This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Graham, P.H. Articles by Graham, J. Search for Related Content PubMed PubMed Citation Articles by Graham, P.H. Articles by Graham, J. Social Bookmarking                            What's this?

Inhalation Aromatherapy During Radiotherapy: Results of a Placebo-Controlled Double-Blind Randomized Trial

From the Cancer Care Centre, St George Hospital, Kogarah, Australia.

Address reprint requests to P.H. Graham, MD, Cancer Care Centre, St George Hospital, Gray St, Kogarah, Australia, 2217, email: grahamp{at}sesahs.nsw.gov.au.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine whether the inhalation of aromatherapy during radiotherapy reduces anxiety.

Patients and Methods: Three hundred thirteen patients undergoing radiotherapy were randomly assigned to receive either carrier oil with fractionated oils, carrier oil only, or pure essential oils of lavender, bergamot, and cedarwood administered by inhalation concurrently with radiation treatment. Patients underwent assessment by the Hospital Anxiety and Depression Scale (HADS) and the Somatic and Psychological Health Report (SPHERE) at baseline and at treatment completion.

Results: There were no significant differences in HADS depression or SPHERE scores between the randomly assigned groups. However, HADS anxiety scores were significantly lower at treatment completion in the carrier oil only group compared with either of the fragrant arms (P = .04).

Conclusion: Aromatherapy, as administered in this study, is not beneficial.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
COMPLEMENTARY THERAPIES are widely used by cancer patients.¹ Aromatherapy has previously been tested in randomized trials using anxiety as the main end point.^2–8 These are generally poor-quality trials, as summarized in a review by Cooke and Ernst.⁹ Four trials were weakly positive and two were positive. Only one trial was a pure test of inhalation aromatherapy, with six trials combining aromatherapy with limited or full body massage. The only negative trial was also the only trial with double blinding. A total of 498 patients were distributed among 18 treatment groups, reflecting the small size of the trials. Despite this limited clinical evidence base, there exists basic science indicating that certain essential oils are both rapidly absorbed by inhalation and alter brain function.^10–12 In our institution, area inhalation aromatherapy was being used in various wards and treatment areas, including the Cancer Care Centre at St George Hospital (Kogarah, Australia), without prior formal review or prescription by medical staff. Inhalation aromatherapy is said to be the most effective route for the management of stress and depression.¹³ In view of the mixed evidence and the paucity of evidence related to the clinical application of pure respiratory administration of essential oils, it was decided to formally investigate aromatherapy using a double-blind placebo-controlled randomized trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study was conducted with ethics approval from the South Eastern Sydney Area Health Service. Written informed consent was obtained from all participants.

The primary end points of this study were changes in levels of anxiety and or depression as assessed primarily by the Hospital Anxiety and Depression Scale (HADS) and also by the Somatic and Psychological Health Report (SPHERE), which is composed of the General Health Questionnaire (GHQ) and Symptoms of Fatigue and Anergia (SOFA) scales.^14,15 HADS applied to oncology populations has demonstrated stable factor structure and internal consistency of the subscales.¹⁶ It has been used in prospective randomized trials of psychologic therapy and antidepressants in oncology patients, with assessment intervals of 5 to 8 weeks.^17,18 Previous aromatherapy trials have used HADS to demonstrate changes in anxiety.^8,19 The GHQ subscale of the SPHERE assesses anxiety and depression and represents a secondary measurement tool; however, the main motivation to administer this instrument concurrently was the interest at this institution in the investigation of fatigue, which is common in cancer patients, and for which the SOFA subscale of the SPHERE is particularly suited.^20–22

