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Recent advances: Palliative care

Thursday, August 20, 1970

BRITISH MEDICAL JOURNAL

Sept 2, 2000 and several letters to the editor from Jan 27, 2001 edition



BMJ 2000;321:555-558 (2 September)Clinical review

(and several letters to the editor from Jan 27, 2001 edition)



Recent advances: Palliative care

J Andrew Billings, director.

Palliative Care Service, Founders 600, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114-2698, USA

JBillings@partners.org

Palliative care is defined as comprehensive, interdisciplinary care of patients and families facing a terminal illness, focusing primarily on comfort and support.1 Key aspects include meticulous symptom control; psychosocial and spiritual care; a personalised management plan that maximises patient-determined quality of life; family oriented care that extends through the time of bereavement; and delivery of coordinated services, especially in the home but also in hospital, extended care facilities, day care centres, and specialised units. In this article I introduce current concepts about palliative care and review advances in this subject over the past five years, highlighting developments of particular interest to generalists.

Methods

My choice of topics derives from my familiarity with patterns of medical practice, particularly in the United States; presentations at meetings; review of current textbooks; and monitoring of general medical journals, selected specialty journals on pain and cancer, and nine palliative care journals (see extra box on the BMJ 's website).

Why the need for palliative care?

Numerous recent studies confirm earlier observations that dying people and their families experience a wide range of unmet needs, while receiving very costly care.2 One large US study, SUPPORT, underscores many of these problems.3 This investigation enrolled patients who were admitted to an academic hospital with common, severe medical conditions and who had a median survival of six months. Considerable suffering and inappropriate use of resources were observed. Many patients died in pain or with high "symptom burdens."4 Doctors proved no better than chance in judging whether their patients wanted cardiopulmonary resuscitation. Family members often experienced social and financial devastation --- having to quit a job or suffering major losses of income or savings --- because of the illness.

Recent advances

Better management of chronic cancer pain through thoughtful use of common analgesics, including opioids, and recognition that neuropathic pain requires additional treatment with anticonvulsants or tricyclic antidepressants

Improved management of other symptoms --- gastrointestinal symptoms, dyspnoea, confusional states, and depression

Increasing use of advance care planning to preserve patient autonomy and choice around the time of death, when the capacity to make decisions may be impaired

Improved understanding of the role of artificial feeding and hydration for dying people, especially those with neurological impairments.

General consensus on the acceptability of withholding or withdrawing life sustaining supports and of the rule of double effect, which permits use of opioids and sedatives to relieve suffering even if death may ensue

Doctors' prognostic estimates are important to both patients and clinicians in making good decisions about appropriate terminal care. Recent studies indicate not only that doctors seem reluctant to speak to patients about death, but also that they are inaccurate and systematically optimistic about the future, thus delaying timely sharing of information and referral to appropriate palliative care services.5

Compared with conventional care, palliative care seems to improve patient and family satisfaction and the identification of their needs while reducing overall costs through decreased use of acute hospital care.6 Studies of medical school curriculums, postgraduate physician training programmes,7 and standard medical textbooks8 reveal disappointingly little attention to end of life issues. However, numerous palliative care journals, textbooks, courses, and websites are now available to help clinicians in providing good terminal care (see extra box on the BMJ 's website for details). Increasing evidence confirms that "bedside manner" (communication and psychosocial skills) for terminal care can be taught.9

Advances in pain management

Almost all pain faced by terminally ill people can be adequately relieved by simple, easily understood oral regimens that generally do not produce troublesome side effects.10 However, clinical practice continues to be characterised by unrelieved pain, illogical prescribing of analgesics, and widespread "opiophobia."

