteristics were computed for all patients andby randomized gas sequence. For all patientsand the subgroup of hypoxic patients, thechange in VAS score and oxygen saturationfrom pre- to postadministration of gas was an-alyzed using analysis of variance for a 2� 2crossover design.24 In a 2� 2 crossover trial,it is necessary to consider the effects of carry-over and period. Carry-over refers to the possi-bility that the effect of the treatment given inthe first period (e.g., oxygen) may be carriedover to the second period when the next treat-ment is given (e.g., air), and so might influ-ence response to the second treatment. Theperiod effect refers to the possibility that theresponse in the first treatment period may


tend to be different from the response in thesecond period irrespective of the treatmentgiven. In the analysis of variance, an estimateand test for the carry-over effect, the period ef-fect, and the treatment effect were under-taken. Treatment comparisons were thenmade allowing for the effects of carry-overand period. Results are presented accordingto the gas received first in accordance with ap-propriate statistical analysis for a 2� 2 cross-over design. Pearson’s Chi-squared test wasused to assess if the change in EORTC verbalrating was dependent on the gas used, both be-fore the first and the second gas. Patient pref-erence for oxygen or air was compared usingPrescott’s test.24 Cohen’s kappa statistic wasused to measure agreement between patientand investigator assessment of gas preference.The Spearman rank correlation coefficient wascomputed between VAS score and oxygen satu-ration after administration of the first and sec-ond gas.

Two-tailed P-values were reported for all sta-tistical tests. Hypoxic patients were defined asthose with oxygen saturation <90% prior tocommencing treatment. Statistical analysiswas performed using Genstat for Windows7th edition (VSN International, UK, 2003)and StatXact 6.0 (Cytel Software Corporation,USA, 2003) software.

ResultsA total of 51 eligible patients were accrued

to the study between August 13, 2001 and Jan-uary 12, 2005, 17 from The Alfred Hospitaland 34 from the Peter MacCallum Cancer Cen-ter. Twenty-seven patients (53%) were random-ized to the ‘‘Air first’’ arm and 24 (47%) to the‘‘Oxygen first’’ arm. The patient baseline char-acteristics are outlined in Table 1. All patientshad been exposed to intermittent oxygen ther-apy prior to trial enrollment.

For 47 patients (92%), cancer was directlyresponsible for dyspnea. Of these, cancer wasdeemed to be solely responsible for the symp-tom in 29. The remaining patients had othercauses of dyspnea related either to complica-tions of cancer, such as pneumonia (fivepatients), or to the treatment of cancer, suchas radiation pneumonitis (two patients).Fifteen patients (29%) had unrelated causes

contributing to dyspnea, including 11 withCOPD. In total, 32 patients had a single causeof dyspnea, 17 had two causes, and 2 had threeor more causes.

Response to GasdVASDescriptive statistics are presented in Table 2

of VAS scores prior to and after 15 minutes oneach gas. For the ‘‘Air first’’ arm, the medianchange was an improvement in VAS score of3 mm (range, �19 to 70 mm) after air and10 mm (range, �19 to 63 mm) after oxygen.For the ‘‘Oxygen first’’ arm, the medianchange was an improvement of 11.5 mm(range, �20 to 45 mm) after air and 7 mm(range, �33 to 71 mm) after oxygen. After al-lowing for carry-over and period effects, therewas no significant difference between the twogas types in the mean change in VAS score(P¼ 0.622, air¼ 8.7 mm, oxygen¼ 10.5 mm).Mean VAS scores before and after administra-tion of the first and second gas are shown inFig. 1.

Response to GasdEORTC Verbal RatingA summary of EORTC verbal ratings before

and after administration of each gas is pre-sented in Tables 2 and 3. According to theEORTC descriptors, patients were assessed ashaving ‘‘improved,’’ ‘‘stayed the same,’’ or‘‘worsened’’ in their shortness of breath frompre- to post-intake of gas. After the first gas,12 patients (44%) who received air reportedan improvement in their shortness of breath,compared to 10 (42%) of those who receivedoxygen (P¼ 0.888). After the second gas, 9 pa-tients (38%) improved with air and 7 patients(26%) with oxygen (P¼ 0.767) (Fig. 2).

