Vol. 7 No. I January 1992
Jolrnzal of Pain and Syn$?on Management
elirium in a
Robin Fainsinger, MD, and Eduardo Bruera, MD Palliative Care Program, Edmonton General Hospital, Edmonton, Can&
Case Report A 64-yr-old man was diagnosed in 1984 as having carcinoma of the prostate. He t-esponded to hormonal treatment until 1989, when he was found to have disseminated bone metastases. He received radiotherapy to a numher of areas over the course of the next year and was transferred to the Palliative Care Unit, Edmonton General Hospital in late 1990 with problems of pain and organic mental syndrome (OMS) characterized by confusion and agitation. Initial treatment on admission for pain was hydromorphone 4 mg/4 hr orally around the clock (ATC) with 3 mglhr orally as required for breakthrough pain. The OMS was treated with haloperidol 2 mg/2 hr subcutaneous (SC) as required for agitation and lorazepam 0.5 m&4 hr orally as required for anxiety. The pain was due to bone metastases and was not difficult to control. During the first 2 wk of his admission, he was stabilized on hydromorphone 10 mg/4 hr SC ATC with 6 mglhr SC as required for breakthrough pain and remained in good pain control for the duration of his admission. The OMS was far more problematic. Routine investigation revealed no cause for the delirium. One wk after admission, the haloperidol was increased to 2 mg/8 hr SC; 6 days later, the dose was again increased to 3 mgl6 hr SC every 6 hr, and constant nursing supervision was ordered.
This section of the Journal of Pain and SymptomManagement publishes transcribed versions of Palliative Care Rounds. Authors interested in submitting materials to this section should send manuscripts to Eduardo Bmera, MD, do Journal of Pain and Symptom Management.Questions and comments on the cases published in this section should also he addressed to Dr. Bruera.
0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsevier, New York, New York
When the agitated delirium persisted, the haloperidol and lorazepam were discontinued, and methotrimeprazine 20 mg SC was given foltowed by 10 mgl6 hr SC. The methotrimeprazine had to be increased to 20 mg/8 hr SC, and benztropine 2 mg SC was given twice daily to counter the extrapyramidal side effects of the methotrimeprazine. The methotrimeprazine proved ineffective in treating the patient’s symptoms, and it was discontinued after 48 hr. A continuous SC infusion of midazolam was started at 1 mg/hr that was later increased to 2 mglhr. The patient’s family had been severely distressed by the persistent delirium, and they were extremely relieved as the midazolam sedated the patient and brought the delirium under control. An attempt was made to treat the underlying OMS by empirically treating with dexamethasone 10 mg SC three times daily and switching the narcotic to morphine 50 mg14 hr SC ATG and 30 mg/hr as required for breakthrough pain. Two days later the midazo!am was decreased to 0.5 mg/hr in an attempt to assess the underlying OMS. Unfortunately, the previous symptoms recurred, requiring upward titration of the midazolam dose to 4 mglhr. During this period, the patient’s family again became distressed as the agitation recurred and then settled as the patient once again was sedated. An autopsy later found no cause for the OMS. There was no evidence of tumor, limbic encephalitis, infection, or leptomeningeal disease.
The initial treatment of delirium in terminally ill patients is aimed at identifying and correcting the underlying cause. ’ In our patient, no cause
Vol. 7 No. 1 Janucq
for tbe delirium could be found. Tbis is in keeping with the report by Bruera and colleagues,* which notes that the cause of cognitive failure can be determined in less than one-half of terminally ill cancer patients. One of the initial treatment maneuvers in this patient was to increase the nursing supervision and family presence at the bedside; as agitation worsened, a constant nursing presence in the patient’s room became necessary. These and other nondrug measures have been recommended as treatment options for patients with delirium. Specifically, approaches have included treating the patient with courtesy and respect, avoiding restraints, using a night light, explaining procedures, increasing the presence of family members, providing continuity in nursing staff or one-to-one nursing observations, and orienting objects in the room (e.g., calendar, clock, or objects familiar to the patient). ‘~-6 Adams ‘*s has observed, however, that attempts at orientation are without demonstrated value and that a 4-point physical restraint may be necessary as an initial temporary safety measure until the delirium is controlled by medical treatment. The initial medical treatment in our patient comprised haloperidol and lorazepam. Although doses were adjusted upward (to a maximum haloperidol dose of 12 mg124 hr and lorazepam dose of 2-3 mg/24 hr), the doses achieved were far less than the maximum recommended dose used by other centers. Twycross and Lack’ suggest haloperidol as the drug of choice with paranoid or psychotic patients and suggest a dose range of l-20 mg; he advocates treatment with anticholinergic drugs only if extrapyramidal symptoms develop. Massie and colleagues4 and Massie and Holland5 also recommend haloperidol as the most effective and most commonly prescribed drug for delirium in terminally ill cancer patients and note that it causes less orthostatic hypotension and fewer anticholinergic effects than other neuroleptic agents such as chlorpromazine or thioridazine. Their recommended dose is haloperidol 0.5 mg by mouth or 0.25-0.5 mg parenterally, with repeat doses every 39-60 min to titrate against symptoms; they suggest that extrapyratidal symptoms should be treated with benztropine 2 mg twice daily. Fernandez and colleagues9 report using high doses of haloperidol and lorazepam to treat de-
