J Am Board Fam Pract: first published as 10.3122/jabfm.6.5.502 on 1 September 1993. Downloaded from Prolonged Delirium Tremens Requiring Massive Doses Of Medication

Kathleen M. Wolf, MD, Allen F Shaughnessy, PharmD, and Donald B. Middleton, MD

Delirium tremens, the most severe manifestation ence of psoriatic lesions, muscle wasting, and spi­ of alcohol withdrawal, occurs in at least 5 percent der hemangiomata, findings of the rest of the of hospitalized alcoholic patients and is associated physical examination were unremarkable. He had with a mortality rate of 1 to 15 percent.1 Delirium no signs of hepatitis or pancreatitis and showed no tremens usually develops on the 3rd to 5th day of other signs of delirium tremens on admission. alcohol abstinence and persists for 1 to 6 days; on Laboratory studies, including liver function tests, rare occasions, the condition can last for weeks. were normal except for an elevated hemoglobin Patients with delirium tremens respond to nu­ (16.7 mgldL) and hematocrit (49.3 percent) and a merous pharmacologic agents and supportive decreased urea nitrogen (4 mg/dL). therapies. Mildly affected patients need only gen­ The patient was admitted to an unmonitored eral nursing care, cardiovascular stabilization, re­ bed with the diagnoses of Wernicke encephalopa­ assurance, and low doses of sedative medications. thy and chronic alcoholism for observation of Dramatically ill patients often require higher than alcohol withdrawal. Treatment consisted of thia­ expected doses of drugs to quell the symptoms of mine, folate, and fluid repletion, and oral chlordi­ neurologic and cardiovascular instability. Agents azepoxide was given as needed for agitation. Dur­ used include paraldehyde, barbiturates, magne­ ing the next several days, he became progressively sium, ~-blockers, clonidine, haloperidol, alcohol confused and disoriented. Five days after admis­ itself, such narcotics as fentanyl, and various sion the patient was transferred to a monitored benzodiazepines, including diazepam, chlordiaze­ bed after he developed marked autonomic insta­ poxide, oxazepam, lorazepam, and midazolam. 1,2 bility, hallucinations, and extreme agitation de­ Benzodiazepines are favored because of their spite receiving up to 275 mg/d of oral chlordiaze­ effectiveness and large therapeutic index. We poxide. This dosage was further increased during report a patient who required massive doses of the next 4 days to a total of 810 mg daily, and medication, primarily benzodiazepines, during supplemental doses of intravenous diazepam also an 8-week period to survive prolonged delirium were given as necessary. http://www.jabfm.org/ tremens. On day 10 the patient was intubated to decrease the risk of aspiration of copious secretions. Intra­ Case Report venous lorazepam was begun and titrated up to A 67 -year-old man was brought to the emergency 24 mg daily, with supplemental doses given to department with a 3-day history of tremors and control tremor, sweating, fever, agitation, and gait instability. According to family members, he confusion. On day 12 intravenous haloperidol was on 2 October 2021 by guest. Protected copyright. had a long history of alcohol and tobacco abuse. substituted, with dosages of up to 40 mg/d failing His last drink followed a period of continuous to control agitation. On day 14 the haloperidol intake and occurred about 3 days before admis­ was discontinued, and intravenous fentanyl, in dos­ sion. Physical examination showed him to be an ages of up to 130 j.Lg!h, was still ineffective in con­ unkempt, disoriented man with mild diaphoresis, trolling behavior and autonomic hyperactivity. tachycardia, tachypnea, tremulousness, brisk re­ On day 16 fentanyl was stopped, and a continu­ flexes, and ocular dysmetria. Except for the pres- ous intravenous infusion of midazolam was begun. Starting with an initial dose of 50 mglh, Submitted, revised, 14 May 1993. the dosage was doubled every hour until symp­ From the Department of Medical Education, St. Margaret toms were controlled, reaching a maximum rate Memorial Hospital, Pittsburgh, PA Address reprint requests to of 520 mglh. During a 25-hour period the patient Allen F. Shaughnessy, PharmD, Family Practice Residency Pro­ received a total of 2025 mg of midazolam. The gram, Harrisburg Hospital, P.O. Box 8700, Harrisburg, PA 17105-8700. development of metabolic acidosis and acute renal