The original design was a two-arm trial, with a fragrance-matched artificial placebo to be provided by an essential oil supplier (In Essence, Melbourne, Australia) at no cost. The remainder of the trial was to be conducted independent of the supplier. This study design required 200 patients to achieve a power of 90% to detect a reduction in anxiety cases from 40% to 20% at P = .05 (two-sided). Baseline anxiety levels were based on a previous cross-sectional survey of 760 Cancer Care Centre outpatients and a previous survey of Australian breast cancer patients.^23,24 Research staff had already been employed when 1 week before scheduled trial activation, the supplier withdrew support, attributed to a change in management. Without the industrial expertise of the supplier to provide a perfect fragrant artificial control, rather than abandon the trial, it was modified to a design with three arms. This included one control arm with carrier oil only (which has no fragrance), a second control arm of carrier oil with fractionated low-grade essential oils, and a third arm of pure essential oils. Patient numbers were increased, and revised ethics approval was obtained. Patients were eligible for the study if a course of eight or more fractions of radiotherapy was prescribed. Patients were not permitted to use aromatherapy outside of the study during the study period. Random assignment was conducted by telephone to a separate data management center. Patients and physicians were blinded to product allocation.

Two qualified aromatherapists employed as nurses by the South Eastern Area Health Service were consulted on essential oil selection and administration technique. The inhalation aromatherapy technique and dose complied with the South Eastern Sydney Area Health Service procedural guidelines on complementary therapies.²⁵ The use of a few drops of essential oil applied to a tissue, or bedding, or garment in proximity to the subject’s head is just one of the wide range of well-accepted essential oil administration techniques.^26–29 Direct application of undiluted essential oil to the skin is avoided because of potential irritation. Patients wore a necklace with a plastic-backed paper bib (such as worn at the dentist), donned before treatment each day and removed after exiting the treatment bunker. Three drops of oil were applied to the bib. The typical duration of exposure was 15 to 20 minutes. Patients were seated in waiting areas segregated according to study-arm allocation (known as arms A, B, or C until completion of analysis) to avoid cross-exposure by close physical proximity.

The essential oils were lavender, bergamot, and cedarwood in a ratio of 2:1:1. Lavender and bergamot have been shown to be associated with brain-wave relaxation by Torri et al.¹² Lavender was used by Buckle, ² Dunn et al, ³ and Corner et al⁸ in their respective randomized trials of aromatherapy relaxation in association with massage. Antidepressant effects are included in the properties attributed to bergamot.³⁰ Davis³¹ recommends a combination of lavender and bergamot for relaxation. Kite et al¹⁹ used lavender and bergamot inter alia in their aromatherapy study, which showed reductions in anxiety in breast cancer patients. Our study population was predicted to have an even sex ratio (compared with previous studies, which have focused on predominantly female populations), and cedarwood was added to maximize the olfactory acceptability to a mixed-sex sample in the design phase of the study. While Torri et al did not assess brain-wave function in response to cedarwood, there is no evidence that cedarwood is anxiety provoking.¹² A relaxation blend currently marketed in Australia lists its ingredients as bergamot, cedarwood, geranium, lavender, and marjoram but does not list their proportions. Although the original essential oil supplier (In Essence) withdrew support, pure 100% essential oils were still sourced from In Essence via a retail outlet because In Essence was the only supplier known to us at the time in the Australian market to have their products independently assayed by liquid gas chromatography to ensure purity, as verified by the Therapeutic Goods Administration. The carrier oil was sweet almond cold-pressed pure vegetable oil. The fractionated oils were oils of unknown purity from a different supplier (Naturistics, Hornsby, Australia), and cost approximately 15% of the price of the pure essential oils. These fractionated oils were diluted further for the study in a ratio of one part oil blend to two parts carrier oil. All study treatments were administered by 1.5 full-time equivalent personnel, employed specifically for this task in a department treating 100 patients daily, of whom approximately one third were on study during the study period.

Before analysis, comprehensive end point data checking was performed on 10% of patients selected by random number generation. A data entry error rate of 0.3% was detected. Full statistical analysis was performed before the allocation code was broken. Outcomes were dichotomized into cases and noncases of anxiety, depression, and so on, at treatment completion. Logistic regression, including baseline case status as a covariate, was used in all univariate and multivariate analyses.³² Treatment was analyzed as a factor with three levels. Variables found to have a P value less than .25 on univariate modeling were included in the initial multivariate models. Final models after stepwise reduction included only variables with a P value of less than .05. No two-way interaction terms were found to have a P value of less than .05.

