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Agitation, disorientation, and hallucinations in patients on cimetidine
Brief Reports This section will carry communications of work in progress, preliminary research reports, or interesting and unusual vignettes. Such reports will be considered for their practical clinical relevance or heuristic value.
Agitation, Disorientation, Patients on Cimetidine
and Hallucinations
in
A Report of Three Cases and Literature Review Stuart C. Yudofsky, M.D. Clinical Director, New York State Psychiatriclnstitute, and Director, Neuropsychiatric Columbia-Presbyterian Medical Center, New York, New York
Diagnosticand
Treatment Unit,
Geary Ahern, M.D. Liaison Fellow, Columbia-Presbyterian
Medical Center, New York, New York
Richard Brockman, M.D. Co-Director,
Psychiatric
lnpatien t Seruice, University of Arizona Health Sciences
Abstract: Cimetidine, thefirst of a new class of pharmacologic agents that dramatically inhibit basal gastric acid secretion, is achieving widespread use for the treatment of such acid peptic disorders as duodenal ulcers, gastritis, and reflux esophagitis. Three patients are presented who experienced agitation, disorientation, and hallucinations while being treated with cimetidine. A review of the literature revealed that central neroous system side effects of cimetidine can occur within 24 hours of treatment with the drug; are often unrecognized or misdiagnosed by clinicians, and are reversed within 12 to 48 hours after the discontinuation of the medication.
Center,
Tucson,
Arizona
cal journals have reported 10 cases of mental confusion and agitation in patients who had received cimetidine (2-10). Nevertheless, a recent article which reviewed 3000 cases for the adverse effects of cimetidine did not include agitation, disorientation, or psychosis in its report of side effects (11). The following are three case reports of patients with prominent psychosis, agitation, and disorientation related to cimetidine.
Case 1 Although cimetidine, a histamine I-&-receptor antagonist, has been on the U.S. market for less than 2 years, the medication has gained unusually wide acceptance and use for the treatment of acid-peptic disorders (1). Letters to the editors of several mediGeneral Hospifnl Psyrhtify 3, 233-2.36, 1980 @ Elsevier North Holland, Inc., 1980 52 Vanderbilt Ave., New York, N.Y. 10017
Mr. S is a 3%year-old male with a history of episodic “weekend drinking” who was admitted to the medical
ICU with a chief complaint of “stomach pain,” nausea,
and vomiting for the previous 10 days. Married and the father of two children, he had an excellent 16-year
233 ISSN OKi-8343/80/030233-WWZ.25
S. C. Yudofsky et al.
work record at a chemical factory. The patient had no past history of significant medical or neurological impairment. At the time of admission his lab values included: BUN 56, glucose 218, amylase 300, Na+ 134, K+ 2.6, Cl 63.6, CO, 40, Hct 42, and WBC 17.5. The patient’s stool was guiac-positive, and his emesis was “heme-positive with coffee grounds.” Described as “lethargic but oriented,” Mr. S was placed on replacement intravenous solutions and cimetidine, 300 mg IV q.6h. Twenty-four hours after admission and initiation of cimetidine, he became frightened, disoriented, and experienced visual hallucinations. The internist felt that the symptoms were consistent with delirium tremens, and Librium (chlordiazepoxide hydrochloride), 50 mg IM q4h, as well as thiamine and MgSO4 were added. Although the patient’s electrolytes, blood glucose, and BUN returned to normal ranges, he remained incoherent and episodically agitated, disoriented, and aggressive. His behavior was so difficult to manage that Valium (diazepam), 10 mg by hourly IV push, was added to his IM Librium. Eight days after the onset of his confusion and agitation, a psychiatric consultation was requested. The patient was found to be sedated and disoriented to place, time, and person (he believed his physicians to be “salesmen”). In addition, his memory and ability to calculate were grossly impaired (“33% nickels to a dollar”). The psychiatrist believed that the patient’s drinking history, the development, the persistence, and the nature of his organic mental symptoms did not support the diagnosis of delirium tremens. He suggested that cimetidine be discontinued, and within 48 hours the mental status of Mr. S had returned to normal.