502 JABFP Sept.-Oct. 1993 Vol. 6 No.5 J Am Board Fam Pract: first published as 10.3122/jabfm.6.5.502 on 1 September 1993. Downloaded from

failure corresponding with the midazolam infu­ Several authors have reported that massive sion, however, necessitated its discontinuation. benzodiazepine doses were required during treat­ These complications resolved following cessation ment of acute alcohol withdrawal and delirium of this infusion. tremens.3:5 The only previous report of high-dose On day 17 intravenous diazepam, 500 mg every midazolam involved a total of 2850 mg of mid­ 8 hours, was restarted and titrated to 500 mg azolam administered during a 50-day period to a every 6 hours with resolution of agitation and 25-year-old patient.3 As in the patient we de­ autonomic instability. Diazepam dosages were de­ scribe, respiratory depression did not occur de­ creased during the next 12 days to 30 mgld. At spite extremely high doses. this time periodic attempts at more rapid taper The mechanisms explaining the need for such met with recurrent hallucinations, agitation, trem­ high doses of benzodiazepine are complex. The ors, and vascular instability, so a slowly progres­ resistance to high-dose benzodiazepine is prob­ sive decrease in dosage was prescribed. ably a central effect, because the pharmacokinet­ On day 52 of his hospitalization the patient ics of diazepam are not altered in alcohol with­ received the last dose of diazepam. Ten days later drawal. 5 Benzodiazepines exert their actions in he was discharged to a nursing home with trache­ alcohol withdrawal by augmenting the effect of ostomy and gastrostomy tubes. At this time the pa­ gamma-aminobutyric acid (GABA), an inhibitory tient was awake, fullowing oommands, and perform­ neurotransmitter, at the GABAA receptor in the ing most daily activities with minimal assistance. central nervous system. Alcohol might also exert During his nearly 8-week hospitalization the its effect through an effect on GABA. 6,7 patient received a total of 17,658.5 mg of ben­ Chronic alcohol use, as occurred in this case, zodiazepine, including daily doses of 1000 mg could influence the activity of benzodiazepines, or more of diazepam for a 6-day period. Three either by decreasing the number of benzodiaze­ electroencephalograms, three computerized tomo­ pine binding sites8 or by desensitizing the GABA­ graphic scannings of the brain, and a spinal tap all benzodiazepine receptor to the effects of benzo­ failed to reveal any specific abnormality. Three diazepine.9,lO In addition, chronic benzodiazepine neurologic consultants and a drug rehabilitation use might cause down-regulation of receptor specialist supported the diagnosis ofWemicke en­ function. 11 -13 Thus, the apparent insensitivity of cephalopathy and delirium tremens. this patient to normal doses of benzodiazepine At the nursing home the patient's cognitive might at first have been due to alcohol-induced function dramatically improved, and he was dis­ receptor insensitivity and later to the massive charged to his home after removal of the trache­ doses of benzodiazepine itself. http://www.jabfm.org/ ostomy and gastrostomy tubes. At a follow-up High-dose midazolam might not be a suitable visit 6 months after the date of admission, the treatment for alcohol withdrawal. Metabolic aci­ patient scored 21124 on a mini-mental state ex­ dosis occurred in this patient, probably as a result amination, which was limited by his inability to of the high acid load associated with the extremely read or write. The patient had no memory of the high dose of midazolam. To maintain stability of events that occurred during his hospitalization. the product, the pH of midazolam solution is on 2 October 2021 by guest. Protected copyright. adjusted to approximately 3.0. Although the exact Discussion volume of fluid administered to this patient is This report describes a patient who required mas­ not known (midazolam concentrations of both sive doses of benzodiazepine to control delirium 1 mg/mL and 5 mglmL were used), a conserya­ tremens; during 8 weeks, the patient received tive estimate would be 2025 mL of this acid solu­ 12,462.5 mg of diazepam (up to 2 g/d), 121 mg of tion during 25 hours. lorazepam, 3050 mg of chlordiazepoxide, and Another factor to be considered is the cost of 2025 mg ofmidazolam. Despite these large doses, midazolam. At a cost of $3/mg, control of this clinical symptoms of agitation and autonomic hy­ patient's symptoms for only 25 hours cost $50,335 peractivity were barely controlled, though seizures and depleted citywide supplies of the drug. In were prevented. The patient experienced no episodes contrast, considering the relatively low cost of of respiratory depression requiring medical inter­ intravenous diazepam, a dosage of 2000 mgld vention but was intubated to prevent aspiration. amounts to only $440.