Analgesics for chronic pain should be administered at whatever dose is required to relieve distress. They should be prescribed "around the clock," based on their duration of action (usually every 4 hours for opioids), not when required, and must be supplemented by a "breakthrough" or "rescue" dose that is given as needed between the regular administrations. The analgesics may be supplemented with adjuvants, such as tricyclic antidepressants, anticonvulsants, psychostimulants, and glucocorticoids. All patients receiving opioids regularly require treatment to prevent constipation. An oral, poorly absorbed opioid antagonist, such as naloxone, can be helpful when usual laxatives are not working.11

Palliative care focuses primarily on alleviation of symptoms and support

Neuropathic pain is increasingly recognised for its importance in pain that is difficult to control.12 The treatment drugs of choice are anticonvulsants and tricyclic antidepressants. Gabapentin is a first line anticonvulsant drug for neuropathic pain. 13 14 Tricyclic antidepressants are effective in alleviating neuropathic pain even in patients who are not depressed, while selective serotonin reuptake inhibitors have not shown consistent benefit.15 Other drugs for managing pain include

Bisphosphonates to prevent and treat bony metastases and

associated pain in a variety of cancers,16 as well as radioisotopes such as strontium-89

New opioid preparations, particularly long acting oral

formulations and transdermal delivery systems, that simplify drug administration and may have other advantages * Systemically administered local anaesthetics, such as parenteral

lignocaine (lidocaine) or oral mexiletine, and ketamine for neuropathic pain

Psychostimulants to counteract sedative effect of opioids * Topical local anaesthetics, such as Emla cream (lignocaine and

prilocaine), to reduce skin pain from medical procedures * Specialised pain relieving procedures, such as nerve blocks and

spinal (epidural and intrathecal) analgesia.

Advances in alleviating other symptoms

Gastrointestinal symptoms

The use of prokinetic drugs and new serotonin antagonist antiemetics has improved the management of cancer related gastroparesis, nausea, and vomiting. Octreotide relieves AIDS related diarrhoea and can help in the management of intestinal obstruction. Nutritional supplements, including total parenteral nutrition,17 have failed to show benefit in patients with advanced cancer who have an intact digestive tract. Progestational drugs, such as megestrol acetate, and glucocorticoids improve anorexia.18

Dyspnoea

Opioids and oxygen are the drugs of choice for managing dyspnoea, and benzodiazepines are added for the almost inevitably accompanying anxiety. Nebulised opioids have not proved superior to oral or parenteral drugs in managing breathlessness.19

Confusional states

Delirium in terminally ill people is underrecognised and undertreated, with considerable associated morbidity.20 A study comparing haloperidol, chlorpromazine, and lorazepam in treating delirious AIDS patients confirms that the first two drugs, often in low doses, are superior in managing this condition. Importantly, the neuroleptics improved the organisation of thinking both for patients with agitation or other behavioural disturbances (so called "hyperactive delirium") and for more tranquil patients with confusion ("hypoactive delirium"), who may not have been routinely treated in the past.21

Depression and use of psychostimulants

Depression is common in terminal illness but is underrecognised and undertreated. Many clinicians incorrectly presume that depression is normal or expected in advanced illness, rather than viewing it as a biologically based and treatable form of suffering distinct from sadness.22 The biological signs that usually form the basis of a diagnosis of major depression are often present in a terminal condition but are attributable to the medical illness rather than the psychological state. Clinicians must assess patients for classic depressive signs that cannot be ascribed to the underlying illness (for example, early morning waking that is not due to pain) and rely more on such psychological findings as excessive hopelessness, helplessness, worthlessness, and guilt and suicidal ideation. One study has suggested that simply asking "Are you depressed?" will identify practically all dying people with substantial mood disorders.23

Because of their rapid onset of action, psychostimulants are now the drugs of choice for treating depression associated with advanced terminal disease.22 Clinicians can prescribe increasing doses of dexamfetamine or methylphenidate over three to four days, watching for a response or toxicity.

Advance care planning

With our expanding ability to prolong life, death increasingly occurs after decisions have been made to forego life sustaining measures. Such decisions are familiar in an intensive care unit, but they may also be appropriate at home, where hydration or antibiotic treatment may be foregone. Approaches to preserving patient autonomy and choice around the time of death, when the capacity to make informed decisions may be impaired, have been the subject of great interest in the United States. Since so many dying people are no longer able to make decisions, designation of a healthcare proxy is indicated for all adults. Advance care directives are not legally binding in many jurisdictions and are generally not available, retrieved, or honoured during acute hospital care. They also do not influence the use of resources and costs, 24 25 except perhaps in rare communities or specific institutions that have made systematic efforts to educate the public and make the directives readily available. 26 27



