February 22, 2011

The Last Hours of Living: Practical Advice for Clinicians: Two Roads to Death

MedscapeCME - Linda Emanuel, MD, PhD; Frank D. Ferris, MD; Charles F. von Gunten, MD, PhD; Jamie H. von Roenn, MD

4. Two Roads to Death

Decreasing Level of Consciousness

Most patients traverse the "usual road to death." They experience increasing drowsiness, sleep most if not all of the time, and eventually become unarousable. Absence of eyelash reflexes on physical examination indicates a profound level of coma equivalent to full anesthesia.

Communication with the unconscious patient. Families will frequently find the inability to communicate with their loved one distressing. The last hours of life are the time when they most want to communicate with their loved one. As many clinicians have observed, the degree of family distress seems to be inversely related to the extent to which advance planning and preparation occurred. The time spent preparing families is likely to be very worthwhile.

Although we do not know what unconscious patients can actually hear, extrapolation from data from the operating room and "near death" experiences suggests that at times their awareness may be greater than their ability to respond. Given our inability to assess a dying patient's comprehension and the distress that talking "over" the patient may cause, it is prudent to assume that the unconscious patient hears everything. Advise families and professional caregivers to talk to the patient as if he or she were conscious.

Encourage families to create an environment that is familiar and pleasant. Surround the patient with the people, children, pets, objects, music, and sounds that he or she would like. Include the patient in everyday conversations. Encourage family members to say the things they need to say. At times, it may seem that a patient may be waiting for permission to die. If this is the case, encourage family members to give the patient permission to "let go" and die in a manner that feels most comfortable. The physician, nurse, social worker, chaplain, or other caregivers might suggest to family members other words like:
  • "I know that you are dying; please do so when you are ready."
  • "I love you. I will miss you. I will never forget you. Please do what you need to do when you are ready."
  • "Mommy and Daddy love you. We will miss you, but we will be okay."
As touch can heighten communication, encourage family members to show affection in ways they are used to. Let them know that it is okay to lie beside the patient in privacy to maintain as much intimacy as they feel comfortable with.

Terminal delirium. An agitated delirium may be the first sign to herald the "difficult road to death." It frequently presents as confusion, restlessness, and/or agitation, with or without day-night reversal.[19] To the family and professional caregivers who do not understand it, agitated terminal delirium can be very distressing. Although previous care may have been excellent, if the delirium goes misdiagnosed or unmanaged, family members will likely remember a horrible death, "in terrible pain," and cognitively impaired "because of the drugs," and they may worry that their own death will be the same. Bruera and associates[20] have documented the distressing impact of delirium on patients and families.

In anticipation of the possibility of terminal delirium, educate and support family and professional caregivers to understand its causes, the finality and irreversibility of the situation, and approaches to its management. It is particularly important that all onlookers understand that what the patient experiences may be very different from what they see.

If the patient is not assessed to be imminently dying, it may be appropriate to evaluate and try to reverse treatable contributing factors such as pain, urinary retention, or severe constipation/impaction. The treatment of reversible delirium is to find and correct reversible causes. The drug class of first choice for symptomatic management of reversible delirium is the neuroleptics.[21,22] On the other hand, irreversible delirium can also affect patients in the final hours of living. In this setting, it is referred to as irreversible terminal delirium.[23] Irreversible delirium does not respond to conventional treatment for reversible delirium. Focus on the management of the symptoms associated with terminal delirium in order to settle the patient and the family[24]

When moaning, groaning, and grimacing accompany the agitation and restlessness, these symptoms are frequently misinterpreted as physical pain.[25] However, it is a myth that uncontrollable pain suddenly develops during the last hours of life when it has not previously been a problem. Although a trial of opioids may be beneficial in the unconscious patient who is difficult to assess, clinicians must remember that opioids may accumulate and add to delirium when renal clearance is poor.[26,27]If the trial of opioids does not relieve the agitation or makes the delirium worse by increasing agitation or precipitating myoclonic jerks or seizures (rare), then pursue alternative therapies directed at suppressing the symptoms associated with delirium.

