Terminal Agitation: Symptoms, Causes and Treatment

Terminal agitation is a distressing condition commonly seen in patients nearing the end of life. It involves a combination of restlessness, confusion, and sometimes aggressive or disruptive behaviors. For families and healthcare professionals alike, witnessing terminal agitation can be alarming and emotionally taxing. Understanding its symptoms, underlying causes, and available treatments is crucial for ensuring compassionate, effective care during the final days and hours of life.

Symptoms of Terminal Agitation

Terminal agitation manifests through a range of physical and psychological symptoms that can emerge suddenly or escalate over time. These symptoms not only affect the patient’s comfort but also deeply impact families and caregivers. Prompt recognition is key to providing timely and appropriate interventions.

Symptom	Description	Frequency/Prevalence	Source(s)
Restlessness	Inability to remain still; fidgeting	Common in final days of life	1, 2, 4
Delirium	Acute confusion, disorientation	High prevalence	2, 3, 7
Agitation	Physical or verbal aggression, anxiety	Up to 80% in dying patients	2, 4, 7
Sleep Disturbance	Insomnia, disrupted sleep-wake cycle	Frequently observed	1, 2
Autonomic Dysfunction	Abnormal vital signs (e.g., tachycardia)	May accompany agitation	1, 5

Table 1: Key Symptoms

Understanding the Symptom Profile

Terminal agitation is more than just restlessness or confusion; it is often a multifaceted syndrome.

Restlessness and Motor Activity

Patients may become unable to stay still, frequently shifting positions in bed, pulling at sheets, or attempting to get up. This motor restlessness is one of the earliest and most visible signs, often prompting concern from families and caregivers 1, 4.

Cognitive Changes and Delirium

Delirium is a hallmark of terminal agitation. Patients may become acutely confused, unable to recognize loved ones, or misinterpret their surroundings. Disorientation to time and place is common, and hallucinations or paranoid thoughts may also occur 2, 3, 7.

Emotional and Behavioral Symptoms

Agitation can manifest as anxiety, irritability, or even aggression. Some patients may shout, resist care, or appear frightened. These behaviors can fluctuate rapidly, making the situation unpredictable 2, 4.

Sleep-Wake Disturbances

Insomnia and disrupted sleep cycles are frequently noted. Some patients may become awake and restless at night, further contributing to caregiver exhaustion 1, 2.

Autonomic and Physiological Signs

Alongside psychological symptoms, patients may exhibit sweating, elevated heart rate, and changes in blood pressure—signs of autonomic nervous system involvement, sometimes due to withdrawal states or medication effects 1, 5.

Causes of Terminal Agitation

The causes of terminal agitation are diverse and often multifactorial. Identifying contributing factors is essential for tailoring interventions and improving patient comfort. While some causes are reversible, others are intrinsic to the dying process.

Cause	Mechanism/Trigger	Reversibility	Source(s)
Medication Effects	Opioids, anticholinergics, withdrawal	Sometimes	1, 5
Metabolic Imbalance	Hypercalcemia, renal failure	Occasionally	2, 5
Structural Brain Disease	Tumor, stroke, infection	Rarely	2, 3
Alcohol Withdrawal	Cessation after chronic use	Potentially	1, 5
Delirium of Dying	Multifactorial, terminal process	Irreversible	2, 4, 7

Table 2: Common Causes

Exploring the Underlying Triggers

Medication-Related Agitation

Certain medications, including opioids and anticholinergics, can induce or exacerbate agitation through their effects on the central nervous system. Conversely, abrupt withdrawal from substances such as benzodiazepines or alcohol can also precipitate severe agitation 1, 5.

• Alcohol Withdrawal: A frequently overlooked yet significant cause, especially in patients with a history of chronic alcohol use. Symptoms may persist for months after cessation and include tremors, insomnia, anxiety, and abnormal vital signs 1.

Metabolic and Systemic Factors

Metabolic derangements like hypercalcemia, hypoxia, or renal failure can provoke delirium and agitation. These conditions may sometimes be reversible with prompt intervention, but in advanced terminal stages, correction may not always be feasible or desirable 2, 5.

Structural Brain Disease

Tumors, metastatic disease, stroke, or infections affecting the brain can disrupt normal neurological function, resulting in agitation and delirium. In such cases, agitation is often resistant to conventional treatments 2, 3.

Terminal Delirium (Delirium of Dying)

For many patients, agitation is part of the natural dying process—a complex interplay of organ failure, inflammation, and reduced cerebral perfusion. This form of delirium is usually irreversible and signals approaching death 2, 4, 7.

