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Prophylactic anticholinergic dosing once death was imminent in hospice patients reduced death rattle, the SILENCE trial showed.

Subcutaneous scopolamine butylbromide (which is not FDA approved) cut the incidence of grade 2 or greater noisy breathing from mucus in the respiratory tract to 13% compared with 27% with placebo (P=0.02).

Time from recognition that the patient was in the active dying phase to onset of death rattle also favored scopolamine (HR 0.44, 95% CI 0.20-0.92), reported Harriëtte van Esch, MD, of Erasmus Medical Center Cancer Institute in Rotterdam, the Netherlands, and colleagues .

Adverse events of concern for an anticholinergic were similar between the drug and placebo groups:

• Restlessness (28% vs 23%)
• Dry mouth (10% vs 15%)
• Urinary retention (23% vs 17%)

With such minimal risks, the trial "provides the most rigorous available evidence" supporting prophylactic anticholinergic medications for dying patients, with the goal of reducing upper airway secretions before they form, noted Jared R. Lowe, MD, and Laura C. Hanson, MD, MPH, both of the University of North Carolina School of Medicine at Chapel Hill, in an .

"Anticholinergics decrease the production of mucus and therefore do not affect existing mucus; thus administering an anticholinergic drug after the onset of a death rattle may be less effective than prophylactic use (i.e., before its onset)," the researchers agreed.

Still, death rattle is controversial as a target of therapy because it is not necessarily distressing to patients, the editorialists pointed out.

"One counterargument is to embrace humility and acknowledge that the internal experience of the dying, nonverbal patient cannot be fully known, but when in doubt regarding comfort, it is best to try treatment," they argued. Also, the patient's family is part of the unit of care, so attending to their distress and discomfort at what can be interpreted as air hunger or choking is appropriate and may help reduce complex grief, depression, and post-traumatic symptoms that might result from such negative experiences, they added.

"Despite the significant findings of this well-conducted randomized clinical trial, the results may have limited applicability to change current practice, particularly in the United States," Lowe and Hanson wrote.

The trial was done in six hospices in the Netherlands among 162 patients with a life expectancy of 3 or more days who gave advance informed consent and were randomized when the dying phase was recognized to double-blind treatment with subcutaneous scopolamine butylbromide, 20 mg four times a day, or placebo. Most of the patients had cancer as their primary diagnosis (84% and 89%, respectively).

Study medication continued until death or until the occurrence of grade 2 or higher death rattle (audible from the foot of the bed) at two consecutive time points 4 hours apart. After that, patients received care as usual, which could include open-label anticholinergics.

Thus, the intervention likely would be applicable only to inpatient settings, Lowe and Hanson pointed out. Scopolamine butylbromide is not approved in the U.S. in the formulation used in the study, and the transdermal form of it may require an estimated five to eight patches to reach such doses and have a different adverse event profile, they added.

Additional research on other anticholinergic medications such as atropine, glycopyrrolate, or parenteral hyoscine would need to be studied for efficacy and safety of prophylactic administration before changing standard practice, Lowe and Hanson argued.

"Perhaps even more significant for clinicians who care for dying patients, the research methods employed by the SILENCE investigators offer confirmation that high-quality end-of-life research is feasible," they wrote. "Clinical trials of palliative care and hospice care are relatively rare, and investigators must overcome major ethical and practical challenges in design."

About half of hospice patients weren't eligible, "largely because of an inability to understand the information and imminent death," the researchers noted, and some others dropped out subsequently or were withdrawn from the study due to not actually being in the active death phase.

Still, advance written consent was a novel and successful method that other trials can emulate, along with the structured symptom distress outcome measures, the editorialists acknowledged. "This approach provides a model of data gathering that can guide future clinical trial design in end-of-life care."

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