Currently, no studies specifically address the management of terminal delirium. Palliative experts base their treatment recommendations on the goals of treatment and the mechanisms of action of classes of medication. Benzodiazepines are generally not recommended for first-line management of delirium, especially if the delirium is thought to be reversible, because they can worsen delirium and cause paradoxic excitation.[28] However, because they are anxiolytics, amnestics, skeletal muscle relaxants, and antiepileptics,[27] benzodiazepines are recommended by palliative care experts for the management of irreversible terminal delirium, where the goal of therapy is sedation. Benzodiazepines are also the drug class of first choice for management of delirium complicated by seizures or caused by alcohol or sedative withdrawal.[29] Common starting doses are:
  • Lorazepam, 1-2 mg as an elixir, or a tablet predissolved in 0.5-1.0 mL of water and administered against the buccal mucosa every hour as needed until agitation subsides. Most patients will be controlled with 2-10 mg per 24 hour period. It can then be given in divided doses, every 3-4 hours, to keep the patient calm. For a few extremely agitated patients, high doses of lorazepam, 20-50+ mg/24 hours, may be required.
  • Midazolam 1-5 mg/hour subcutaneously or intravenously by continuous infusion, preceded by repeated loading boluses of 0.5 mg every 15 minutes to effect, may be a rapidly effective alternative.
Barbiturates or propofol have been suggested as alternatives for management of refractory agitation.[30,31] Seizures may be managed with high doses of benzodiazepines or alternatively with other antiepileptics such as intravenous phenytoin, subcutaneous fosphenytoin, or phenobarbital 60-120 mg rectally, intravenously, or intramuscularly every 10-20 minutes as needed until control is established.

If benzodiazepines cause paradoxical excitation, the patient may require neuroleptic medications to control delirium. Haloperidol has fewer sedating and hypotensive effects, but in bedbound patients in whom sedation is desirable, chlorpromazine is a better choice:
  • Chlorpromazine 10-25 mg orally or rectally every 60 minutes, or subcutaneously/intravenously every 30 minutes until agitation is controlled. Titrate to effect, then give the summed dose nightly to every 6 hours to maintain control.[32]
  • Haloperidol 0.5-2.0 mg intravenously every 10 minutes, subcutaneously every 30 minutes, or rectally every hour until agitation is controlled (titrate to effect, then give the summed dose nightly to every 6 hours to maintain control).[33]
Respiratory dysfunction. Changes in a dying patient's breathing pattern may be indicative of significant neurologic compromise.[34-36] Breaths may become very shallow and frequent with a diminishing tidal volume. Periods of apnea and/or Cheyne-Stokes pattern respirations may develop. (Cheyne-Stokes is a disorder characterized by recurrent central apneas during sleep, alternating with a crescendo-decrescendo pattern of tidal volume.[37]) Accessory respiratory muscle use may also become prominent. A few (or many) last reflex breaths may signal death.

Families and professional caregivers frequently find changes in breathing patterns to be one of the most distressing signs of impending death. Many fear that the comatose patient will experience a sense of suffocation. Knowledge that the unresponsive patient may not be experiencing breathlessness or "suffocating," and may not benefit from oxygen (which may actually prolong the dying process) can be very comforting. Low doses of opioids or benzodiazepines are appropriate to manage any perception of breathlessness.

Some clinicians express concern that the use of opioids or benzodiazepines for symptom control near the end of life will hasten death. Consequently, they feel they must invoke the ethical principle of "double effect" to justify treatment. The principle of double effect applies in situations where there is a difference in the effects of an intended action (alleviating suffering) and the unintended possible consequences of the same action (hastening death). To be acceptable, the action must comply with the following requirements:
  • The treatment proposed must be beneficial or at least neutral (relief of intolerable symptoms);
  • The clinician must intend only the good effect (relieving pain or symptoms), although some untoward effects might be foreseen (hastening death or loss of consciousness);
  • The untoward effect must not be a means (not necessary) to bring about the good effect; and
  • The good result (relief of suffering) must outweigh the untoward outcome (hastening death).[38]
Although it is true that patients are more likely to receive higher doses of both opioids and sedatives as they get closer to death, there is no evidence that initiation of treatment or increases in dose of opioids or sedatives is associated with precipitation of death. In fact, the evidence suggests the opposite.[39]