Case 2 Mr. W is an 89-year-old male who presented to the emergency room with a 2-day history of acute abdominal pain. The initial note described Mr. W as “an alert pleasant man who is oriented to time, place and person.“ Laboratory data included SMA 60 and SMA 12160 consistent with dehydration, and flat plate and upright x-rays showed subdiaphragmatic free air. Seen by the surgical consultant who diagnosed a probable perforated peptic ulcer, the patient was admitted to the hospital and started on clindamycin, gentamicin, and cimetidine, 300 mg IV q6h. An operation was performed within several hours of his presentation, and a perforated ulcer in the area of the pylorus was noted. His abdomen was drained, and this “routine, uneventful” operation was completed within 45 minutes. He was returned in good condition. The postoperative course progressed well until 48 hours after the admission, when the patient pulled out his IV and refused to allow the resident to reinsert it. 234
Later that morning, the nurse described Mr. W as “confused and disoriented, looking for his clothes and calling for his wife.” Later that day he became very agitated, yelled at the nurses and staff, pulled out his NG tube and another IV line. That evening he threw an IV bottle at the window. He was restrained in bed; haloperidol, 2 mg IM, and sodium amytal, 150 mg, were given with little effect. A psychiatry consult was called the next morning. When first visited by the psychiatrist, the patient was strapped down in the bed, agitated, and disoriented. He did not look at the interviewer, but focused his attention on the curtains near his bed. He conversed with the curtains by barking out rapid-fire directives. When touched, he pulled away, appeared starled and frightened. The cimetidine was discontinued and chlorapromazine initiated. Thirty-six hours later he was less agitated but remained confused and disoriented. The next morning, about 48 hours after the cimetidine had been discontinued, he was calm and oriented. He was able to reflect abstractly about his psychosis: “I must have been crazy. I don’t know what got into me.” Chlorpromazine was discontinued, and the patient has remained “an alert, pleasant man, oriented to time, place, and person. . . .”
Case 3 Mr. H is a 72-year-old male who presented to the emergency room with a l-week history of abdominal pain and a 2-day history of continuous nausea and vomiting which produced coffee-ground emesis. Three weeks prior to his admission the patient suffered a right middle cerebral artery infarction for which he was treated with aspirin, 600 mg twice per day. Prior to his cerebral vascular accident, the patient was a healthy married male with no prior history of psychiatric problems, alcoholism, smoking, or drug abuse. At the time of admission the patient was said to have a “normal sensorium,” was “oriented times three, appropriate, and a good historian.” At the time of his admission for his gastrointestinal problem the patient was placed on cimetidine, 300 mg IV q4h, a regimen that he sustained for 5 days. Upon the fifth day of hospitalization the patient was noticed to be sad and tearful; he felt that his pain was related to the ingestion of “poison“ that his physicians were “giving it to me because they were under the influence of the drug companies.” A psychiatric consultation was called. The psychiatrist believed the patient to be suffering from auditory hallucinations and gave the overall diagnostic impression of “acute paranoid psychosis.” At that time the patient’s cimetidine was decreased to 300 mg p.o. twice per day with the addition of 0.05 mg p.o. haloperidol twice per day. Within 24 hours the patient‘s paranoid fears and audi-
Table 1. Published
Author(s)
reports of emotional
Case
Age (yr)
Sex
and behavioral
Highest daily cimetidine dose (mg)
changes associated
Cimetidine-related symptoms “Mental confusion,” dizziness “Confused,“ agitated, unmanageable Erratic driving, “emotionally upset” Loss of concentration, “confusion,” memory loss, confabulation Drowsy, “confused,” restless Disoriented, agitated, “nonsensical” Agitation, delirium, coma Agitated, “confused,” lethargic “Confused,” belligerent
Crimson
1
50
M
Delaney & Ravey
2
74
M
2000 p.0. (overdose) 1000 p.o.
Robinson & Mulligan
3
55
M
1000 p.o.
4
65
M
Undocumented
Meruies-Gow
5
78
M
“Normal dosage”
Nelson
6
25
M
12,000 p.o. (overdose)
McMillen, Ambis, & Siegel
7
71
M
1200 p.o.
8
56
M
24001V
9
56
F
18OOIV
10
72
M
1200 p.o.