Response to GasdOxygen SaturationOxygen saturation levels pre- and post-

administration of gas are shown in Table 2.The change in oxygen saturation levels frompre- to post-intake of gas was computed forall patients after they received each of the twogas types. There is a significant differencebetween the two gas types in the mean increasein oxygen saturation (P< 0.001, air¼ 0.94%,oxygen¼ 5.43%). There was no evidence ofa significant correlation between VAS scoreand oxygen saturation. The Spearman rankcorrelation coefficient was 0.019 (P¼ 0.895)


Table 1Patient Baseline Characteristics

Characteristic Category

Overall (n¼ 51) Air First (n¼ 27) Oxygen First (n¼ 24)

n % n % n %

Sex Male 31 61 19 70 12 50Female 20 39 8 30 12 50

Age (years) Median 65 65 64Range 33e82 33e81 37e82

ECOG performancestatus

2 13 25 7 26 6 253 37 73 19 70 18 754 1 2 1 4 0 0

Cancer diagnosis NSCLC 22 43 15 56 7 29Small cell lung cancer 6 12 2 7 4 17Breast cancer 8 16 3 11 5 21Colorectal cancer 4 8 1 4 3 13Othera 11 22 6 22 5 21

Time since diagnosisof cancer (months)

Median 10.7 12.9 9.7Range 0.1e247.4 0.3e186.2 0.1e247.4

NSCLC¼ non-small-cell lung cancer.aOther diagnoses include lymphoma, melanoma, sarcoma, carcinoid tumors, and cancers from skin, bladder, and pharyngeal origins.

after the first gas and 0.056 (P¼ 0.695) afterthe second gas.

Gas PreferenceTwenty-one patients (41%) expressed a pref-

erence for oxygen, 15 (29%) expressed a pref-erence for air, and 15 (29%) expressed nopreference. There was no evidence of a signifi-cant difference in patient preference for air oroxygen (P¼ 0.357). The investigator assess-ment of patient preference was 20% for air,35% for oxygen, 43% no preference, andone patient was not assessed. Using Cohen’skappa statistic, the agreement between patientand investigator in their assessment of gaspreference was significant (P< 0.001,kappa¼ 0.501, 95% confidence interval:0.305e0.697).

Hypoxic PatientsIn the subgroup of 17 hypoxic patients,

mean change in VAS score did not differ signif-icantly between air and oxygen (P¼ 0.812,air¼ 15.4 mm, oxygen¼ 13.3 mm) but meanoxygen saturation levels increased significantlymore for oxygen than for air (P¼ 0.005,air¼ 2.7%, oxygen¼ 10.7%). Following oxy-gen administration, hypoxia was corrected in13 of the 17 patients. Of the 17 hypoxic pa-tients, 35% expressed a preference for air,

24% expressed a preference for oxygen, and41% expressed no preference.

DiscussionA number of authors have commented upon

the difficulties in conducting clinical researchin palliative care. The problems encounteredhave included the difficulties of recruitmentand attrition of patients.25,26 Having enrolledpatients, difficulties arise with the problemsof isolating the effect of a single interventionfrom the complexities of an ever-changing dis-ease state and the heterogeneity of the patientgroup.27,28 In an attempt to circumvent someof these difficulties encountered by otherresearchers, the intervention in this trial wassimple and brief, with the data collectioncompleted within 2 hours of enrollment. In ad-dition, the symptom examined was one that iscommon in a cancer population. Despite this,recruitment continued for almost 5 years untilthe required 50 participants were enrolled. Asignificant component of this related to theclinical fragility of the patients. Many patientswere screened and complained of dyspnea,and for reasons of accessibility, these werelargely inpatients. But unless patients identi-fied as eligible were able to be enrolled in thetrial within 24 hours, most deteriorated, withcognitive impairment or increasing oxygen


Table 2Patient Responses Pre- and Post-administration of Gas

Assessment Category

Overall (n¼ 51) Air First (n¼ 27) Oxygen First (n¼ 24)

n % n % n %

Breathlessness immediatelybefore first gas (mm)

Median 45 52 43Range 23e92 23e92 31e78

Breathlessness after 15 minuteson first gas (mm)

Median 43 45 34.5Range 0e83 10e83 0e68

Breathlessness immediatelybefore second gas (mm)

Median 53 57 42Range 10e88 15e88 10e70

Breathlessness after 15 minuteson second gas (mm)

Median 34 40 30.5Range 0e92 4e92 0e90

Shortness of breathimmediately before first gas

Not at all 1 2 1 4 0 0A little 22 43 10 37 12 50Quite a bit 23 45 13 48 10 42Very much 4 8 2 7 2 8Not recorded 1 2 1 4 0 0

Shortness of breath after 15minutes on first gas

Not at all 6 12 3 11 3 13A little 33 65 17 65 16 67Quite a bit 12 24 7 26 5 21Very much 0 0 0 0 0 0