Study Population
The mean patient age was 65 years, with a range from 33 to 90 years. Seventy-two percent of patients were married or with a partner. Fifty-two percent were male. Twelve percent were smokers. Forty-one percent of patients had used a complementary or alternative medicine before recruitment, and 28% had used aromatherapy in the past. Sixty-six percent had symptoms related to their illness, and 55% were being treated with curative intent. Twenty percent of patients had received previous radiotherapy, and 75% were within a year of their cancer diagnosis. The body sites receiving radiotherapy were thoracic in 29% of patients, abdominal or pelvic in 28%, breast in 20%, and head and neck in 19%, with the remainder of patients receiving radiotherapy at multiple or skin sites. The mean number of treatment fractions was 21, and the median number of fields was two.

Compliance and Blinding
At the completion of the treatment course, patients were asked which aromatherapy treatment they believed they had received, whether they actively liked the aroma, and whether they believed it had been helpful. Their responses and the proportion of possible aromatherapy treatments administered are listed in Table 1. Reasons for not receiving the full number of possible aromatherapy treatments included research assistant illness and absence, failure to complete the planned radiotherapy course, and withdrawal from receiving aromatherapy. Of the 313 patients who were randomly assigned, 285, 286, and 295 completed baseline, HADS anxiety (HADSA), HADS depression (HADSD), and SPHERE questionnaires, respectively, providing 91% to 94% questionnaire compliance for analysis of these scores. There was no significant difference in missing data by allocated arms.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We conclude that, as administered in this study, aromatherapy does not reduce anxiety or depression levels in patients undergoing radiotherapy. It is possible that it may contribute to persistent anxiety. This may be explained by a negative Pavlovian effect induced by the association of the aromas with the anxiety provoking experience of radiotherapy. A Medical Research Council–funded randomized trial is in progress in the United Kingdom, which separates the time and location of the aromatherapy from the cancer treatment to avoid this potential problem. However, this creates difficulties with additional travel for patients, and the study does not offer a pure test of aromatherapy because it also incorporates massage. Of course, if the components of the essential oils are significantly pharmacologically anxiolytic, this would counter the postulated negative Pavlovian effects.

There are a number of potential criticisms of this trial. There is no qualified aromatherapist on the authorship. However, there was direct consultation with both qualified aromatherapists and the essential oil industry. The research process for the study was rigorous, the selection of oils was well-founded, and the administration technique was well-documented as an accepted essential oil inhalation aromatherapy technique. Aromatherapists may argue that the selection of essential oils is best individualized to each patient; however, this ignores the underlying hypothesis of this study that certain oils are pharmacologically anxiolytic. A number of the previous positive trials of aromatherapy have used a standardized essential oil selection (commonly lavender) rather than individualized essential oil selection. Additionally, it is common for aromatherapy texts to claim that combination oils are more effective than single-oil selections. The criteria for selection of oils included their putative anxiolytic properties and the olfactory acceptability of the blend to a mixed-sex group of healthy volunteers in the study design phase. Although the daily duration of exposure was relatively brief, rapid systemic absorption of these volatile oils by respiratory exposure occurs within a few minutes, and the duration of exposure to achieve absorption was more than adequate. None of the patients in the carrier oil–only arm requested dose reductions (achieved by using fewer drops); whereas, 35% of the patients in the fragrant arms requested this because of the initial strength of the olfactory sensation. This makes it unlikely that patients did not receive adequate exposure. None of the previous randomized trials reported on olfactory sensation. We have reported the proportion of patients who were smokers or who had received chemotherapy, unlike previous studies. The potential for these factors to degrade the olfactory sensation and, therefore, reduce aromatherapy effectiveness is conjecture only. In any event, smokers and patients who had previously received chemotherapy made up a relatively small minority of the population, randomization equally distributed these patients among treatment arms, and this population adequately represents the general radiation oncology population for whom the technique would have been applied if successful. Although chemotherapy experience was associated with increased anxiety, there was no significant aromatherapy-chemotherapy interaction.

