At the extreme end of life, patients often develop noisy respiration that is secondary to salivary or bronchial secretions that accumulate in the oropharynx. It is most commonly observed in terminal patients who are too weak to expectorate. Type 1 death rattle is sometimes defined as noisy breathing caused by loss of swallowing reflex in patients near death. Type 1 noisy breathing, sometimes referred to as "true death rattle," is thought to result from the unpredictable accumulation of salivary secretions during the last few hours of the patient's life. In contrast, type 2 noisy breathing, sometimes referred to as "pseudo death rattle," is thought to result from the accumulation of secretions of a bronchial origin over several days when a patient is too weak to cough effectively. Neurogenic pulmonary edema is an underrecognized cause of death rattle thought to be resistant to antisecretory medications or any positional and postural changes.
While not FDA labeled specifically for use in death rattle and with limited evidence to support their use, antimuscarinic drugs are often used to mitigate the disturbing symptoms. Commonly used medications include atropine, glycopyrronium (glycopyrrolate), and hyoscine (scopolamine).
The injectable forms of glycopyrrolate and atropine bear an FDA-approved indication for use in peri-operative secretion reduction, though neither has explicit approval for the reduction of noisy breathing near death. Scopolamine hydrobromide injection is available for use outside of the United States and is dosed at 0.3 to 0.6 g to reduce secretions.
A small study performed in thirteen patients demonstrated greater efficacy of glycopyrronium over scopolamine for death rattle. A larger trial showed that hyoscine bromine 0.4 mg was superior to glycopyrrolate 0.2 mg in reducing a noise score (nursing assessment combined with noise meter reading). Glycopyrrolate was further associated with a greater need for repeat injection and added sedation. The dose of glycopyrrolate for secretion reduction usually is 0.4 mcg/kg; this dosing disparity may limit the findings of this study.
A randomized, double-blind placebo-controlled trial comparing 1 mg sublingual atropine to placebo found no difference in death rattle, as evidenced by the death rattle scoring system previously used by Back et al. This study used sublingual atropine at a dose equivalent to the injectable form, with the evaluation of the noise score at 2 and 4 hours; the lack of pharmacokinetic and dosing data for the sublingual route, combined with a semi-subjective rating score, are limitations of this study.
The timing of pharmacologic intervention may be an important factor that impacts the outcomes. An open-label randomized study performed in 132 patients at the end of life found that hyoscine bromide administered as prophylaxis significantly reduce death rattle, compared to hyoscine bromide administered after the onset of a death rattle.
Mechanism of Action
Earn CME credit as you help guide your clinical decisions.
Anti-muscarinic drugs are a class of antisialagogue that works by competitively antagonizing acetylcholine at muscarinic receptors with minimal impact on nicotinic receptors. There are five subclasses of muscarinic receptors, two of which are relevant in the pathophysiology of airway secretions: M2 involving cardiac tissue and airway smooth muscle and M3 receptors on glandular tissue, including salivary glands, and airway mucosa.The M2 receptors located in airway smooth muscle primarily act as autoreceptors, regulating the activation of the M3 receptors.
If conditions such as infection cause dysfunction of the M2 receptors, severe hyperreactivity of the M3 receptors may ensue, which then causes increased secretion and bronchoconstriction. M3 receptors are exquisitely sensitive to any cholinergic stimulation, while M2 receptors are much less sensitive. Oral glycopyrronium (also known as glycopyrrolate) at doses of 4 and 8 mg respectively have demonstrated a profound reduction in the secretion of saliva between 3 and 6 hours of drug administration with 50% of baseline secretion at 6 hours. Peak effects generally appeared at around 30 minutes after drug administration.