Shortness of breathimmediately beforesecond gas


Shortness of breath after 15minutes on second gas


Oxygen saturationimmediately before first gas

Median 93 93 93Range 70e98 70e98 71e98

Oxygen saturation after 15minutes on first gas

Median 94 93 97Range 69e100 69e98 73e100

Oxygen saturation immediatelybefore second gas

Median 92 93 90Range 69e98 74e98 69e98

Oxygen saturation after 15minutes on second gas

Median 97 98 93Range 73e99 86e99 73e98

Hypoxic prior to first gas 17 33 8 30 9 38Hypoxic after first gas 13 25 9 33 4 17Hypoxic prior to second gas 18 35 8 30 10 42Hypoxic after second gas 12 24 4 15 8 33

requirements, to the point where they wereunable to participate in the study. Despite thisstudy being specifically designed to cater tothis particular group of patients, it neverthelessproved difficult for them to participate in theintervention.

The experience of the researchers was thatdyspnea in an inpatient cancer population in-dicated an extremely poor prognosis. Thiswas confirmed by the Eastern Cooperative On-cology Group (ECOG) Performance Status,with the majority of patients (73%) having anECOG performance status rating of 3. In addi-tion, they had extensive malignant disease,with nearly half of the participants having mul-tiple causes for the complaint of dyspnea.However, it is a particular strength of this trial

that it did in fact study the palliative care pop-ulation of interest.

The improvement of oxygen saturationwhen oxygen was administered indicated effec-tive delivery of oxygen within the short studytime of 15 minutes. While hypoxia was not cor-rected in all cases, with four patients remain-ing hypoxic despite oxygen administration,the oxygen flow mimicked the standard appli-cation of oxygen administered in the domicili-ary setting. Under these conditions, theimprovement of mean oxygen saturations didnot correlate with a reduction of mean VAS rat-ings of dyspnea. Instead, average VAS scoresimproved with both interventions. It shouldnot be anticipated that there would be a linearrelationship between oxygen saturations and


complaints of dyspnea in view of the subjectivenature of symptom reporting, the multiple fac-tors contributing to the generation of dyspnea,and the complexity of the physiology of oxy-gen-hemoglobin binding, which does notoccur according to linear dynamics. Neverthe-less, the lack of correlation between oxygensaturation and dyspnea complaints is an im-portant finding of this study to disseminate,since much practice in acute hospitals revolvesaround ‘‘treating’’ dyspnea by responding tooxygen saturation levels. Other authors havesimilarly demonstrated that standard clinicaltools, such as forced expiratory volume inone second and forced vital capacity, do notcorrelate with the experience of dyspnea in pa-tients with advanced cancer.29 The results ofthis study add further weight to the statement

(a)

0

10

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70

Air OxygenFirst Gas

Mean

b

reath

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ess sco

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m)

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Fig. 1. Mean VAS score before and after adminis-tration of the first (a) and second (b) gas. The errorbar represents standard error of mean.

that dyspnea is a subjective symptom and its ad-equate management requires full inquiry of thepatient, not simply responding to abnormal in-vestigations. Appropriate management of pa-tients with advanced cancer must include anevaluation of the burden of symptoms irrespec-tive of the results of investigations.

Consistent with the results of Booth et al.,patients on average improved with gas admin-istration.20 Air was not considered a placeboarm in this trial, with air administration on av-erage conferring considerable benefit. Thebenefits of air and oxygen were not signifi-cantly different. Since hypoxia was not cor-rected with oxygen in 4 of the 17 patients,the lack of significant difference between thegases in this group needs to be interpretedwith caution. But this finding has clinical im-plications, because while using the equivalentof standard domiciliary oxygen flow, patientsdemonstrated no difference in response be-tween air and oxygen. Importantly, no clearpreference expressed for either treatmentarm according to the criteria set for the trial.It appears that the act of treatment is impor-tant, with treatment in this study consistingof gas administration via nasal prongs. Themechanism by which this improvement isachieved is not clear.

The possibility of a placebo response to anytreatment including air must be considered.Since all these patients had previously been ex-posed to gas administration, it is not treatmentnaivety informing the results. The trial was con-ducted over a short treatment period, and it maybe that the initial response to air would lessenduring longer-term administration, as wouldbe expected in a placebo response.