Loss of ability to swallow. Weakness and decreased neurologic function frequently combine to impair the patient's ability to swallow. The gag reflex and reflexive clearing of the oropharynx decline and secretions from the tracheobronchial tree accumulate. These conditions may become more prominent as the patient loses consciousness. Buildup of saliva and oropharyngeal secretions may lead to gurgling, crackling, or rattling sounds with each breath.[40] Some have called this the "death rattle" (a term that should be avoided, as it is frequently disconcerting to families and caregivers).

Once the patient is unable to swallow, cease oral intake. Warn families and professional caregivers of the risk for aspiration. Muscarinic receptor blockers (anticholinergics) are commonly used agents to control respiratory secretions when death is imminent. These agents have been compared in several retrospective studies and in a recent prospective randomized trial, which compared subcutaneous administration of atropine with hyoscine hydrobromide (scopolamine) and hyoscine butylbromide (not available in the United States). All agents were found to be equally effective at controlling secretions, with an effectiveness of 37%-42% at 1 hour, increasing to an effectiveness between 60% and 76% at 24 hours. There was no significant difference in side effects or survival time, and effectiveness increased when treatment was initiated at a lower initial intensity of rattle.[41]

Other studies that compared glycopyrronium (glycopyrrolate) (which has a theoretical advantage over other agents because it does not cross the blood-brain barrier) with other agents such as hyoscine, have yielded conflicting reports of comparative efficacy, with no difference in side effects such as agitation.[42,43] Although atropine theoretically has the disadvantage of more cardiac effects or agitation,[44] this has not been borne out in clinical studies to date, which have found it to be equally effective without any evident increased incidence of side effects.[41] Although further studies are necessary to provide definitive evidence-based recommendations, current findings support the use of the commonly used agents in the United States: scopolamine, glycopyrrolate, atropine, and hyoscyamine sulfate. Common starting doses of these medications are:
  • Scopolamine, 0.2-0.4 mg subcutaneously every 4 hours, or
    Scopolamine, 1-3 transdermal patches every 72 hours (onset delayed 12 hours), or
    Scopolamine, 0.1-1.0 mg/hour by continuous intravenous or subcutaneous infusion
  • Hyoscyamine sulfate, 0.125-0.25 mg sublingually every 4 hours
  • Glycopyrrolate, 0.2 mg subcutaneously every 4-6 hours, or
    Glycopyrrolate, 0.4-1.2 mg daily by continuous intravenous or subcutaneous infusion, or
    Glycopyrrolate, 1 mg sublingually every 4-6 hours
  • Atropine, 0.1 mg subcutaneously every 4 hours, or
    Atropine eyedrops, 1 drop (1%) sublingually every 4 hours[45]
These drugs will minimize or eliminate the gurgling and crackling sounds and may be used prophylactically in the unconscious dying patient. Some evidence suggests that the earlier treatment is initiated, the better it works, as larger amounts of secretions in the upper aerodigestive tract are more difficult to eliminate. However, premature use in the patient who is still alert may lead to unacceptable drying of oral and pharyngeal mucosa.

If excessive fluid accumulates in the back of the throat and upper airways, it can be cleared by repositioning the patient or performing postural drainage. Turning the patient onto one side or into a semiprone position may reduce gurgling. Lowering the head of the bed and raising the foot of the bed while the patient is in a semiprone position may cause fluids to move into the oropharynx, from which they can be easily removed. Do not maintain this position for more than a few minutes at a time, as stomach contents may also move unexpectedly, increasing the risk for aspiration.

Oropharyngeal suctioning is not recommended. Suctioning is frequently ineffective, as fluids are beyond the reach of the catheter, and may only stimulate an otherwise peaceful patient and distress family members who are watching.