Dementia care

References

Two important observations help to clarify the role of artificial feeding and hydration for dying people, especially those with neurological impairments. Firstly, McCann and colleagues observed symptoms in chronic care patients who stopped drinking. The only evidence of physical suffering was a dry mouth, which was readily treatable with simple mouth care.28 Dehydration in advanced illness therefore does not seem to cause physical discomfort and need not be treated or prevented with artificial hydration. Secondly, patients who are aspirating continue to do so even after placement of nasogastric or percutaneous gastric tubes. Feeding tubes should definitely not be inserted in order to prevent aspiration.29 Among patients aged 65 or over who have gastrostomies placed in hospital, 24% die within 30 days and 63% within a year, suggesting a limited role for this intervention in sustaining life or improving wellbeing.30

Volicer and colleagues have outlined a remarkable "hospice approach" to the care of patients with advanced dementia.31 In a special dementia care unit, the staff provide regular conferences to share information with patients' families and make recommendations about five levels of supportive care --- "Full care," "Do not resuscitate" (DNR), DNR plus "Do not transfer to a hospital" (DNT), DNR plus DNT plus "Do not work up fevers" (DNWU), and all of the above plus "Do not tube feed" (DNTF). In a comparable dementia unit where the only alternate to full care was DNR, a third of patients died receiving full care. In the specialised dementia unit, 62% of patients die with orders for the lowest level of support and only 2% are receiving full care.

Hastening death

No aspect of palliative care has received as much attention recently as the ethics and possible legalisation of physician assisted suicide for terminally ill people. Practical experience in the state of Oregon32 sheds light on the subject. In the first 14 months in which physician assisted suicide was legalised in the state of Oregon, which has a population about 3.5 million and a monthly death rate of about 2400, fewer than two people a month requested and received a prescription for a lethal drug dose, and about half used the prescription.33 Physicians granted one in six requests for a lethal medication, and only one in 10 requests resulted in a suicide.32

Attention should shift away from the very small number of patients who persistently want to hasten their death to the growing information about the nature of suffering at the end of life, the motivation for seeking hastened death, guidelines on evaluating such requests, and general acceptance by ethicists, clinicians, and the US courts of appropriate management strategies based on widely recognised ethical distinctions.34 No patient should turn to suicide because of treatable, reversible conditions such as pain or other physical suffering, loneliness, depression, anxiety, or concerns about being a burden on the family.35 As many as 60% of dying people who express a wish to hasten their death are depressed and hence have treatable and potentially reversible suffering.22

Even under the best of care, however, a small fraction of patients, probably less than 1%, will persistently wish to have death hastened.34 These patients seem to be motivated more by concerns about not being able to function at a reasonable physical and mental level or about being a burden, rather than because of physical discomfort. Withholding or withdrawing life sustaining measures according to the wishes of the patient is now commonly endorsed in the United States and some other societies.

Likewise, decisions about foregoing life prolonging measures for incompetent patients can often be made by a proxy, particularly a formally assigned proxy or a close relative. The "rule of double effect" --- providing a medical treatment for the purpose of relieving suffering even though a foreseeable, unintended consequence of the treatment is to hasten death --- has been broadly accepted, though also criticised. 36 37 This rule should justify the liberal use of opioids and sedatives to control pain or dyspnoea or even emotional distress in terminal illness, a practice that can assure relief of suffering yet is considered distinct from euthanasia. An additional approach, voluntarily stopping eating and drinking, has been recommended so that patients may hasten their death without requiring a physician's direct assistance.38 Finally, some commentators have endorsed "terminal" sedation, more accurately termed "sedation for intractable suffering in the dying patient,"39 whereby a terminally ill person with irremediable suffering is sedated to unconsciousness. If fluids are not provided to such an unconscious patient, death soon ensues. With awareness of these options, physicians are better able to respond to a "bad death" as a medical emergency.40

Acknowledgments

I thank Drs Robert Arnold, Diane Meier, and Thomas J Smith and Martha Henderson for their helpful initial advice on topics to address. Drs Susan D Block and William Zinn helped greatly in editing of the manuscript. Derek Doyle generously made many suggestions on the paper in its final revision. Nan Lawless provided cheerful secretarial support.