Despite the frequency of complementary therapy, including aromatherapy, in western oncology populations, previous studies have neither specified exclusion of prior aromatherapy users nor reported prior aromatherapy experience in their study populations. There were no differences in outcome by prior aromatherapy exposure in this study. Had these patients been better at detecting which treatment they received compared with aromatherapy-naïve patients, any potential bias introduced would have been towards amplification of the likelihood of finding a positive effect of aromatherapy.

Aromatherapy is primarily defined by the application of essential oils for therapeutic benefit, not by the method of administration. An aromatherapy package of massage, music, essential oils, and a room with calming pictures and a soothing therapist is a common perception of aromatherapy, but it is only one form of the varied aromatherapy methods. Although aromatherapy commonly uses essential oils in combination with massage, this study was not designed to test massage. In our or any other standard radiotherapy department, it is impossible to provide such a treatment without substantial escalation of costs and resource consumption. Nonetheless, pleasant music is played in the department common areas and treatment suites, calming trompe d’oeils are painted on the treatment suite walls and ceilings, healthy and attractive plants are included in the décor, and our therapy staff are regularly complimented by patients on their supportive, calming manner. To be a viable method of anxiolysis within the practical environment of a busy radiation department, massage aromatherapy was not an option. Besides, to consider massage aromatherapy as the only effective technique would ignore the breadth of aromatherapy practice and the evidence of physiologic and psychologic activity of essential oils in animals and humans achieved in isolation of other interventions. For this study, the staff was employed to administer the inhalation aromatherapy, largely to facilitate blinding and maximize compliance. It was envisaged that, if it was found to be effective, patients could be given instruction and then self-administer aromatherapy, so significant increases in staff establishment would not be necessary.

As mentioned in the introduction, area inhalation techniques, such as oil aromatizers operating in areas containing many people or patients, have become common and prompted this investigation. This technique has been used in hospital-ward settings with apparent benefit in the control of agitation, anxiety, or insomnia.^26,33 The principle of activity in this approach is pure inhalation aromatherapy but is not amenable to good hypothesis testing, nor does it enable individual patient choice about whether or not to be exposed to aromatherapy. Our individual administration of inhalation aromatherapy does provide a test system amenable to robust statistical assessment.

Although a similar majority (52% to 60%) of patients in each group stated they did not know whether they had received essential oil therapy, the nonfragrant placebo group had a significantly lower proportion of patients who believed that they had received essential oils. Thus, our attempts to blind patients were not 100% effective, although most were uncertain or wrong about which type of treatment they actually received. Given the direction of trends of anxiety levels, however, this actually strengthens the confidence in our findings because it is counter to the expected direction of a placebo detection effect. It could also be argued that the fragrant placebo group was not a true placebo because there was some essential oil in the blend. There was, however, no difference between the fragrant placebo and the pure essential oil groups to indicate a dose-response effect, which would be secondary support for pharmacoefficacy of the essential oils. The observation that 27% to 40% of patients believed the treatment to be beneficial highlights the requirement for placebo controls and the fact that anxiety levels tend to fall during the progress of radiation treatment. Although there seemed to be no difference with the use of aromatherapy, the decline in anxiety levels over time for the whole population emphasizes the limitations of pretest-posttest studies without appropriate controls, which characterizes many clinical aromatherapy reports.