Drug administration of glycopyrronium is possible via oral, intramuscular (IM), intravenous (IV) routes. The reduction in salivary secretions of oral glycopyrronium at 4 and 8 mg produced reduction significantly in salivary secretions of 3 and 6 hours post-administration, after which 6 hours secretion was approximately 50% of baseline, however, felt 24 hours after initial administration. The oral/parenteral ratio was 35 to 1 in terms of calculation. Intramuscular (IM) injections resulted in an 85% reduction at approximately 6 hours, and again, patients felt the effects similar to oral beyond 12 hours. Similar to IV, Intramuscular (IM) injections had produced similar effects; however, the peak effects of IM had appeared later, around 1 hour compared to 30 minutes with IV formulations.
Glycopyrronium is known to have little effect on visual accommodation and heart rate at lower doses, but at higher doses (400 mcg) can result in bradycardia 6 hours post-dose administration (approximately 20% reduction in pulse rate.)
Hyoscine butyl bromide affects heart rate causing tachycardia in a dose-dependent fashion (20% increase at 20 mg and 50% increase at 56 mg) while at higher doses of approximately 200 mcg is known to cause bradycardia.
Both hyoscine and atropine cross the blood-brain barrier and are known to cause confusion, and all of the antimuscarinic agents are generally known to cause dryness of the oral mucosa and may precipitate urinary retention. Glycopyrronium has greater cardiovascular stability and a longer duration of action, whereas hyoscine exhibits a shorter onset and duration of action but will cause sedation. In the appropriate clinical context and setting, sedation may be desirable to alleviate distressing symptoms, but precipitation of agitation will not be beneficial. Whether or not these pharmacological differences are clinically significant and relevant in the patient near the end of life and death remains to be investigated.
Antisialogogues, including atropine, scopolamine, hyoscyamine, methantheline, propantheline, and glycopyrrolate, are contraindicated in several conditions. Identifying clinically relevant and significant situations in patients at the end of their lives and dying and avoiding harm is essential. Contraindications include glaucoma, prostate hypertrophy, myasthenia gravis, obstructive disease of the gastrointestinal tract. Patients with asthma or an allergy to the drug are not good candidates. Contraindications for these drugs include ambulatory patients or patients who are pregnant.
Depending on the clinical symptom (e.g., drooling), various dosages of the antisialogogues may be used. Interactions with antihistamines, TCAs, MAO-inhibitors, and phenothiazine tranquilizers require monitoring. The blocking/inhibition of acetylcholine action and its effects are generally dose-dependent and, at lower doses, depresses salivary, lacrimal, bronchial, and sweat secretions. Dilation of pupils, photophobia, tachycardia, flushing with a reduction in tone and mobility of the gastrointestinal tract, and urine retention are common adverse effects. Various sedative effects of drugs need to be monitored appropriately in the clinical context.
Administration of neostigmine methylsulfate, which does not cross the blood-brain "barrier," can be administered as an antidote in incremental intravenous dosages of 0.25 mg in adults and can be repeated every 5 to 10 minutes until anticholinergic activity noted is reversed up to a maximum of 2.5 mg.
If CNS symptoms including restlessness, excitement, convulsions, or psychotic behavior are to occur, physostigmine which does cross the blood-brain "barrier" should be used and slowly administered in dosages of 0.5 to 2 mg administered IV and is repeatable as indicated up to a total of 5 mg in adults.
Supportive care generally is undertaken to reverse hypotension, including pressors with supportive care as needed.
In acute overdose, a curare-like action may occur in which neuromuscular blockade leading to muscular weakness, including paralysis, where artificial respiration and mechanical ventilation in patients whose code status/advanced directive/POLST allows will need to be instituted and maintained until effective respiratory action returns.