Footnotes

Funding: This work was supported in part by National Cancer Institute grant No R25 CA 66818-04 and the Robert Wood Johnson Foundation.

Competing interests: None declared.

A list of journals, books, and websites about palliative care appears on the BMJ's website

References

1. Billings JA. What is palliative care? J Palliat Med 1998; 1: 73-81. 2. Field MJ, Cassel CK, eds. Committee on Care at the End of Life. Institute of Medicine. Approaching death: improving care at the end of life. Washington DC: National Academy Press, 1997. (www2.nas.edu/hcs/21da.htm)

3. The SUPPORT Principal Investigators. A controlled trial to improve care of seriously ill hospitalized patients: the study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA 1995; 274: 1591-1598[Medline]. 4. Desbiens NA, Mueller-Rizner N, Connors Jr AF, Wenger NS, Lynn J, for the SUPPORT Investigators. The symptom burden of seriously ill hospitalized patients. J Pain Symptom Manage 1999; 17: 248-255[Medline].

5. Christakis NA, Lamont EB. Extent and determinants of error in doctors' prognoses in terminally ill patients: prospective cohort study. BMJ 2000; 320: 469-473[Abstract/Full Text]. 6. Hearn J, Higginson IJ. Do specialist palliative care teams improve outcomes for cancer patients? A systematic literature review. Palliat Med 1998; 12: 317-322[Medline].

7. Billings JA, Block SD. Palliative care in undergraduate medical education: status report and future directions. JAMA 1997; 278: 733-738[Medline].

8. Rabow MW, Hardie GE, Fair JM, McPhee SJ. End-of-life care content in 50 textbooks from multiple specialties. JAMA 2000; 283: 771-778[Medline].

9. Baile WF, Kudelka AP, Beale EA, Glober GA, Myers EG, Greisinger AJ, et al. Communication skills training in oncology. Description and preliminary outcomes of workshops on breaking bad news and managing patient reactions to illness. Cancer 1999; 86: 887-897[Medline]. 10. Abrahm JL, for the ACP-ASIM End-of-life Care Consensus Panel. Management of pain and spinal cord compression in patients with advanced cancer. Ann Intern Med 1999; 13: 37-46[Medline]. 11. Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K. Oral naloxone reverses opioid-associated constipation. Pain 2000; 8: 105-109[Medline].

12. Foley KM. Advances in cancer pain. Arch Neurology 1999; 56: 413-417[Medline].

13. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1988; 280: 1831-1836[Medline].

14. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial [see comments]. JAMA 1998; 280: 1837-1842[Medline]. 15. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326: 1250-1256[Medline]. 16. Body JJ, Bartl R, Burckhardt P, Delmas PD, Diel IJN, Fleisch H, et al, for the International Bone and Cancer Study Group. Current use of bisphosphonates in oncology. J Clin Oncol 1998; 16: 3890-3899[Abstract].

17. Souba WW. Nutritional support. N Engl J Med 1997; 336: 41-48[Medline].

18. Bruera E, Neumann CM. Management of specific symptom complexes in patients receiving palliative care. Can Med Assoc J 1998; 158: 1717-1726.

19. Davis C. The role of nebulized drugs in palliating respiratory symptoms of malignant disease. Eur J Palliat Care 1995; 2: 9-15. 20. Mazzocato C, Stiefel F, Buclin T. Psychopharmacology in supportive care of cancer: a review for the clinician. Support Care Cancer 1999; 8: 89-97[Medline].

21. Breitbart W, Marotta R, Platt M, Weisman H, Derevenco M, Grau C, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153: 231-237[Abstract]. 22. Block SD, for the ACP-ASIM End-of-Life Care Consensus Panel. Assessing and managing depression in the terminally ill patient. Ann Intern Med 2000; 132: 209-218[Medline].

23. Chochinov HM, Wilson KG, Enns M, Lander S. Are you depressed? Screening for depression in the terminally ill. Am J Psychiatry 1997; 154: 674-676[Abstract].

