Atropine Eyedrops for Death Rattle in a Terminal Cancer Patient

Introduction

“Death rattle” is a term used to describe the noisy sound produced by dying patients. It is caused by the oscillatory movements of secretions in the upper airways in association with the inspiratory and expiratory phases of respiration. ¹ The absence of swallowing and coughing reflexes, as well as patients being in a supine or semi-recumbent position, can result in secretions pooling in the oropharynx and bronchi. ² Death rattle is observed in 23% to 92% of dying cancer patients and occurs between 17 and 57 hours prior to death. ³ Some antimuscarinic drugs, including atropine, scopolamine (hyoscine hydrobromide), hyoscine butylbromide, and glycopyrronium, have been used to diminish the noisy sound by reducing airway secretions.^1–3 One randomized study reported that muscarinic receptor antagonists clearly improved the intensity of the rattle up to 24 hours in terminally ill patients, with no significant differences in the effectiveness of atropine, hyoscine butylbromide, and scopolamine. ¹ Although in most clinical studies antimuscarinic drugs are administered subcutaneously, a buccal or sublingual route of administration is more convenient in clinical practice. We report on the effectiveness of sublingual atropine eyedrops in alleviating death rattle in a terminal cancer patient.

Case Description

A 58-year-old man with pancreatic cancer was admitted to the hospital for severe dyspnea, cough, and audible upper airway secretions thought to be secondary to multiple lung metastases and a 20-year smoking history. The patient's dyspnea and cough did not improve with 2 mg betamethasone, codeine, carbocisteine, and oxycodone on demand as antitussive drugs. The severe cough often interfered with the patient's conversations with his caregiver and family. To suppress cough and the audible upper airway secretions, we planned to administer morphine and scopolamine via continuous subcutaneous injection. The patient rejected this plan on the grounds that he did not want to limit his daily activities by carrying an injection pump around. In addition, the patient was not happy about the possibility of daytime somnolence as an adverse effect of the morphine and scopolamine: He wanted to be able to maintain his ability to communicate with those around him and to continue to eat and swallow. Accordingly, we administered 1% atropine eyedrops sublingually, three drops 3 times a day and rescue dose at any time, to obviate the need for any equipment and to avoid somnolence. The sublingual administration of 1% atropine eyedrops satisfactorily suppressed the audible upper airway secretions and persistent cough by clearing the airway, with no adverse effects such as tachycardia and somnolence. The patient continued on this regimen for the last 2 weeks of his life.

Discussion

Bennett and colleagues proposed that “death rattle” be classified into two types: Type 1 death rattle, which is caused by decreased levels of consciousness and can be treated satisfactorily by antimuscarinic drugs, which inhibit salivary secretion; and Type 2 death rattle, which is related to increased bronchial secretion in pulmonary infection and edema and causes severe distress in conscious patients. ⁴ Morita and coworkers supported Bennett's hypothesis that the development of death rattle is influenced by brain and lung malignancies. ⁵ The death rattle in the present case fits with the pathophysiology of Type 2 death rattle given the patient's lucidity and the duration of treatment over 2 weeks. Generally, Type 2 death rattle tends to be refractory to standard treatments, which is managed by repositioning and clearing the upper airways of fluid, or by the administration of an antimuscarinic drug.^5,6 As an alternative, nebulized antimuscarinic, opioid, or local anesthetic drugs are recommended for the suppression of cough receptor stimulation by excessive bronchial secretions becoming refractory to antimuscarinic drugs and gentle aspiration, which is a specific associated problem in conscious patients with Type 2 death rattle. ⁴ Steroids and/or antibiotics may also be useful to control symptoms in cases suspected of having pulmonary infection. ⁴

Antimuscarinic drugs, such as atropine, scopolamine (hyoscine), glycopyrronium, and hyoscine butylbromide, are used as standard treatments for the palliation of death rattle. In one randomized comparative study, different antimuscarinic drugs were shown to be equally effective for the treatment of death rattle in terminal patients, ¹ with the specific treatment being more effective when started earlier rather than later. Thus, starting antimuscarinic drugs at the first occurrence of death rattle, even at low intensity, is recommended because the effectiveness is higher. ¹ Pharmacologically, both atropine and scopolamine cross the blood–brain barrier and can thus cause sedation and central nervous system (CNS) side effects; in contrast, glycopyrronium and hyoscine butylbromide only act peripherally. ² However, comparative studies indicate that there are no significant differences in the levels of CNS side effects caused by atropine, scopolamine, and hyoscine butylbromide, ¹ and there are no severe adverse effects caused by atropine eyedrops sublingually.^7,8 In the above case, agitation and/or somnolence were actually not seen following the administration of atropine eyedrops sublingually.

The reason atropine eyedrops were considered in this case is due to limited availability of antimuscarinic formulations in Japan and patient preferences. Our patient preferred not to be tethered to a subcutaneous infusion or have a health care professional be involved with medication administration. Therefore, we did not use scopolamine or suggest hyoscine butylbromide. Both scopolamine and hyoscine butylbromide are only available as injections in Japan, such that a health care professional would need to cut the ampule and load the syringe to measure the applied dosage each time before the administration. Glycopyrronium, both intravenously and as a nebulizer, and transdermal scopolamine can also be used in the treatment of death rattle in terminal patients and is an attractive alternative because of its favorable side-effect profile.^9–11 However, glycopyrronium and transdermal scopolamine are not available in Japan.

Although atropine eyedrops have been described anecdotally for distressing upper respiratory secretions,^12,13 and is even an option on some hospice formularies in the United States, there are no studies describing their efficacy in this clinical situation. Literature searches on MEDLINE, CINAHL, and EMBASE revealed the efficacy of atropine eyedrops for drooling with upper digestive cancer patients and sialorrhea with neurological disorders.^7,8 This case report is the first to document the clinical use of atropine eyedrops to palliate death rattle in a cancer patient.

On the basis of our experience, we conclude that atropine eyedrops, administered sublingually for distressing upper respiratory secretions, may be an effective alternative to the injection of antimuscarinic drugs, or as an option when other antimuscarinic formulations are not available. Additional studies investigating atropine eyedrops sublingually for patients at the end of life with distressing death rattle should be conducted.