Enhancing Healthcare Team Outcomes
Few randomized clinical trials to effectively compare the antisialogogues exist, and therefore, an interprofessional effort necessary to coordinate the highest level of care for each patient. Individualizing each patient and prioritizing symptom relief to provide supportive care at the end of life must be discussed to improve patient safety and enhance patient-centered care. Coordinating end-of-life care with antisialogogues may at times appear to be a clinically challenging pathophysiological endeavor, and as such, requires the efforts of an interprofessional team, including a clinician who specializes in end-of-life medicine. Nursing interventions alone have demonstrated significant improvement in death rattle therapy; nurses can monitor the patient's response as well as check for adverse events and report to the prescriber. Pharmacists are also essential personnel in planning such interventions; they can assist the prescriber in agent selection, verify dosing, and counsel the patient and/or family regarding the purpose of the drug. Employing an interprofessional team approach to supportive care strategies given the above information remains the best holistic and integrated approach to help achieve the best outcome for the patient and the patient's family near the end of life. [Level 5]
van Esch HJ, Geijteman ECT, van der Rijt CCD. Response to "Hyoscine Butylbromide for the Management of Death Rattle: Sooner Rather Than Later". Journal of pain and symptom management. 2019 Apr:57(4):e1-e2. doi: 10.1016/j.jpainsymman.2019.01.004. Epub 2019 Jan 17 [PubMed PMID: 30660674]
Wildiers H, Menten J. Death rattle: prevalence, prevention and treatment. Journal of pain and symptom management. 2002 Apr:23(4):310-7 [PubMed PMID: 11997200]
Boland JW, Currow D, Johnson M. Response to "Hyoscine Butylbromide for the Management of Death Rattle: Sooner Rather Than Later". Journal of pain and symptom management. 2019 Mar:57(3):e12-e13. doi: 10.1016/j.jpainsymman.2018.11.018. Epub 2018 Nov 26 [PubMed PMID: 30496789]
Bonello M, Pullicino R, Larner AJ. Acute pulmonary oedema: not always cardiogenic. The journal of the Royal College of Physicians of Edinburgh. 2017 Mar:47(1):57-59. doi: 10.4997/JRCPE.2017.112. Epub [PubMed PMID: 28569284]
Wee B, Hillier R. Interventions for noisy breathing in patients near to death. The Cochrane database of systematic reviews. 2008 Jan 23:2008(1):CD005177. doi: 10.1002/14651858.CD005177.pub2. Epub 2008 Jan 23 [PubMed PMID: 18254072]Level 1 (high-level) evidence
Bennett M, Lucas V, Brennan M, Hughes A, O'Donnell V, Wee B, Association for Palliative Medicine's Science Committee. Using anti-muscarinic drugs in the management of death rattle: evidence-based guidelines for palliative care. Palliative medicine. 2002 Sep:16(5):369-74 [PubMed PMID: 12380654]Level 1 (high-level) evidence
Likar R, Rupacher E, Kager H, Molnar M, Pipam W, Sittl R. [Efficacy of glycopyrronium bromide and scopolamine hydrobromide in patients with death rattle: a randomized controlled study]. Wiener klinische Wochenschrift. 2008:120(21-22):679-83. doi: 10.1007/s00508-008-1094-2. Epub [PubMed PMID: 19116709]Level 1 (high-level) evidence
Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliative medicine. 2001 Jul:15(4):329-36 [PubMed PMID: 12054150]
Heisler M, Hamilton G, Abbott A, Chengalaram A, Koceja T, Gerkin R. Randomized double-blind trial of sublingual atropine vs. placebo for the management of death rattle. Journal of pain and symptom management. 2013 Jan:45(1):14-22. doi: 10.1016/j.jpainsymman.2012.01.006. Epub 2012 Jul 13 [PubMed PMID: 22795904]Level 1 (high-level) evidence