24. Hanson LC, Tulsky JA, Danis M. Can clinical interventions change care at the end of life? Ann Intern Med 1997; 126: 381-388[Medline]. 25. Teno J, Lynn J, Wenger N, Phillips RS, Murphy DP, Connors Jr AF, et al, for the SUPPORT Investigators. Advance directives for seriously ill hospitalized patients: effectiveness with the Patient Self-Determination Act and the SUPPORT intervention. J Am Geriatr Soc 1997; 45: 500-507[Medline].

26. Hammes BJ, Rooney BL. Death and end-of-life planning in one midwestern community. Arch Intern Med 1998; 158: 383-390[Medline]. 27. Molloy DW, Guyatt GH, Russo R, Goeree R, O'Brien BJ, B√ądard M, et al. Systematic implementation of an advance directive program in nursing homes. JAMA 2000; 283: 1437-1444[Medline]. 28. McCann RM, Hall WJ, Groth-Juncker A. Comfort care for terminally ill patients: the appropriate use of nutrition and hydration. JAMA 1994; 272: 1263-1266[Medline].

29. Finucane TE, Bynum JP. Use of tube feeding to prevent aspiration pneumonia. Lancet 1996; 348: 1421-1424[Medline]. 30. Grant MD, Rudberg MA, Brody JA. Gastrostomy placement and mortality among hospitalized Medicare beneficiaries. JAMA 1998; 279: 1973-1976[Medline].

31. Volicer L, Hurley A. Hospice care for patients with advanced progressive dementia. New York: Springer Publishing, 1998. 32. Ganzini L, Nelson HD, Schmidt TA, Kraemer DF, Delorit MA, Lee MA. Physicians' experience with the Oregon Death with Dignity Act. N Engl J Med 2000; 342: 557-563[Medline].

33. Wineberg H. Oregon's Death with Dignity Act: 14 months and counting. Arch Intern Med 2000; 160: 21-23[Medline]. 34. Quill TE, Meier DE, Block SD, Billings JA. The debate over physician-assisted suicide: empirical data and convergent views. Ann Intern Med 1998; 128: 552-558[Medline].

35. Block SD, Billings JA. Patient requests to hasten death: evaluation and management in terminal care. Arch Intern Med 1994; 154: 2039-2047[Medline].

36. Quill TE, Dresser R, Brock DW. The rule of double effect --- a critique of its role in end-of-life decision making. N Engl J Med 1997; 337: 1768-1771[Medline].

37. Sulmasy DP, Pellegrino ED. The rule of double effect: clearing up the double talk. Arch Intern Med 1999; 159: 545-550[Medline]. 38. Quill TE, Byock IR, for the ACP-ASIM End-of-Life Care Consensus Panel. Responding to intractable terminal suffering: the role of terminal sedation and voluntary refusal of food and fluids. Ann Intern Med 2000; 132: 408-414[Medline].

39. Krakauer E, Penson RT, Truog RD, King LA, Chabner BA, Lynch TJ. Sedation for intractable distress of a dying patient: acute palliative care and the principle of double effect. Oncologist 2000; 5: 53-62. 40. Quill TE. "You promised me I wouldn't die like this!" A bad death as a medical emergency. Arch Intern Med 1995; 155: 1250-1254[Medline].

_________________________________________________________________

This article has been cited by other articles:

* Szlosarek, P. W, Goldman, A. (2001). Recent advances in palliative

care. BMJ 322: 234-234 [Full text]

Rapid Response responses to this article:

Read all Rapid Response responses

Depression in the terminally ill

Habib ur Rehman

bmj.com, 8 Sep 2000 [Response]

The UK approach to palliative care

Peter W Szlosarek, Clinical Research Fellow , 44 Lincoln's Inn fields, London WC2A 3PX

bmj.com, 23 Oct 2000 [Response]

Palliative care

Steven J Baumrucker

bmj.com, 15 Jan 2001 [Response]

Related letters in BMJ:

Recent advances in palliative care

Peter W Szlosarek and Ann Goldman

BMJ 2001 322: 234. [Letter]

Other related articles in BMJ:

EDITOR'S CHOICE

Let speculation run riot.