This study has a number of strengths over previous studies. First, it was designed with adequate statistical power to detect a clinically significant change in the primary end point. Second, it is the first, true, blinded test of aromatherapy alone without other complementary modalities, such as massage and counseling, being used concurrently. The rationale and validity of this isolated testing of inhalation aromatherapy has already been stated. Third, this study was testing a delivery method that would have been readily and universally applicable across most healthcare delivery systems while maintaining individual patient choice, unlike previous studies using other methods that would require a significant increase in staffing levels. This study failed to show a benefit of specific essential oils used in a specific manner that was well-justified, but it does not exclude the possibility of other combinations of oils or methods of administration or timing from providing the sought-after effect of anxiety reduction.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. MacLennan AH, Wilson DH, Taylor AW: Prevalence and cost of alternative medicine in Australia. Lancet 347:569–573, 1996[CrossRef][Medline]

2. Buckle J: Aromatherapy: Does it matter which lavender oil is used? Nurs Times 89:32–35, 1993[Medline]

3. Dunn C, Sleep J, Collett D: Sensing an improvement: An experimental study to evaluate the use of aromatherapy, massage and periods of rest in an intensive care unit. J Adv Nurs 21:34–40, 1995[CrossRef][Medline]

4. Stevensen C: The psychophysiological effects of aromatherapy massage following cardiac surgery. Complement Ther Med 2:27–35, 1994[Medline]

5. Wilkinson S: Aromatherapy and massage in palliative care. Int J Palliat Nurs 1:317–328, 1995

6. Morris N, Birtwistle S, Toms M: Anxiety reduction by aromatherapy: Anxiolytic effects of inhalation of geranium and rosemary. Int J Aromatherapy 7:33–39, 1995

7. Wilkinson S, Aldridge J, Salmon I, et al: An evaluation of aromatherapy massage in palliative care. Palliat Med 13:409–417, 1999[Abstract/Free Full Text]

8. Corner J, Cawley N, Hildebrand S: An evaluation of the use of massage and essential oils in the well being of cancer patients. Int J Palliat Nurs 21:34–40, 1995

9. Cooke B, Ernst E: Aromatherapy: A systematic review. Br J General Practice 50:493–496, 2000

10. Falk-Filipsson A, Lof A, Hagberg M, et al: d-limonene exposure to humans by inhalation: Uptake, distribution, elimination, and effects on the pulmonary function. J Toxicol Environ Health 38:77–88, 1993[Medline]

11. Falk A: Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation. Scand J Work Environ Health 16:372–378, 1990[Medline]

12. Torri S, Fukuda H, Kanemoto H, et al: Contingent negative variation (CNV) and the psychological effects of odour, in Van Toller S, Dodd GH (eds): Perfumery: The Psychology and Biology of Fragrance. London, United Kingdom, Chapman and Hall, 1988, pp 107–121

13. Price S, Price L: Aromatherapy for Health Professionals. Melbourne, Australia, Churchill Livingston, 1995

14. Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 67:361–370, 1983[Medline]

15. Hickie IB, Hooker AW, Hadzi-Pavlovic D, et al: Fatigue in selected primary care settings: Sociodemographic and psychiatric correlates. Med J Aust 164:585–588, 1996[Medline]

16. Moorey S, Greer S, Watson M, et al: The factor structure and factor stability of the hospital anxiety and depression scale in patients with cancer. Br J Psychiatry 158:255–259, 1991[Abstract/Free Full Text]

17. Greer S, Moorey S, Baruch JD, et al: Adjuvant psychological therapy for patients with cancer: A prospective randomised trial. BMJ 304:675–680, 1992[Abstract/Free Full Text]

18. Razavi D, Allilare JF, Smith M, et al: The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand 94:205–210, 1996[Medline]

19. Kite SM, Maher EJ, Anderson K, et al: Development of an aromatherapy service at a cancer centre. Palliat Med 12:171–180, 1998[Abstract/Free Full Text]

20. Portenoy RK, Thaler HT, Kornblith AB, et al: Symptom prevalence, characteristics, and distress in a cancer population. Qual Life Res 3:183–189, 1994[CrossRef][Medline]

21. Koschera A, Hickie I, Hadzi-Pavlovic D, et al: Prolonged fatigue, anxiety and depression: Exploring relationships in a primary care sample. Aust N Z J Psychiatry 34:692–695, 2000[CrossRef][Medline]