Another possible explanation for the lack ofdifferential response is that mechanoreceptors

Table 3Change in EORTC Verbal Rating

Improved Same Worse

n % n % n %

First gasAira 12 44 13 48 1 4Oxygen 10 42 13 54 1 4

Second gasAir 9 38 14 58 1 4Oxygen 7 26 19 70 1 4

aOne patient was not assessed prior to first gas.


are stimulated by gas administration, bringingabout a reduction in the sensation of dyspnea.In studies on normal subjects, breathlessnesshas been found to be reduced by oral mucosalstimulation and cold facial stimulation, sug-gesting the mechanism by which open win-dows and fans may be useful.30,31 Othershave suggested that wearing nasal prongs ap-pears to bring about a reduction of breathless-ness in patients with COPD.32 The role of theestablishment of a therapeutic environmentmay also be important in this trial. The pres-ence of an interested researcher throughoutthe intervention may lead to a reduction ofanxiety and fear, which, in turn, may result ina reduction of symptom intensity.

0

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BeforeOxygen

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tag

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Not at all A little

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Fig. 2. EORTC verbal rating before and after ad-ministration of the first (a) and second (b) gas.

There were limitations to this study that mayinfluence the results. First, eligible patientshad to record a dyspnea score at rest of30 mm on VAS. A number of patients com-plained of significant dyspnea with activitybut at rest did not reach this score, renderingthem ineligible for study inclusion. In order tocontrol for differing levels of activity, the studyrequired patients to remain at rest for thestudy duration. It is possible that if gaseswere administered to patients during activity,there may have been a differential preferenceand response to the gases that were not appar-ent at rest. Second, the investigators defineda clinically significant response to oxygen tobe a preference for oxygen chosen by 60% ofpatients. However, the exact nature of whatconstitutes a clinically significant improvementin this symptom is uncertain. While there hasbeen some discussion and attention to this is-sue in pain research,33 the same remains tobe established for other symptoms, includingdyspnea. If a clinically significant improvementoccurred at lower increments of improvement,then this study may not have been adequatelypowered. The study methodology and re-sponse criteria were informed by the consider-able clinical experience of the investigators,and, therefore, this study represents the bestavailable evidence at the time.

ConclusionIn agreement with the findings of Booth

et al.,20 this study established that both oxygenand air administered intranasally improve themean sensation of dyspnea for patients withadvanced cancer. There is no significant differ-ence between the gases in either VAS or prefer-ences expressed. This is despite oxygensignificantly improving mean oxygen satura-tion measures. Nor did the group of hypoxicpatients show mean greater improvementwith, or preference for, oxygen. Notably, oxy-gen saturation measures do not correlatewith ratings of dyspnea, which is in keepingwith the knowledge that dyspnea in advancedcancer is the expression of multiple sensationsand experiences, and not simply related to ox-ygen tension.

This study has highlighted the need to estab-lish what constitutes a clinically significant


improvement of the symptom of dyspnea. Thisrequires investigation as a matter of urgencysuch that future studies may be designed andpowered to reflect clinically relevant out-comes. Once established, the role of oxygento relieve dyspnea in advanced cancer mayrequire further investigation, with particularattention given to longer-term studies. Untilsuch time, the current state of evidence sug-gests that the administration of intranasalgas, either air or oxygen, improves the sensa-tion of dyspnea in advanced cancer.

AcknowledgmentsThe authors wish to acknowledge the contri-

butions of Jenny Smith for her assistance withprotocol development and statistical support,and John Dalla, Michelle Hamrosi, Vina Nguy-en, and Kate Wakelin for their assistance withpatient recruitment and their contribution tothe successful completion of the trial.

References1. Donnelly S, Walsh D. The symptoms of ad-

vanced cancer. Semin Oncol 1995;22:67e72.

2. Forster L, Lynn J. Predicting life span for appli-cants to inpatient hospice. Arch Intern Med 1988;148:2540e2543.

3. Hayes A, Philip J, Spruyt O. Patient reportingand doctor recognition of dyspnea in a comprehen-sive cancer center. Intern Med J 2006;36:381e384.

4. Krech RL, Walsh D. Symptoms of pancreaticcancer. J Pain Symptom Manage 1991;6:360e367.

5. Mercadante S, Armata M, Salvaggio L. Paincharacteristics of advanced lung cancer patients re-ferred to a palliative care service. Pain 1994;59:141e145.

6. Escalante CP, Martin CG, Elting LS, et al. Dysp-nea in cancer patients. Aetiology, resource utiliza-tion, and survivaldimplications in a managed careworld. Cancer 1996;78:1314e1319.

7. American Thoracic Society. Dyspnea. Mecha-nisms, assessment and management: a consensusstatement. American Thoracic Society. Am J RespirCrit Care Med 1999;159:321e340.