lirium in 28 terminally ficiency syndrome (AI fro nous doses ranged haloperidol per day and 4.5-37.5 mg of lorazepam per day, and t e average daily dose for these two drugs was 42 mg and 7.5 mg, respectively. Extrapyramidal symptoms were noted in nearly one-half of the treated patients. Adams’** advocates quick and aggressive pharmacological intervention in tbe early hours of delirium followed by decreasing drug doses to maintenance levels when the behavioral manifestations are resolved. Specifically, he suggested a combination of a neuroleptic, a benzodiazepine, and a narcotic via the intravenous route. Typically, treatment is begun with halopetidol 3 mg, lorazepam 0.5 mg, and hydromorphone 0.5 mg; the hydromorphone is given every 3 hr and haloperidol and lorazepam are given every 20 min until an adequate response is achieved. When the patient is sedated, the lorazepam is discontinued and the haloperidol is decreased to 50% of the dose over the previous 24 hr. Adams’,’ suggests that doses as high as 240 mg/day of haloperidol and 240 mg/day of lorazepam can be used safely for a number of days, although less than 100 mg of each drug is adequate for most cases. The use of haloperidol as a first line treatment for delirium is also recommended by other authors.“’ Methotrimeprazine was administered SC in our patient, up to a maximum dose of 60 mg/ day. This drug produced extrapyramidal side effects, which required the use of benztropine. Oliverlo*” describes the use of methotrimeprazine for confusion and agitation in a dose range of 12.5-59 mg every 4-8 hr for the majority of patients; in his study, 94% of patients with terand confusion minal agitation, restlessness, were improved by this drug, and sedation, which occurred in 56%. was the most common side effect. Hypotension has also been reported as a side effect; and, although it was not a problem in Oliver’s survey to due to the restricted activity of the patients, Twycross and Lack’ feels that the hypotensive and sedative effects limit the usefulness of this drug. Storey and colsuggest that methotrimeprazine may leagues” be useful for anxious patients in doses of 5O300 mg per 24 hr. They warn of the necessity to watch the SC sites for signs of irritation. The agitated delirium in our patient did not appear to respond to the doses of methotrimeprazine
we used, and the presence of extrapyramidal side effects contributed to the decision to change treatment. Midazolam in a dose range of l-4 mglhr by continuous SC infusion proved very successful in controlling our patient’s agitation, albeit with the development of marked sedation. Twycross and Lack’ describe the use of midazolam by this route in a range of 30-100 mg124 hr and suggest it is a useful treatment if sedation is desired or an anticonvulsant action is needed. Other authors also described the use of midazolam to treat delirium or convulsions.13-‘5 Adams’ does not recommend midazolam due to its sedative nature and the potential for hypotension. The difficulty in treating delirium without causing sedation has been demonstrated in two recent reports. Ventafridda and colleagues’6 and Fainsinger and colleagues” report that about 10% of terminally ill patients experienced delirium that was controllable only by sedation. Noting Saunders’rs observations that the manner in which people die remains in the memory of those who live on, a degree of sedation that impairs communication with the family may not be desirable. Nonetheless, symptom control is sometimes gained only at the cost of a decreased level of consciousness. The agitated, restless, and wandering patient can be a danger to himself and can cause both increased emotional distress for the family and management difficulties for the nursing staff. ‘*“J Ironically, one of the major benefits of sedation in patients with refractory delirium can be the observed relief and gratitude of tbe family. These issues were certainly raised by our patient, whose agitation was very distressing for the family and impeded their preparation for his death.
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2. Bruera E, Miller L. McCallion J. Cognitive failure in patients with terminal cancer: a prospective longitudinal study. Psychosocial Aspects of Cancer 1990; 9:308. 3. Twycross RG, Lack SA, eds. Therapeutics in terminal cancer. 2nd ed. London: Churchill Livingston, 1990. 4. Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiat 1983;140: 1048-1050. 5. Massie MJ, Holland JC. The cancer patient with pain: psychiatric complications and their management. Med Clin of North Am 1987;71:243-258. 6. Lipowski ZJ. Delirium (acute confusional JAMA 1987;258: 1789-1792.
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