BMJ 2000 321: 0. [Full text]

EDITOR'S CHOICE [GP]

Let speculation run riot.

BMJ 2000 321: 0. [Full text]



http://www.bmj.com/cgi/content/full/322/7280/234

BMJ 2001;322:234 (27 January), Letters

RECENT ADVANCES IN PALLIATIVE CARE

United Kingdom continues to lead in palliative care Importance of palliative care for children is being increasingly recognised

United Kingdom continues to lead in palliative care

EDITOR --- It was disappointing to read Billings's review on palliative care.1 Many of the so called recent advances mentioned in the first part of the article have been practised for many years in the management of British patients with a terminal condition. Much of the second half of the article does palliative care a deep injustice.

The object of good palliative care is always the alleviation of suffering; hastening death is never the intention. It is wrong to suggest that most dying patients are unable to make decisions and that dehydration with the intention of committing euthanasia is an acceptable management option.

The situation in Oregon, with the promotion of physician assisted suicide, and that in the Netherlands, with high levels of involuntary killing, are a direct consequence of poor access to good palliative care. The United Kingdom pioneered palliative care and continues to lead in it.

Peter W Szlosarek, clinical research fellow. 44 Lincoln's Inn Fields, London WC2A 3PX szlos@doctors.org.uk



1. Billings JA. Recent advances: Palliative care. BMJ 2000; 321: 555-558[Full Text]. (2 September.)



Importance of palliative care for children is being increasingly recognised

EDITOR --- Billings writes about the palliative care needs of adults.1 Although fewer children than adults die, they also require palliative care. I am writing on behalf of the Palliative Care Working Group of the Royal College of Paediatrics and Child Health, which wants to alert readers to some of the special needs of children. 2 3

The illnesses from which children die are different from those from which adults die, and paediatric palliative care has emphasised the importance of developing services for children other than just those with cancer. The need for palliative care arises in four broad groups:

Life threatening conditions for which treatment is available but may fail --- for example, cancer

Conditions in which premature death is expected but long periods of intensive treatment to prolong good quality life are anticipated --- for example, cystic fibrosis, HIV infection/AIDS

Progressive conditions that may extend over many years and for which no curative treatment is available --- for example, Batten disease, mucopolysaccharidoses

Conditions with severe disability that, although not progressive, lead to extreme vulnerability and in which premature death is likely --- for example, cerebral palsy.

The continuing physical, emotional, and cognitive development in children sets them apart from adults. It influences all aspects of their care, including pharmacological treatment, their understanding of their disease, their communication skills, and their level of dependence.

Parents are usually the main carers for children, with care taking place at home. They and the child's siblings will need support throughout the child's illness and their bereavement.

Often, many professional and voluntary agencies are involved, as skill in different aspects of paediatrics and palliative care is needed. Care in hospital, care at home, respite care, and education all need to be coordinated, and community paediatric nurses often do this as key workers.

Many children have prolonged illnesses; an integrated approach is then required, with a gradual change in the emphasis of care between treatments aiming to cure or prolong life and palliative care, rather than one having rigid boundaries.

Although palliative care for children is a relatively young specialty, its importance is being increasingly recognised. The Royal College of Paediatrics and Child Health has established a special interest group to promote the best possible care and develop medical training. Similar commitment exists in nursing. The voluntary sector contributes heavily, particularly with children's hospices, and government help has come through the "Diana nurses" project.

Ann Goldman, covenor, Palliative Care Working Group, Royal College of Paediatrics and Child Health.

Department of Haematology and Oncology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH

ann.goldman@gosh-tr.nthames.nhs.uk

_____________________

1. Billings JA. Recent advances: palliative care. BMJ 2000; 321: 555-558[Full Text]. (2 September.)

2. Association for Children with Life-threatening and Terminal Conditions and their Families (ACT) and the Royal College of Paediatrics and Child Health. A guide to the development of children's palliative care services. London: RCPCH, 1997. 3. American Academy of Paediatrics, Committee of Bioethics and Committee of Hospital Care. Palliative care for children. Pediatrics 2000; 106: 351-357[Abstract/Full Text].

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