Download Evidence Matters The Use of Anticholinergics for the Management

Evidence Matters
Vol. 1, No. 3 • SUMMER 2007
The Use of Anticholinergics for the Management
of Terminal Secretions Melissa Y. Gray, PharmD
What causes terminal secretions?
Terminal secretions are common during the last days of a patient’s life and are recognized as a strong predictor of
impending death. Secretions accumulate in the lungs or oropharynx when dying patients lose consciousness or are
too weak to clear their own secretions. Air passing through or over these secretions during inspiration and expiration can cause a noisy, rattling sound, which led to the term “death rattle” for this phenomenon.1, 2 Excessive secretions in dying patients may also be related to infection, pulmonary edema, and/or fluid overload.
Terminal secretions may be categorized as either type 1 or type 2, based upon their primary source.1 Type 1
secretions are caused by the accumulation of and inability to clear saliva, and type 2 secretions are primarily caused
by the accumulation of bronchial secretions in patients unable to expectorate.1 These subtypes were proposed to
indicate whether a patient’s secretions were likely to respond to anticholinergic therapy. However, the subtypes have
never been validated in a clinical study, and it may be difficult for clinicians to determine the patient’s particular
type of secretion.
Who is at risk for terminal secretions?
The reported prevalence of terminal secretions varies from 23 to 92% depending on the investigator’s definition
and study populations.1–8 Evidence suggests that patients with lung or brain malignancies or those who undergo a
prolonged dying phase are at increased risk for developing terminal secretions.1, 7, 8 Patients with diseases known to
inhibit swallowing reflexes, such as head and neck or esophageal cancers, or those with neurodegenerative processes
have also been associated with a higher risk of terminal secretions.9
What is the impact of terminal secretions on patients and their caregivers?
Although terminal secretions can contribute to dyspnea, restlessness, and insomnia,1, 9, 10 patients experiencing
terminal secretions usually have decreased awareness, therefore, the presence of secretions and associated sounds
may be more distressing to family caregivers than to the patient.9 Studies indicate that family distress related
to terminal secretions varies and some family members view the development of secretions as a helpful sign of
impending death.11 Family members who think that the sound indicates choking or drowning are more likely to be
disturbed by it.12 Because family members (and even some health-care professionals) vary in their interpretations
and responses to noisy respirations, it is important to explain the cause of this symptom.10, 12
What is the role of anticholinergics for terminal secretions?
Anticholinergic (or, more specifically, antimuscarinic) agents inhibit secretion production but have no effect on
secretions that are already present.3, 6, 13, 14 Therefore, if anticholinergic therapy is indicated, agents should be
initiated at the first sign of symptoms. The response rate to anticholinergics varies greatly, ranging from 40 to 80%.
1–8, 13
Salivary (type 1) secretions are more likely to respond to anticholinergic therapy than bronchial (type 2)
secretions.13, 14 One possible explanation for this difference is that bronchial secretions take longer to accumulate
Evidence Matters is Hospice Pharmacia’s newsletter devoted to promoting evidence-based palliative care.
to a clinically noticeable volume.3, 13, 14 Prophylactic treatment with anticholinergic therapy in high-risk patients may
improve outcomes, but more research is needed to support this theory.7 Because the use of anticholinergics may
produce significant side effects, their benefits and burdens should be carefully considered, and for some patients,
non-pharmacologic options may be more appropriate.
Which anticholinergic should I use and what dose and route are appropriate?
The most commonly used anticholinergics to treat excessive secretions include atropine, scopolamine, glycopyrrolate,
and hyoscyamine. Currently, management of terminal secretions is largely based upon anecdotal experience; there is no
conclusive empirical evidence that one agent is more effective than the others.3, 6, 13, 14 Therefore, appropriate agent selection should be based on the agent’s adverse effect profile, onset of action, duration of action, route of administration,
and cost. While higher doses may be observed in practice, the doses provided below are literature-based recommended
starting doses.
