Atropine: Terminal Respiratory Secretions

Abstract

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu.

Data from case reports and a retrospective chart review of palliative care patients indicate that sublingual administration of ophthalmic atropine may provide subjective reductions in noisy respiratory tract secretions, commonly referred to as “death rattle.” The results of a randomized control trial failed to demonstrate a significant benefit after single-dose administration (2 drops) compared to placebo. The quick onset of action and ease of sublingual atropine administration compared to alternative anticholinergic agents may make sublingual atropine an acceptable option in end-of-life care.

Rationale

Terminal respiratory secretions are associated with noisy breathing commonly known as “death rattle” and may occur in up to 51.4% of terminally ill patients during the final 2 weeks of life. Death rattle is not harmful. The goal of treatment is to reduce distress to the patient if present, but more often to relieve distress of family and caregivers. The optimal treatment is unknown; however, anticholinergic agents including scopolamine, glycopyrrolate, hyoscine butylbromide, and atropine have been used to reduce salivation and bronchial secretions.^1,2

Population

Terminally ill adult hospice patients.

Dosing Studied

Sublingual (using 1% ophthalmic solution): Initial dose of 1 to 2 drops every 2 to 4 hours, with a usual dose range of 2 to 4 drops every 2 to 4 hours. ³

Discussion

Data from case reports and a retrospective chart review of palliative care patients indicate that sublingual administration of ophthalmic atropine may provide subjective reductions in noisy respiratory tract secretions, commonly referred to as “death rattle.” The results of a randomized control trial failed to demonstrate a significant benefit after single-dose administration (2 drops) compared to placebo. The quick onset of action and ease of sublingual atropine administration compared to alternative anticholinergic agents may make sublingual atropine an acceptable option in end-of-life care.

Controlled Trial

A double-blind, placebo-controlled trial enrolled 160 terminally ill adult palliative care hospice inpatients with audible respiratory tract secretions. Mean patient age was 77.2 years (median, 78 years), and 43% had a principal terminal diagnosis of cancer. More patients in the atropine group were female (73% vs 50.8%; P = .001). Patients were randomized to receive a single dose of 2 drops of sublingual atropine 1% solution or placebo saline solution at the first sign of an audible death rattle, as assessed by bedside nurses. Patients were assessed at 2 and 4 hours after dose administration. The primary endpoint was the proportion of patients with improvement in noise score at 2 hours, defined as a reduction of 1 or more points on the noise scale (quantified by bedside nurses; 0 = inaudible, 1 = audible only very close to the patient, 2 = clearly audible at the end of the bed, 3 = clearly audible at about 20 feet in a quiet room). Secondary endpoints included improvement in noise score at 4 hours after dose and change in heart rate from baseline to 2 hours. Data were available for 137 patients at the 2-hour assessment and 128 patients at the 4-hour assessment due to death of participants prior to assessment. The study was terminated prematurely after 71% of planned enrollment was reached due to futility. The proportion of patients that experienced a reduction in noise score was not significantly different between patients treated with atropine and those treated with placebo at 2-hour (37.8% vs 41.3%; P = .73) or 4-hour (39.7% vs 51.7%; P = .21) assessments. Change in heart rate was not significantly different between groups. No adverse effects were reported. Results of this study did not suggest that a single dose of sublingual atropine was more effective than placebo at reducing the noise associated with death rattle. Results may have been limited by the single-dose design and small sample size; however, the futility analysis demonstrates that a significant difference would have been unlikely if enrollment had continued as planned. ¹

Case Reports/Case Series

In a retrospective chart review, 147 hospice inpatients receiving terminal care were identified. Admission orders for all patients included 2 drops of atropine 1% ophthalmic solution sublingually every 2 hours as needed for terminal secretions. Main outcome measures included level of restlessness and respiratory rate. Of the charts reviewed, 40 patients (27%) developed noisy terminal respiratory secretions. Twenty-two of these were treated with only atropine (dose range, 1 to 7 mg), 10 were treated with an alternative medication with or without atropine, and 8 patients were not treated with medication. Nineteen of the 22 patients treated with only atropine had a documented reduction or resolution of terminal respiratory secretions, as documented by the nurse who recognized the onset of noisy terminal respiratory secretions and administered treatment. The majority of patients (68%) required 1 or 2 doses of sublingual atropine to prevent further noisy terminal respiratory secretions. Median time from onset of terminal respiratory secretions to death was 27.6 hours in patients treated with atropine only. No changes in heart rate, respiratory rate, or level of restlessness were reported. These results suggest that atropine ophthalmic drops administered sublingually improve terminal respiratory secretions. Limitations included small study size and subjective assessment of effects of atropine administration. ³

A 58-year-old male with terminal pancreatic cancer developed audible upper airway secretions, possibly related to multiple lung metastases and a long history of smoking. He was admitted to the hospital for dyspnea, cough, and audible airway secretions. Dyspnea and cough did not improve with the administration of 2 mg betamethasone, codeine, carbocisteine, and oxycodone as needed for antitussive therapy. The patient requested treatment for these symptoms that would not produce significant adverse reactions such as somnolence. Three drops of atropine 1% ophthalmic solution were administered sublingually 3 times daily with a rescue dose as needed. This suppressed the audible upper airway secretions and persistent cough to a level satisfactory to the patient. No adverse effects such as tachycardia and somnolence occurred. This regimen was continued for the last 2 weeks of the patient's life. ⁴

Risk/Benefit Considerations

This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, Warnings/Precautions, Adverse Reactions, Drug Interactions).

No adverse effects were reported in the included studies; however, atropine use has been associated with anticholinergic adverse reactions such as dry mouth, urinary retention, agitation, confusion, delirium, and tachycardia.

Sublingual use of an ophthalmic preparation may result in medication errors. A 55-year-old woman was mistakenly prescribed atropine 1% ophthalmic drops to both eyes 3 times daily when admitted to the hospital. The order was mistranscribed from her home medication list; atropine was intended for sublingual use. Ophthalmic administration resulted in blurry vision until the error was resolved. ⁵