22. Hadzi-Pavlovic D, Hickie IB, Wilson AJ, et al: Screening for prolonged fatigue syndromes: Validation of the SOFA scale. Soc Psychiatry Psychiatr Epidemiol 35:471–479, 2000[CrossRef][Medline]

23. Lovell M, Graham P, Hickie I, et al: Diagnosing depression in oncology outpatients: A comparison of two questionnaires. 50th Annual Royal Australian and New Zealand College of Radiologists Scientific Meeting, Syndey, Australia, October 21–25, 1999. Programme and Book of Abstracts 197: 1999 (abstr 28)

24. Kissane DW, Clarke DM, Ikin J, et al: Psychological morbidity and quality of life in Australian women with early-stage breast cancer: A cross sectional survey. Med J Aust 169:192–195, 1998[Medline]

25. Gassib-Spain L, Stewart A, Tranter J, et al: Complementary therapies and nursing practice. Primrose House, South East Health, Dolls Point, Australia, 2001, pp 19–24 (manual)

26. Cannard G: The effect of aromatherapy in promoting relaxation and stress reduction in a general hospital. Complement Ther Nurs Midwifery 2:38–40, 1996[CrossRef][Medline]

27. Stevenson CJ: Aromatherapy, in Micozzi MS (ed): Fundamentals of Complementary and Alternative Medicine. Melbourne, Australia, Churchill Livingston, 1996, pp 137–148

28. Stevenson C: Aromatherapy, in Rankin-Box D (ed): The Nurses Handbook of Complementary Therapies. Melbourne, Australia, Churchill Livingston, 1995, pp 51–57

29. Wafer MV: Finding the formula to enhance care: Guidelines for the use of complementary therapies in nursing practice. Prof Nurse 9:414–417, 1994[Medline]

30. Trevelyan J, Booth B: Aromatherapy: The history, therapeutic value and implications for nurses, midwives and health visitors. Nurs Times 90:3–12, 1994[Medline]

31. Davis P: Aromatherapy: An A to Z. Essex, United Kingdom, C.W. Daniel, 1988

32. Assman SF, Pocock SJ, Enos LE, et al: Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 355:1064–1069, 2000[CrossRef][Medline]

33. Mills J: Aromatherapy on the ward: The whiff of ‘de-stress’—Results for carers and clients alike. Aust J Holistic Nurs 4:41–44, 1997

Submitted October 24, 2002; accepted April 10, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. Imanishi, H. Kuriyama, I. Shigemori, S. Watanabe, Y. Aihara, M. Kita, K. Sawai, H. Nakajima, N. Yoshida, M. Kunisawa, et al. Anxiolytic Effect of Aromatherapy Massage in Patients with Breast Cancer Evid. Based Complement. Altern. Med., March 1, 2009; 6(1): 123 - 128. [Abstract] [Full Text] [PDF]

				B. R. Cassileth, G. E. Deng, J. E. Gomez, P. A. S. Johnstone, N. Kumar, and A. J. Vickers Complementary Therapies and Integrative Oncology in Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition) Chest, September 1, 2007; 132(3_suppl): 340S - 354S. [Abstract] [Full Text] [PDF]

				S. M. Wilkinson, S. B. Love, A. M. Westcombe, M. A. Gambles, C. C. Burgess, A. Cargill, T. Young, E. J. Maher, and A. J. Ramirez Effectiveness of Aromatherapy Massage in the Management of Anxiety and Depression in Patients With Cancer: A Multicenter Randomized Controlled Trial J. Clin. Oncol., February 10, 2007; 25(5): 532 - 539. [Abstract] [Full Text] [PDF]

				K. I. Block, C. Gyllenhaal, and M. N. Mead Safety and Efficacy of Herbal Sedatives in Cancer Care Integr Cancer Ther, June 1, 2004; 3(2): 128 - 148. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Graham, P.H. Articles by Graham, J. Search for Related Content PubMed PubMed Citation Articles by Graham, P.H. Articles by Graham, J. Social Bookmarking                            What's this?