Atropine (Atreza™, Sal-Tropine®, Isopto-Atropine®, others) is commonly used to manage terminal secretions. It may be
administered by oral (PO), intramuscular (IM), intravenous (IV), or subcutaneous (SC) routes at a starting dose of 0.4
mg every 4–6 hours as needed.15–18 Atropine 1% eye drops can be given orally to the back of the throat or sublingually
to provide rapid relief of symptoms.10 The initial recommended dose for the oral administration of eye drops is 1–2
drops every 4–6 hours as needed.16–18 Findings from a single unpublished study indicated that atropine ophthalmic
solution administered sublingually was effective at reducing terminal respiratory secretions.19 Other studies have
reported limited success using atropine drops for other hypersalivary conditions.20–22
Scopolamine (Transderm Scop®, Scopace®, Isopto Hyoscine®) may be administered by PO, IM, IV, and SC routes. Oral
therapy is initiated at a starting dose of 0.4 mg every 8 hours as needed, whereas parenteral dosage forms are initiated at
a starting dose of 0.4 mg every 4 hours as needed.3, 15, 17, 23 Scopolamine is also available as a transdermal patch, which is
applied behind the ear and changed every 72 hours.9 There is limited evidence to support the application of more than
one patch. One case report and one study showed that two patches were tolerated,24, 25 but the use of three patches is
based solely upon anecdotal reports.14, 15 Because the patch may take up to 12 hours for effect, there are limited benefits
for actively dying patients.9, 14
Glycopyrrolate (Robinul®, Robinul Forte®) may be administered by PO, IM, IV, and SC routes. The recommended
parenteral starting dose is 0.2–0.4 mg three to four times daily as needed.3, 26 Studies comparing glycopyrrolate and
scopolamine found that glycopyrrolate injection had a slower onset and longer duration of action compared to
scopolamine injection, but there was no evidence to support the use of one agent over the other.3, 5, 13, 27 Oral
glycopyrrolate, in the form of tablets or liquid, has slow, erratic absorption and usually requires higher starting doses
around 1–2 mg two to three times daily as needed for effect.28, 29
Hyoscyamine (Levsin®, Levbid®, Levsin SL®, others) is most commonly administered PO or SL. It is available as an
immediate-release disintegrating tablet and oral liquid and as a sustained-release tablet/capsule. An injectable form
may also be given IV, IM, or SC. The recommended starting dose for immediate-release oral and parenteral formulations is 0.125–0.25 mg every 4 hours as needed.15, 30 Use of hyoscyamine for terminal secretions is purely anecdotal
and based on its anticholinergic mechanism of action.14, 15
What side effects should I monitor for with anticholinergic therapy?
While anticholinergic medications can effectively manage some secretions, it is important to weigh the risks of potential
side effects versus the potential benefits. Elderly patients are particularly sensitive to side effects from anticholinergics.
However, during the terminal phase of a patient’s life, the potential benefit of the drugs in reducing secretions and
easing respirations may outweigh the burden of side effects.
Atropine and scopolamine are capable of crossing the blood-brain barrier and are, therefore, likely to produce
CNS side effects such as drowsiness, confusion, delirium, hallucinations, paradoxical agitation, and restlessness.
In comparison, glycopyrrolate and hyoscyamine are far less likely to penetrate this barrier and are relatively free of
central side effects.16, 23, 26, 29, 30
To cite this article: Gray MY. The Use of Anticholinergics for the Management of Terminal Secretions. Evidence Matters. Summer 2007; 1(3).
Anticholinergics may also cause blurred vision, constipation, dry mouth, urinary retention, and cardiac side
effects (tachycardia or bradycardia, arrhythmias),16, 23, 26, 29, 30 although the degree to which these side effects are
bothersome in dying patients is not known. Compared to the other agents available, atropine is more likely to
cause tachycardia.2, 28 In addition, although rare, some patients may experience an anaphylactic or serious adverse
reaction to atropine. Because scopolamine and hyoscyamine are chemically related to atropine, patients prescribed
these medications may experience a cross reaction. However, because of the marked differences in the chemical
structures, it is unlikely that a patient who reacts to atropine will react to glycopyrrolate in the same manner. In
general, the severity of side effects tends to be dose-related, and side effects are cumulative when patients are taking
more than one medication with anticholinergic activity (e.g., tricyclic antidepressants or antipsychotic agents).
HP Partners, please refer to the secretions algorithm on page 80 in the Hospice Pharmacia Medication Use
Guidelines, 8th Edition for more information on therapeutic options.
Conclusion
• Terminal
secretions occur in a large number of dying patients and are a strong predictor of impending death.
respiratory secretions can be, but are not always, a source of distress to relatives. Providing education
and reassurance about the cause and management of secretions may help relieve caregiver distress.
• Salivary secretions are more likely to respond to anticholinergic therapy than bronchial secretions.