8. McClosky DI. Kinesthetic sensibility. Physiol Rev1978;58:763e820.

9. Corner J, Plant H, A’Hern R, Bailey C. Non--pharmacological interventions for breathlessnessin lung cancer. Palliat Med 1996;10:299e305.

10. Filshie J, Davis CL, Van Der Molen B. The shortterm effects of acupuncture in terminal dyspnea.Palliat Med 1996;10:145e150.

11. Ahmedzai S, Davis CL. Nebulized drugs in palli-ative care. Thorax 1997;52:S57eS77.

12. Bruera E, Macmillan K, Pither J,MacDonald RN. Effects of morphine on the dysp-nea of terminal cancer patients. J Pain SymptomManage 1990;5:341e344.

13. Bruera E, MacEachern T, Ripamonti C,Hanson J. Subcutaneous morphine for dyspnea incancer patients. Ann Intern Med 1993;119:906e907.

14. Cowcher K, Hanks GWC. Long-term manage-ment of respiratory symptoms in advanced cancer.J Pain Symptom Manage 1990;5:320e330.

15. Light RW, Muro JR, Sato RI, et al. Effects of oralmorphine on breathlessness and exercise tolerancein patients with chronic obstructive pulmonary dis-ease. Am Review Respir Med 1989;139:126e133.

16. Walsh D. Dyspnea in advanced cancer. Lancet1993;342:450e451.

17. Woodcock A, Gross ER, Gellert A, et al. Effectsof dihydrocodeine, alcohol, and caffeine on breath-lessness and exercise tolerance in patients withchronic obstructive lung disease and normal bloodgases. N Engl J Med 1981;305:1611e1616.

18. O’Donohue WJ. Home oxygen therapy. MedClin North Am 1996;80:611e622.

19. Bruera E, de Stoutz N, Velasco-Leiva A,Schoeller T, Hanson J. Effects of oxygen on dyspneain hypoxaemic terminal-cancer patients. Lancet1993;342:13e14.

20. Booth S, Kelly MJ, Cox NP, Adams L. The treat-ment of dyspnea in cancer patientsddoes oxygenhelp? Prog Palliat Care 1994;2:8.

21. Katzman R, Brown T, Fuld P, et al. Validation ofa short orientation memory concentration test ofcognitive impairment. Am J Psychiatry 1983;140:734e739.

22. Bergman B, Aaronson N, Ahmedzai S, et al. TheEORTC QLQ-LC13: a modular supplement to theEORTC Core Quality of Life Questionnaire(QLQ-C30) for use in lung cancer clinical trials.Eur J Cancer 1994;30A:635e642.

23. Heyse-Moore L. Two new measures of dyspneain advanced cancer. Prog Palliat Care 1994;2:8.

24. Jones B, Kenward MG. Design and analysis ofcross-over trials. London: Chapman and Hall Ltd.,1989.

25. Maddocks I. Issues in the conduct of therapeu-tic trials in palliative care: an Australian perspective.Drugs Aging 2002;19:495e502.

26. Rinck G, van den Bos G, Kleijnen J, de Haes H,Schade E. Methodologic issues in effectiveness


research on palliative care patients: a systematicreview. J Clin Oncol 1997;15:1697e1707.

27. Hudson P, Aranda S, Kristjanson L. Rando-mised controlled trials in palliative care: overcom-ing the barriers. Int J Palliat Nurs 2001;7:427e434.

28. Bottomley A. To randomise or not to random-ise: methodological pitfalls of the RCT design inpsychosocial intervention studies. Eur J CancerCare 1997;6:222e230.

29. Heyse-Moore L, Beyon T, Ross V. Does spirome-try predict dyspnea in advanced cancer? Palliat Med2000;14:189e195.

30. Simon PM, Basner RC, Weinberger SE, et al.Oral mucosal stimulation modulates intensity of

breathlessness induced in normal subjects. Am RevRespir Dis 1991;144:419e422.

31. Schwartzstein RM, Lahive K, Pope A,Weinberger SE, Weiss JW. Cold facial stimulation re-duces breathlessness induced in normal subjects.Am Rev Respir Dis 1987;136:58e61.

32. Liss HP, Grant BJ. The effect of nasal flow onbreathlessness in patients with chronic obstructivepulmonary disease. Am Rev Respir Dis 1988;137:1285e1288.

33. Farrar JT, Portenoy RK, Berlin JA, Kinman JL,Strom BL. Defining the clinically important differ-ence in pain outcome measures. Pain 2000;88:287e294.

a randomized, double-blind, crossover trial of the effect of oxygen on dyspnea in patients with...

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