Other Factors

• Pain and Uncontrolled Symptoms: Unmanaged pain, urinary retention, or constipation can also contribute to agitation 2, 5.
• Environmental Stressors: Overstimulation, unfamiliar surroundings, or lack of familiar caregivers may exacerbate distress in dying patients 2.
• Sleep Deprivation: Prolonged lack of sleep can heighten confusion and restlessness, especially in hospital or ICU settings 5.

Treatment of Terminal Agitation

The management of terminal agitation is both an art and a science, requiring a personalized approach that balances symptom control with the preservation of patient dignity. Interventions range from non-pharmacological measures to targeted pharmacological therapies, and, in some cases, palliative sedation.

Treatment	Approach/Drug	Effectiveness	Source(s)
Non-Pharmacological	Reassurance, environment	First-line, supportive	4, 5
Antipsychotics	Haloperidol, chlorpromazine	Effective in most cases	3, 4, 7
Benzodiazepines	Midazolam	Rapid symptom control	6, 7
Combination Therapy	Neuroleptic + benzodiazepine	For refractory cases	3, 7
Terminal Sedation	Deep sedation (ethics guided)	Last resort	2, 4

Table 3: Treatment Strategies

Approaches to Treatment

Non-Pharmacological Measures

Initial steps should always include supportive, non-drug interventions:

• Ensuring a calm, familiar environment
• Reassuring presence of loved ones
• Reducing noise and bright lights
• Addressing any unmet needs (e.g., toileting, thirst)

These measures can sometimes reduce agitation and are essential for holistic care 4, 5.

Pharmacological Treatments

Antipsychotics

• Haloperidol: Widely used and effective, often considered the first-line pharmacological agent for terminal agitation. It can be administered orally, intravenously, or subcutaneously 3, 4, 7.
• Chlorpromazine and Levomepromazine: Alternatives to haloperidol; these are particularly useful when initial therapy is ineffective or poorly tolerated. Evidence suggests that chlorpromazine and levomepromazine may reduce the need for medication changes compared to haloperidol 7.
• Algorithm-Based Use: Structured protocols for antipsychotic use improve symptom control and safety, especially in specialist palliative care units 4.

Benzodiazepines

• Midazolam: Fast-acting and effective, particularly for severe agitation or when antipsychotics alone are insufficient. Both intranasal and subcutaneous routes have been shown to be effective and well-tolerated, with intranasal administration offering a non-invasive alternative 6, 7.
• Benzodiazepines may be especially indicated in cases of agitation due to alcohol or benzodiazepine withdrawal 1, 5.

Combination Therapy

For refractory cases—where single-agent therapy fails—a combination of neuroleptics and benzodiazepines may be employed. Clinical trials indicate that both escalation of haloperidol, rotation to another antipsychotic, or combination strategies all significantly reduce agitation, with comparable efficacy 3, 7.

Terminal Sedation

When agitation is refractory to all other measures and is causing significant distress, terminal sedation (continuous deep sedation until death) may be considered. This step requires:

• Careful ethical consideration
• Informed consent from patient (if possible) and family
• Ongoing assessment and transparent communication

Nurses and physicians must collaborate to ensure this decision is made with integrity and patient-centered values 2, 4.

Special Considerations

• Monitoring and Safety: All pharmacological interventions should be closely monitored for adverse effects such as hypotension, respiratory depression, or extrapyramidal symptoms 3, 4, 6.
• Tailored Therapy: The choice of agent and dosing should be individualized based on patient history, co-morbidities, and likely etiology (e.g., withdrawal states, metabolic causes) 1, 5, 7.
• Education and Support for Families: Clear communication about what to expect and the goals of care is essential to reduce anxiety and promote trust 2, 4.

Conclusion

Terminal agitation is a complex and challenging syndrome at the end of life, but with careful assessment and a multidisciplinary approach, its distressing symptoms can be alleviated. Here’s what we covered:

• Symptoms: Restlessness, delirium, agitation, sleep disturbance, and autonomic changes are key features.
• Causes: Agitation may arise from medication effects, metabolic abnormalities, structural brain disease, alcohol withdrawal, or the natural dying process.
• Treatment: Management involves non-pharmacological support, antipsychotics, benzodiazepines, combination therapy, and—in severe cases—terminal sedation.

By recognizing the multifactorial nature of terminal agitation and applying evidence-based interventions, healthcare providers can ensure comfort and dignity for patients in their final days, while offering vital support to families and caregivers.