Prolonged Delirium Tremens 503 J Am Board Fam Pract: first published as 10.3122/jabfm.6.5.502 on 1 September 1993. Downloaded from

Summary 4. Nolop KB, Natow A. Unprecedented sedative re­ Delirium tremens might last for weeks and treat­ quirements during delirium tremens. Crit Care Med ment requires massive benzodiazepine doses, yet 1985; 13:246-7. 5. Woo E, Greenblatt DJ. Massive benzodiazepine re­ it is possible to manage patients with this condi­ quirements during acute alcohol withdrawal. Am J tion successfully. In this case of delirium tremens, Psychiatty 1979; 136:821-3. standard agents at the usual recommended doses 6. Mehta AK, Ticlru MK. Ethanol potentiation of were not sufficient to achieve control of confusion GABAergic transmission in cultured spinal cord and agitation or to stabilize neurologic and car­ neurons involves gamma-aminobutyric acidA-gated chloride channels. J Pharmacol Exp Ther 1988; diovascular parameters. The patient required ex­ 246:558-64 .. traordinarily high doses of central nervous system 7. Suzdak PD, Schwartz RD, Skolnick P, Paul SM. Eth­ depressants for an extended period. Midazolam, a anol stimulates gamma-aminobutyric acid receptor­ short-acting benzodiazepine, was used but was mediated chloride transport in rat brain syn­ associated with metabolic acidosis and was ex­ aptoneurosomes. Proc Nad Acad Sci USA 1986; tremely expensive. Although high-dose mid­ 83:4071-5. 8. Volicer L, Biagioni TM. Effect of ethanol adminis­ azolam should probably be avoided, extremely tration and withdrawal on benzodiazepine receptor high dose benzodiazepine use for an extended binding in the rat brain. Neuropharmacology 1982; period might be necessary in some cases. In this 21:283-6. circumstance we advise diazepam because of its 9. Morrow AL, Suzdak PD, Karanian Jw. Paul SM. low cost and relative safety. The tendencies to Chronic ethanol administration alters gamma­ aminobutyric acid, pentobarbital and ethanol-medi­ withhold large doses for fear of side effects or to ated 36Cl-uptake in cerebral cortical synaptoneuro­ give up in cases requiring prolonged intensive somes J Pharmacol Exp Ther 1988; 246: 158-64. support must be resisted to minimize the mortal­ to. Nutt D, Adinoff B, Linnoila M. Benzodiazepines in ity from this severe illness. the treatment of alcoholism. Recent Dev Alcohol 1989; 7:283-313. 11. Zorumski CF, Isenberg KE. Insights into the struc­ ture and function of GABA-benzodiazepine recep­ References tors: ion channels and psychiatty. Am J Psychiatty 1. Turner RC, Lichstein PR, Peden JG Jr, Busher JT, 1991; 148:162-73. Waivers LE. Alcohol withdrawal syndromes: a re­ 12. Miller LG, Greenblatt DJ, Barnhill JG, Shader RI. view of pathophysiology, clinical presentation, and Chronic benzodiazepine administration. I. Toler­ treatment. J Gen Intern Med 1989; 4:432-44. ance is associated with benzodiazepine receptor 2. Guthrie SK. The treatment of alcohol withdrawal. downregulation and decreased gamma-aminobu­

Pharmacotherapy 1989; 9: 131-43. tyric acidA receptor function. J Pharmacol Exp Ther http://www.jabfm.org/ 3. Lineaweaver WC, Anderson K, Ring DN. Massive 1988; 246: 170-6. doses of midazolam infusion for delirium tremens 13. Gallager DW, LakoskiJM, Gonsalves SF, Rauch SL. without respiratory depression. Crit Care Med 1988; Chronic benzodiazepine treatment decreases post­ 16:294-5. synaptic GABA sensitivity. Nature 1984; 308:74-7. on 2 October 2021 by guest. Protected copyright.

504 JABFP Sept.-Oct. 1993 Vol. 6 No.5