• Anticholinergic agents should be initiated as soon as symptoms appear; although they can inhibit production of
secretions, they have no effect on secretions that are already present.
• There is no conclusive evidence that one anticholinergic agent is more effective than the others, however, the sideeffect profile among the available agents differ. Further comparative clinical trials and evidence-based guidelines
are needed.
• Consider the risk versus benefit before starting anticholinergic therapy, especially in the elderly.
• Terminal
References*
1. Bennett MI. Death rattle: An audit of hyoscine (scopolamine) use and review of management. J Pain Symptom Manage.
Oct 1996;12(4):229–233.
2. Wildiers H, Menten J. Death rattle: Prevalence, prevention and treatment. J Pain Symptom Manage. 2002;23(4):310–317.
3. Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle.
Palliat Med. Jul 2001;15(4):329–336.
4. Ellershaw JE, Sutcliffe JM, Saunders CM. Dehydration and the dying patient. J Pain Symptom Manage. 1995;10(3):192–197.
5. Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: A comparison between glycopyrronium and hyoscine
hydrobromide. J Palliat Med. Apr 2006;9(2):279–284.
6. Hughes A, Wilcock A, Corcoran R, Lucas V, King A. Audit of three antimuscarinic drugs for managing retained secretions. Palliat Med. May
2000;14(3):221–222.
7. Kass RM, Ellershaw J. Respiratory tract secretions in the dying patient: A retrospective study. J Pain Symptom Manage.
Oct 2003;26(4):897–902.
8. Morita T, Tsunoda J, Inoue S, Chihara S. Risk factors for death rattle in terminally ill cancer patients: a prospective exploratory study. Palliat
Med. Jan 2000;14(1):19–23.
9. Spiller JA, Fallon M. The use of Scopoderm in palliative care. Hosp Med. 2000;61(11):782–784.
10. Sorenson HM. Managing secretions in dying patients. Respir Care. 2000;45(11):1355–1363.
13. Bennett M, Lucas V, Brennan M, Hughes A, O’Donnell V, Wee B. Using anti-muscarinic drugs in the management of death rattle:
Evidence-based guidelines for palliative care. Palliat Med. 2002;16(5):369–374.
14. Owens DA. Management of upper airway secretions at the end of life. J Hosp Palliat Nurs. 2006;8(1):12–14.
27. Lawrey H. Hyoscine vs glycopyrronium for drying respiratory secretions in dying patients. Br J Community Nurs. Sep 2005;10(9):
421–424, 426.
*Reference numbers correspond with those noted in the text. For a complete list of references, please visit our
website, www.hospicepharmacia.com/evidencematters
Please send comments or ideas for clinical topics to [email protected] or give us a call at 215.282.1724
S U M MER 2007
Evidence Matters
Dear Clinician,
This latest issue of Evidence Matters, the newsletter devoted to sharing clinical informa-
Additional copies of this
tion and promoting an evidence-based approach to palliative medicine, elucidates The Use of
Anticholinergics for the Management of Terminal Secretions.
newsletter can be
downloaded from the
This newsletter is a production of the Quality Outcomes team at excelleRx. Our team is
dedicated to building the evidence base and improving outcomes related to chronic illness
and palliative care. We welcome your feedback and questions as well as your suggestions for
Quality Outcomes section of
www.hospicepharmacia.com
future topics.
We hope you find this publication a valuable resource.
Sincerely,
The Quality Outcomes Team • [email protected] • 215.282.1724
1601 Cherry Street, Suite 1700
Philadelphia, PA 19102
Full reference list
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Bennett MI. Death rattle: An audit of hyoscine (scopolamine) use and review of
management. J Pain Symptom Manage. Oct 1996;12(4):229-233.
Wildiers H, Menten J. Death rattle: Prevalence, prevention and treatment. J Pain Symptom
Manage. 2002;23(4):310-317.
Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide
and glycopyrrolate in the treatment of death rattle. Palliat Med. Jul 2001;15(4):329-336.
Ellershaw JE, Sutcliffe JM, Saunders CM. Dehydration and the dying patient. J Pain
Symptom Manage. 1995;10(3):192-197.
Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: A
comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med. Apr
2006;9(2):279-284.
Hughes A, Wilcock A, Corcoran R, Lucas V, King A. Audit of three antimuscarinic drugs for
managing retained secretions. Palliat Med. May 2000;14(3):221-222.
Kass RM, Ellershaw J. Respiratory tract secretions in the dying patient: A retrospective
study. J Pain Symptom Manage. Oct 2003;26(4):897-902.