Visual hallucinations
11
58
M
1200 p.o.
12
58
F
900 p.o.
13
38
M
1200 IV
14
89
M
1200 IV
15
72
M
1200 IV
Confusion, disorientation, visual hallucination Confusion, disorientation Visual hallucinations disorientation Confused, agitated, disoriented, hallucinations Auditory hallucinations, paranoid fears
Wood, Isaacson, & Hibbs Agarwal
Bornhardt & Bowden
Yudofsky, Ahern, & Brockman
with cimetidine
Significant pre-existing medical complications
Number of hours from discontinuation of cimetidine to return of normal mental status
-
24
-
24
Deep vein thrombosis
Undocumented
Left parietal vascular occlusion
24
-
24
-
24
-
48
Vasoactive intestinal peptide-secreting tumor Mild impairment of renal functioning
24
Bilateral frontoparietal subdural hematomas -
10
24
Schizophrenia
24
Dehydration
48
-
Middle cerebral artery infarction
48
48
24
235
S. C. Yudofsky et al.
tory hallucinations had ceased, although he remained sad and tearful. The patient’s haloperidol was discontinued at that point as was his cimetidine, and the patient% mental status has remained unchanged.
Discussion Although other causes could be proposed for the mental changes of the three patients presented, their symptoms are most likely related to cimetidine. For example, the agitated psychosis of Mr. S could be attributed to dehydration with electrolyte imbalance, but why did these symptoms persist 6 days beyond the reversal of this condition? In addition, Mr. W’s symptoms were not consistent with the prototypic course of a postoperative psychosis (E!), nor did his vital signs, blood cultures, or other clinical data support such etiologies as a delirium related to electrolyte imbalance, atelectasis, or wound infection. Finally, although Mr. I-I’s paranoid psychosis could be attributed to psychotic depression or to organic mental syndrome related to his cerebral vascular accident, these symptoms did not persist after the discontinuation of the cimetidine. More important, the three cases described share important common features with published reports of central nervous system dysfunction related to cimetidine (Table 1). Significant among these features are: (a) agitation, disorientation, and psychosis, which can occur from 2 hours to 3 days after the initiation of cimetidine by either oral or intravenous routes; (b) the symptoms can occur within the dose range recommended for the treatment for acid-peptic disorders, 300 mg every 6 hours; and (c) The symptoms reverse within 12 to 48 hours after the discontinuation of cimetidine. Certain reports suggest that patients who receive high doses of the medication (2,6,7) or patients with
236
renal (8) or central nervous system impairment (4,9) have increased susceptibility to the side effects. Because the use of cimetidine is rapidly increasing and because the mental changes related to this therapy are of potentia1 danger to the patient and may be misdiagnosed by the practitioner, the clinician should be alerted to the presence and prominent features of these side effects.
References W, Isselbacher KJ: Drug Therapy: 1. Finklestein Cimetidine. N Engl J Med 299:992-996, 1978 2. Grimson TA: Reactions to cimetidine. Lancet 1:858, 1977 3. Delaney JC, Ravey M: Cimetidine and mental confusion. Lancet 2:512, 1977 4. Robinson TS, Mulligan TO: Cimetidine and mental confusion. Lancet 2:719, 1977 5. Menzies-Gow N: Cimetidine and mental confusion. Lancet 2:928, 1977 6. Nelson PC: Cimetidine and mental confusion. Lancet 21928, 1977 7. McMillan MA, Ambis D, Siegel JH: Cimetidine and mental confusion. N Engl J Med 298:284-285, 1978 8. Wood CA, Isaacson ML, Hibbs MS: Cimetidine and mental confusion. JAMA 2392550-2551, 1978 9. Agarwal SK: Cometidine and visual hallucinations. JAMA 240~214, 1978 10. Bornhardt C, Bowden CL: Toxic psychosis with cimetidine. Am J Psychiatry 136:725-726, 1979 11. Kruss DM, Littman A: Safety of cimetidine. Gastroenterology 74:478483, 1978 12. Knox SJ: Severe psychiatric disturbances in the postoperative period-Five year survey of Belfast hospitals. J Men Sci 107:1078-1096, 1961 Direct reprint requests to: Stuart C. Yudofsky, M.D. Clinical Director New York State Psychiatric Institute 722 West 168 Street New York, NY 10032