Loss of sphincter control. Fatigue and loss of sphincter control in the last hours of life may lead to incontinence of urine and/or stool. Both can be very distressing to patients and family members, particularly if they are not warned in advance that these problems may arise. If they occur, attention needs to be paid to cleaning and skin care. A urinary catheter may minimize the need for frequent changing and cleaning, prevent skin breakdown, and reduce the demand on caregivers. However, it is not always necessary if urine flow is minimal and can be managed with absorbent pads or surfaces. If diarrhea is considerable and relentless, a rectal tube may be similarly effective.

Pain. Although many people fear that pain will suddenly increase as the patient dies, there is no evidence to suggest that this occurs. Although difficult to assess, continuous pain in the semiconscious or obtunded patient may be associated with grimacing and continuous facial tension, particularly across the forehead and between the eyebrows. The possibility of pain must also be considered when physiologic signs occur, such as transitory tachycardia that may signal distress. However, do not overdiagnose pain when fleeting forehead tension comes and goes with movement or mental activity (eg, dreams or hallucinations). Do not confuse pain with the restlessness, agitation, moaning, and groaning that accompany terminal delirium. If the diagnosis is unclear, a trial of a higher dose of opioid may be necessary to judge whether pain is driving the observed behaviors.

Knowledge of opioid pharmacology becomes critical during the last hours of life. The liver conjugates codeine, morphine, oxycodone, and hydromorphone into glucuronides. Some of their metabolites remain active as analgesics until they are renally cleared, particularly the metabolites of morphine. As dying patients experience diminished hepatic function and renal perfusion, and usually become oliguric or anuric, routine dosing or continuous infusions of morphine may lead to increased serum concentrations of active metabolites, toxicity, and an increased risk for terminal delirium. To minimize this risk, discontinue routine dosing or continuous infusions of morphine when urine output and renal clearance stop. Titrate morphine breakthrough (rescue) doses to manage expressions suggestive of continuous pain. Consider the use of alternative opioids with inactive metabolites such as fentanyl or hydromorphone.

Loss of ability to close eyes. Eyes that remain open can be distressing to onlookers unless the condition is understood. Advanced wasting leads to loss of the retro-orbital fat pad, and the orbit falls posteriorly within the orbital socket.[46] Because the eyelids are of insufficient length to both extend the additional distance backward and cover the conjunctiva, they may not be able to fully appose. This may leave some conjunctiva exposed even when the patient is sleeping. If conjunctiva remains exposed, maintain moisture by using ophthalmic lubricants, artificial tears, or physiologic saline.[47]

Medications. As patients approach death, reassess the need for each medication and minimize the number of drugs that the patient is taking. Continue only those medications needed to manage symptoms such as pain, breathlessness, excess secretions, and terminal delirium and to reduce the risk for seizures. Choose the least invasive route of administration: the buccal mucosa or oral routes first, the transcutaneous/transdermal route if appropriate, the subcutaneous or intravenous routes only if necessary, and the intramuscular route almost never. Rectal administration can also be considered, especially if the oral route is not possible.

Dying in Institutions

The preceding discussion is relevant to patients dying in any setting (eg, at home, in hospitals, in nursing homes, other extended care facilities, prisons, etc.). However, there are particular challenges to ensuring a comfortable death in an institution where the culture is not focused on end-of-life care.[48]

When death is imminent, it is appropriate that patients remain with caregivers that they know rather than being transferred to another facility. Institutions can help by making the environment as home-like as possible. It is appropriate for the physician, nurse practitioner, or physician's assistant to order a private room where family can be continuously with the patient if they so choose and be undisturbed. The clinician will want to talk with the professional staff and encourage continuity of care plans across nursing shifts and changes in house staff.

Priorities and care plans at the end of life differ considerably from priorities and plans focusing on life prolongation and cure. It is frequently challenging for physicians, nurses, and other healthcare professionals to incorporate both kinds of care into a busy hospital or skilled nursing facility. For this reason, specialized units where patients and families can be assured of the environment and the skilled care they need have been developed in many institutions.[49,50]

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