Mercadante S, Marinangeli F, Masedu F, Valenti M, Russo D, Ursini L, Massici A, Aielli F. Hyoscine Butylbromide for the Management of Death Rattle: Sooner Rather Than Later. Journal of pain and symptom management. 2018 Dec:56(6):902-907. doi: 10.1016/j.jpainsymman.2018.08.018. Epub 2018 Aug 31 [PubMed PMID: 30172864]
Ponduri S, Turnbull N, Birnie D, Ireland AJ, Sandy JR. Does atropine sulphate improve orthodontic bond survival? A randomized clinical trial. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics. 2007 Nov:132(5):663-70 [PubMed PMID: 18005841]Level 1 (high-level) evidence
Silvestre-Donat FJ, Silvestre-Rangil J. Drooling. Monographs in oral science. 2014:24():126-34. doi: 10.1159/000358793. Epub 2014 May 23 [PubMed PMID: 24862600]
Chabicovsky M, Winkler S, Soeberdt M, Kilic A, Masur C, Abels C. Pharmacology, toxicology and clinical safety of glycopyrrolate. Toxicology and applied pharmacology. 2019 May 1:370():154-169. doi: 10.1016/j.taap.2019.03.016. Epub 2019 Mar 21 [PubMed PMID: 30905688]
Falk J, Borgwardt R, MacLeod S. Posttraumatic Parotid Sialocele Complicating a Mandibular Fracture: A Case Report. Craniomaxillofacial trauma & reconstruction. 2017 Dec:10(4):314-317. doi: 10.1055/s-0036-1593891. Epub 2016 Dec 13 [PubMed PMID: 29109843]Level 3 (low-level) evidence
Anzueto A, Levine SM, Jenkinson SG. The technique of fiberoptic bronchoscopy. Diagnostic and therapeutic uses in intubated, ventilated patients. The Journal of critical illness. 1992 Oct:7(10):1657-64 [PubMed PMID: 10148148]
Wolff MS, Kleinberg I. The effect of ammonium glycopyrrolate (Robinul)-induced xerostomia on oral mucosal wetness and flow of gingival crevicular fluid in humans. Archives of oral biology. 1999 Feb:44(2):97-102 [PubMed PMID: 10206327]
Chor WPD, Wong SYP, Ikbal MFBM, Kuan WS, Chua MT, Pal RY. Initiating End-of-Life Care at the Emergency Department: An Observational Study. The American journal of hospice & palliative care. 2019 Nov:36(11):941-946. doi: 10.1177/1049909119836931. Epub 2019 Mar 12 [PubMed PMID: 30862168]Level 2 (mid-level) evidence
Broens SJL, Boon M, Martini CH, Niesters M, van Velzen M, Aarts LPHJ, Dahan A. Reversal of Partial Neuromuscular Block and the Ventilatory Response to Hypoxia: A Randomized Controlled Trial in Healthy Volunteers. Anesthesiology. 2019 Sep:131(3):467-476. doi: 10.1097/ALN.0000000000002711. Epub [PubMed PMID: 31045894]Level 1 (high-level) evidence
Bae YJ, Reinelt J, Netto J, Uhlig M, Willenberg A, Ceglarek U, Villringer A, Thiery J, Gaebler M, Kratzsch J. Salivary cortisone, as a biomarker for psychosocial stress, is associated with state anxiety and heart rate. Psychoneuroendocrinology. 2019 Mar:101():35-41. doi: 10.1016/j.psyneuen.2018.10.015. Epub 2018 Oct 28 [PubMed PMID: 30408721]
Formeister EJ, Dahl JP, Rose AS. Surgical management of chronic sialorrhea in pediatric patients: 10-year experience from one tertiary care institution. International journal of pediatric otorhinolaryngology. 2014 Aug:78(8):1387-92. doi: 10.1016/j.ijporl.2014.06.005. Epub 2014 Jun 16 [PubMed PMID: 24974144]
Gurney BF. Chemotherapy in dental practice. Antisialagogues. Dental digest. 1967 Jun:73(6):270-1 [PubMed PMID: 5229337]
Gallanosa A, Stevens JB, Quick J. Glycopyrrolate. StatPearls. 2023 Jan:(): [PubMed PMID: 30252291]
Tashkin DP. The safety of anticholinergic bronchodilators for the treatment of chronic obstructive pulmonary disease. Expert opinion on drug safety. 2015:14(11):1759-72. doi: 10.1517/14740338.2015.1093621. Epub 2015 Sep 24 [PubMed PMID: 26401729]Level 3 (low-level) evidence