Agitation, Disorientation, Patients on Cimetidine
and Hallucinations
in
A Report of Three Cases and Literature Review Stuart C. Yudofsky, M.D. Clinical Director, New York State Psychiatriclnstitute, and Director, Neuropsychiatric Columbia-Presbyterian Medical Center, New York, New York
Diagnosticand
Treatment Unit,
Geary Ahern, M.D. Liaison Fellow, Columbia-Presbyterian
Medical Center, New York, New York
Richard Brockman, M.D. Co-Director,
Psychiatric
lnpatien t Seruice, University of Arizona Health Sciences
Abstract: Cimetidine, thefirst of a new class of pharmacologic agents that dramatically inhibit basal gastric acid secretion, is achieving widespread use for the treatment of such acid peptic disorders as duodenal ulcers, gastritis, and reflux esophagitis. Three patients are presented who experienced agitation, disorientation, and hallucinations while being treated with cimetidine. A review of the literature revealed that central neroous system side effects of cimetidine can occur within 24 hours of treatment with the drug; are often unrecognized or misdiagnosed by clinicians, and are reversed within 12 to 48 hours after the discontinuation of the medication.
Center,
Tucson,
Arizona
cal journals have reported 10 cases of mental confusion and agitation in patients who had received cimetidine (2-10). Nevertheless, a recent article which reviewed 3000 cases for the adverse effects of cimetidine did not include agitation, disorientation, or psychosis in its report of side effects (11). The following are three case reports of patients with prominent psychosis, agitation, and disorientation related to cimetidine.
Case 1 Although cimetidine, a histamine I-&-receptor antagonist, has been on the U.S. market for less than 2 years, the medication has gained unusually wide acceptance and use for the treatment of acid-peptic disorders (1). Letters to the editors of several mediGeneral Hospifnl Psyrhtify 3, 233-2.36, 1980 @ Elsevier North Holland, Inc., 1980 52 Vanderbilt Ave., New York, N.Y. 10017
Mr. S is a 3%year-old male with a history of episodic “weekend drinking” who was admitted to the medical
ICU with a chief complaint of “stomach pain,” nausea,
and vomiting for the previous 10 days. Married and the father of two children, he had an excellent 16-year
233 ISSN OKi-8343/80/030233-WWZ.25
S. C. Yudofsky et al.
work record at a chemical factory. The patient had no past history of significant medical or neurological impairment. At the time of admission his lab values included: BUN 56, glucose 218, amylase 300, Na+ 134, K+ 2.6, Cl 63.6, CO, 40, Hct 42, and WBC 17.5. The patient’s stool was guiac-positive, and his emesis was “heme-positive with coffee grounds.” Described as “lethargic but oriented,” Mr. S was placed on replacement intravenous solutions and cimetidine, 300 mg IV q.6h. Twenty-four hours after admission and initiation of cimetidine, he became frightened, disoriented, and experienced visual hallucinations. The internist felt that the symptoms were consistent with delirium tremens, and Librium (chlordiazepoxide hydrochloride), 50 mg IM q4h, as well as thiamine and MgSO4 were added. Although the patient’s electrolytes, blood glucose, and BUN returned to normal ranges, he remained incoherent and episodically agitated, disoriented, and aggressive. His behavior was so difficult to manage that Valium (diazepam), 10 mg by hourly IV push, was added to his IM Librium. Eight days after the onset of his confusion and agitation, a psychiatric consultation was requested. The patient was found to be sedated and disoriented to place, time, and person (he believed his physicians to be “salesmen”). In addition, his memory and ability to calculate were grossly impaired (“33% nickels to a dollar”). The psychiatrist believed that the patient’s drinking history, the development, the persistence, and the nature of his organic mental symptoms did not support the diagnosis of delirium tremens. He suggested that cimetidine be discontinued, and within 48 hours the mental status of Mr. S had returned to normal.
