Continuing Education Activity

Antisialagogues are medications often used to manage and treat patients with noisy breathing near the end of life. These medications are members of the antimuscarinic class. This educational activity reviews the indications, actions, and contraindications for antisialagogues as agents in the management of noisy breathing near the end of life; use in other applicable disorders will also be discussed. This activity highlights the mechanism of action, adverse event profile, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for interprofessional team members in the management of patients with noisy breathing near the end of life and related conditions.

Objectives:

• Review the monitoring requirements for patients receiving antisialagogues.
• Describe the pathophysiology of antisialagogue toxicity.
• Identify the indications for administration of antisialagogues in the management of noisy breathing near the end of life.
• Explain the importance of collaboration and communication among the interprofessional team to enhance care coordination for patients affected by noisy breathing near the end of life receiving antisialagogues.

Indications

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.[1][2] 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.[3] Neurogenic pulmonary edema is an underrecognized cause of death rattle thought to be resistant to antisecretory medications or any positional and postural changes.[4]

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.[5] Commonly used medications include atropine, glycopyrronium (glycopyrrolate), and hyoscine (scopolamine).[5][2][6]

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.[7] 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[8]. 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.[8] 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.[9]

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.[10]

Mechanism of Action

Anti-muscarinic drugs are a class of antisialagogue that works by competitively antagonizing acetylcholine at muscarinic receptors with minimal impact on nicotinic receptors.[11] 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.[11][12]The M2 receptors located in airway smooth muscle primarily act as autoreceptors, regulating the activation of the M3 receptors.[12]

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.[11] 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.[12]

Administration

Drug administration of glycopyrronium is possible via oral, intramuscular (IM), intravenous (IV) routes.[13] 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.[11] 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.[14] 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.[15]

Adverse Effects

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.)[16]

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.[17]

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.[1] 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.[12] 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. 

Contraindications

Antisialogogues, including atropine, scopolamine, hyoscyamine, methantheline, propantheline, and glycopyrrolate, are contraindicated in several conditions.[18] Identifying clinically relevant and significant situations in patients at the end of their lives and dying and avoiding harm is essential.[19] 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.[20]

Monitoring

Depending on the clinical symptom (e.g., drooling), various dosages of the antisialogogues may be used.[12] 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.[11] 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.[21]

Toxicity

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.[18]

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.[22]

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.[23]

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.[24] 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]