Morita T, Tsunoda J, Inoue S, Chihara S. Risk factors for death rattle in terminally ill cancer
patients: a prospective exploratory study. Palliat Med. Jan 2000;14(1):19-23.
Spiller JA, Fallon M. The use of Scopoderm in palliative care. Hosp Med. 2000;61(11):782784.
Sorenson HM. Managing secretions in dying patients. Respir Care. 2000;45(11):1355-1363.
Wee BL, Coleman PG, Hillier R, Holgate SH. The sound of death rattle I: Are relatives
distressed by hearing this sound? Palliat Med. 2006;20(3):171-175.
Wee BL, Coleman PG, Hillier R, Holgate SH. The sound of death rattle II: How do relatives
interpret the sound? Palliat Med. 2006;20(3):177-181.
Bennett M, Lucas V, Brennan M, Hughes A, O'Donnell V, Wee B. Using anti-muscarinic
drugs in the management of death rattle: Evidence-based guidelines for palliative care.
Palliat Med. 2002;16(5):369-374.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Owens DA. Management of upper airway secretions at the end of life. J Hosp Palliat Nurs.
2006;8(1):12-14.
Berger AM. Management of Symptoms in the Actively Dying Patients. In: Berger AM,
Portenoy RK, Weissman DE, (eds). Palliative Care and Supportive Oncology. 2nd ed.
Philadelphia: Lippincott Williams and Wilkins; 1998:791.
Sal-Tropine. [package insert]. Hope Pharmaceuticals. Last updated February 2007;
Available at: http://www.hopepharm.com/saltropine/cd_presc.html.
Sherman CR. Atropine and scopolamine for the treatment of sialorrhea [Letter to the Editor].
Am Fam Phys 2005; 71(10). Last updated May 15, 2005; Available at:
http://www.aafp.org/afp/20050515/lettersonline.html. Accessed May 29, 2007.
Sherman CR, Sherman BR. Atropine sulfate--a current review of a useful agent for
controlling salivation during dental procedures. Gen Dent. Jan-Feb 1999;47(1):56-60; quiz
61-62.
Protus BM, Grauer PA, Kimbrel JM, Kennedy WJ. Evaluation of the use of atropine 1%
ophthalmic solution administered sublingually for the management of terminal respiratory
secretions. Presented at: Ohio State University Research Day, 2006.
Hyson HC, Johnson AM, Jog MS. Sublingual Atropine for sialorrhea secondary to
parkinsonism: A pilot study. Mov Disord. 2002;17(6):1318-1320.
De Simone GG, Eisenchlas JH, Junin M, Pereyra F, Brizuela R. Atropine drops for drooling:
A randomized controlled trial. Palliat Med. Oct 2006;20(7):665-671.
Comley C, Galletly C, Ash D. Use of atropine eye drops for clozapine induced
hypersalivation. Aust N Z J Psychiatry. 2000;34(6):1033-1034.
Scopace. [package insert]. Hope Pharmaceuticals. Last updated February 2007; Available at:
http://www.motionsickness.net/prescrib.html.
Dreyfuss P, Vogel D, Walsh N. The use of transdermal scopolamine to control drooling: A
case report. Am J Phys Med Rehab. 1991;70(4):220-222.
Talmi YP, Finkelstein Y, Zohar Y. Reduction of salivary flow with transdermal scopolamine:
A four-year experience. Otolaryngol Head Neck Surg. 1990;103(4):615-618.
Robinul Injection. [package insert]. Baxter Healthcare Corporation. Last updated January
2005; Available at: http://www.fda.gov/medwatch/SAFETY/2004/nov_PI/Robinul_PI.pdf.
Accessed May 29, 2007.
Lawrey H. Hyoscine vs glycopyrronium for drying respiratory secretions in dying patients.
Br J Community Nurs. Sep 2005;10(9):421-424, 426.
Olsen AK, Sjogren P. Oral glycopyrrolate alleviates drooling in a patient with tongue cancer.
J Pain Symptom Manage. Oct 1999;18(4):300-302.
Glycopyrrolate Tablets. [package insert]. United Research Laboratories, Inc. Last updated
2004.
Hyoscyamine Sulfate Sublingual Tablets. [package insert]. Ethex Corporation. Last updated
September 2006; Available at:
http://www.ethex.com/pages/prod_page.asp?PRID=58177025504. Accessed May 29, 2007.