Case 2 Mr. W is an 89-year-old male who presented to the emergency room with a 2-day history of acute abdominal pain. The initial note described Mr. W as “an alert pleasant man who is oriented to time, place and person.“ Laboratory data included SMA 60 and SMA 12160 consistent with dehydration, and flat plate and upright x-rays showed subdiaphragmatic free air. Seen by the surgical consultant who diagnosed a probable perforated peptic ulcer, the patient was admitted to the hospital and started on clindamycin, gentamicin, and cimetidine, 300 mg IV q6h. An operation was performed within several hours of his presentation, and a perforated ulcer in the area of the pylorus was noted. His abdomen was drained, and this “routine, uneventful” operation was completed within 45 minutes. He was returned in good condition. The postoperative course progressed well until 48 hours after the admission, when the patient pulled out his IV and refused to allow the resident to reinsert it. 234
Later that morning, the nurse described Mr. W as “confused and disoriented, looking for his clothes and calling for his wife.” Later that day he became very agitated, yelled at the nurses and staff, pulled out his NG tube and another IV line. That evening he threw an IV bottle at the window. He was restrained in bed; haloperidol, 2 mg IM, and sodium amytal, 150 mg, were given with little effect. A psychiatry consult was called the next morning. When first visited by the psychiatrist, the patient was strapped down in the bed, agitated, and disoriented. He did not look at the interviewer, but focused his attention on the curtains near his bed. He conversed with the curtains by barking out rapid-fire directives. When touched, he pulled away, appeared starled and frightened. The cimetidine was discontinued and chlorapromazine initiated. Thirty-six hours later he was less agitated but remained confused and disoriented. The next morning, about 48 hours after the cimetidine had been discontinued, he was calm and oriented. He was able to reflect abstractly about his psychosis: “I must have been crazy. I don’t know what got into me.” Chlorpromazine was discontinued, and the patient has remained “an alert, pleasant man, oriented to time, place, and person. . . .”
Case 3 Mr. H is a 72-year-old male who presented to the emergency room with a l-week history of abdominal pain and a 2-day history of continuous nausea and vomiting which produced coffee-ground emesis. Three weeks prior to his admission the patient suffered a right middle cerebral artery infarction for which he was treated with aspirin, 600 mg twice per day. Prior to his cerebral vascular accident, the patient was a healthy married male with no prior history of psychiatric problems, alcoholism, smoking, or drug abuse. At the time of admission the patient was said to have a “normal sensorium,” was “oriented times three, appropriate, and a good historian.” At the time of his admission for his gastrointestinal problem the patient was placed on cimetidine, 300 mg IV q4h, a regimen that he sustained for 5 days. Upon the fifth day of hospitalization the patient was noticed to be sad and tearful; he felt that his pain was related to the ingestion of “poison“ that his physicians were “giving it to me because they were under the influence of the drug companies.” A psychiatric consultation was called. The psychiatrist believed the patient to be suffering from auditory hallucinations and gave the overall diagnostic impression of “acute paranoid psychosis.” At that time the patient’s cimetidine was decreased to 300 mg p.o. twice per day with the addition of 0.05 mg p.o. haloperidol twice per day. Within 24 hours the patient‘s paranoid fears and audi-
Table 1. Published
Author(s)
reports of emotional
Case
Age (yr)
Sex
and behavioral
Highest daily cimetidine dose (mg)
changes associated
Cimetidine-related symptoms “Mental confusion,” dizziness “Confused,“ agitated, unmanageable Erratic driving, “emotionally upset” Loss of concentration, “confusion,” memory loss, confabulation Drowsy, “confused,” restless Disoriented, agitated, “nonsensical” Agitation, delirium, coma Agitated, “confused,” lethargic “Confused,” belligerent
Crimson
1
50
M
Delaney & Ravey
2
74
M
2000 p.0. (overdose) 1000 p.o.
Robinson & Mulligan
3
55
M
1000 p.o.
4
65
M
Undocumented
Meruies-Gow
5
78
M
“Normal dosage”
Nelson
6
25
M
12,000 p.o. (overdose)
McMillen, Ambis, & Siegel
7
71
M
1200 p.o.
8
56
M
24001V
9
56
F
18OOIV
10
72
M
1200 p.o.
Visual hallucinations
11
58
M
1200 p.o.
12
58
F
900 p.o.
13
38
M
1200 IV
14
89
M
1200 IV
15
72
M
1200 IV
Confusion, disorientation, visual hallucination Confusion, disorientation Visual hallucinations disorientation Confused, agitated, disoriented, hallucinations Auditory hallucinations, paranoid fears
Wood, Isaacson, & Hibbs Agarwal
Bornhardt & Bowden
Yudofsky, Ahern, & Brockman
with cimetidine
Significant pre-existing medical complications
Number of hours from discontinuation of cimetidine to return of normal mental status
-
24
-
24
Deep vein thrombosis
Undocumented
Left parietal vascular occlusion
24
-
24
-
24
-
48
Vasoactive intestinal peptide-secreting tumor Mild impairment of renal functioning
24
Bilateral frontoparietal subdural hematomas -
10
24
Schizophrenia
24
Dehydration
48
-
Middle cerebral artery infarction
48
48
24
235
S. C. Yudofsky et al.
tory hallucinations had ceased, although he remained sad and tearful. The patient’s haloperidol was discontinued at that point as was his cimetidine, and the patient% mental status has remained unchanged.
Discussion Although other causes could be proposed for the mental changes of the three patients presented, their symptoms are most likely related to cimetidine. For example, the agitated psychosis of Mr. S could be attributed to dehydration with electrolyte imbalance, but why did these symptoms persist 6 days beyond the reversal of this condition? In addition, Mr. W’s symptoms were not consistent with the prototypic course of a postoperative psychosis (E!), nor did his vital signs, blood cultures, or other clinical data support such etiologies as a delirium related to electrolyte imbalance, atelectasis, or wound infection. Finally, although Mr. I-I’s paranoid psychosis could be attributed to psychotic depression or to organic mental syndrome related to his cerebral vascular accident, these symptoms did not persist after the discontinuation of the cimetidine. More important, the three cases described share important common features with published reports of central nervous system dysfunction related to cimetidine (Table 1). Significant among these features are: (a) agitation, disorientation, and psychosis, which can occur from 2 hours to 3 days after the initiation of cimetidine by either oral or intravenous routes; (b) the symptoms can occur within the dose range recommended for the treatment for acid-peptic disorders, 300 mg every 6 hours; and (c) The symptoms reverse within 12 to 48 hours after the discontinuation of cimetidine. Certain reports suggest that patients who receive high doses of the medication (2,6,7) or patients with
236
renal (8) or central nervous system impairment (4,9) have increased susceptibility to the side effects. Because the use of cimetidine is rapidly increasing and because the mental changes related to this therapy are of potentia1 danger to the patient and may be misdiagnosed by the practitioner, the clinician should be alerted to the presence and prominent features of these side effects.
References W, Isselbacher KJ: Drug Therapy: 1. Finklestein Cimetidine. N Engl J Med 299:992-996, 1978 2. Grimson TA: Reactions to cimetidine. Lancet 1:858, 1977 3. Delaney JC, Ravey M: Cimetidine and mental confusion. Lancet 2:512, 1977 4. Robinson TS, Mulligan TO: Cimetidine and mental confusion. Lancet 2:719, 1977 5. Menzies-Gow N: Cimetidine and mental confusion. Lancet 2:928, 1977 6. Nelson PC: Cimetidine and mental confusion. Lancet 21928, 1977 7. McMillan MA, Ambis D, Siegel JH: Cimetidine and mental confusion. N Engl J Med 298:284-285, 1978 8. Wood CA, Isaacson ML, Hibbs MS: Cimetidine and mental confusion. JAMA 2392550-2551, 1978 9. Agarwal SK: Cometidine and visual hallucinations. JAMA 240~214, 1978 10. Bornhardt C, Bowden CL: Toxic psychosis with cimetidine. Am J Psychiatry 136:725-726, 1979 11. Kruss DM, Littman A: Safety of cimetidine. Gastroenterology 74:478483, 1978 12. Knox SJ: Severe psychiatric disturbances in the postoperative period-Five year survey of Belfast hospitals. J Men Sci 107:1078-1096, 1961 Direct reprint requests to: Stuart C. Yudofsky, M.D. Clinical Director New York State Psychiatric Institute 722 West 168 Street New York, NY 10032