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Phenobarbital Versus Diazepam for Delirium Tremens – a Retrospective Study

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Phenobarbital Versus Diazepam for Delirium Tremens – a Retrospective Study Dan Med Bul ϧϩ/Ϫ August DANISH MEDICAL BULLETIN Phenobarbital versus diazepam for delirium tremens – a retrospective study Ida Hjermø Michaelsen1, John Erik Anderson2, Anders Fink-Jensen3, Peter Allerup4 & Jakob Ulrichsen1 ABSTRACT Copenhagen psychiatric departments have recently ORIGINAL ARTICLE INTRODUCTION: Delirium tremens (DT) is a severe and changed their treatment in favour of benzodiazepines. 1) Psychiatric Centre potentially fatal condition that may occur during withdrawal The purpose of the present retrospective study was Gentofte, from chronic alcohol intoxication. The purpose of the pre- to compare the effects and complications of phenobar- 2) Psychiatric Centre sent study was to compare the effects and the rates of com- bital and diazepam treatment in patients who were ad- Bispebjerg, plications of phenobarbital and diazepam treatment in DT. mitted with DT. 3) Psychiatric Centre, MATERIAL AND METHODS: Data were collected retrospect- Copenhagen University Hospital and ively from the medical files of patients who had received DT MATERIAL AND METHODS 4) Danish University of treatment (n = 194) at two psychiatric departments located Subjects were patients with DT who were admitted to Education in the general Copenhagen area in the 1998-2006 period. At the Department of Psychiatry, Rigshospitalet and the one department, all patients were treated with phenobarbi- Department of Psychiatry, Bispebjerg Hospital, in the Dan Med Bul tal (n = 53), while the treatment regimen at the other de- 2010;57(8):A4169 period from 1 January 1998 to 31 December 2006. The partment was changed from phenobarbital (n = 53) to di- files of these patients were studied retrospectively. azepam (n = 88) in 2002. Repeat cases of DT in any patient were allowed. All of RESULTS: Length of DT and hospitalization, mortality and the following inclusion criteria had to be fulfilled: rate of pneumonia (26%) were not affected by treatment. A subpopulation (9%) in the diazepam group was resistant to treatment. Respiratory depression occurred in 4% of the – An International Classification of Diseases 10, F10.4 phenobarbital and in 1% of the diazepam-treated patients. diagnosis Wernicke’s encephalopathy was established in 47% of the – A history of alcoholism and heavy alcohol intake patients. within the 96 hours preceding admission CONCLUSION: Phenobarbital is a safe alternative to diaze- – Two of the following physical alcohol withdrawal pam in the treatment of DT. symptoms: tremor, sweat or psychomotor agitation – Visual hallucinations – A turbid and disoriented state. In its full-blown form, delirium tremens (DT) is the most dramatic and serious of complications to alcoholism. The All patients from Rigshospitalet were treated with phe- clinical manifestations initially comprise severe physical nobarbital. At Bispebjerg Hospital, phenobarbital was alcohol withdrawal symptoms such as tremor, sweating, used from 1 January 1998 to 31 December 2001 (four tachycardia, increased temperature and psychomotor years), while patients who were admitted in the period agitation all in response to a sufficient decrease in blood from 1 January 2002 to 31 December 2006 (five years) alcohol concentration. Within 0-72 hours, the patient were treated with diazepam. Thus, DT patients were becomes visually hallucinated and delirious with insom- divided into the following three groups: nia and clouding of consciousness which typically fluctu- ates markedly over time. Withdrawal seizures are seen – PB Rigshospitalet: DT patients at Rigshospitalet who in approximately 20% of the patients and typically occur were treated with phenobarbital before the patient becomes hallucinated and delirious – PB Bispebjerg: DT patients at Bispebjerg Hospital [1, 2]. DT is a true medical emergency with a 15% mor- who were treated with phenobarbital tality rate [2]. – DZP Bispebjerg: DT patients at Bispebjerg Hospital World-wide, benzodiazepines seem to be the who were treated with diazepam. preferred drugs in DT treatment [3]. In Denmark, how- ever, barbiturates have been used in the treatment of The phenobarbital dose was 100-200 mg hourly (admin- DT for more than 100 years [4]. It has been demonstrated istered intravenously or orally), while diazepam was typ- that barbiturates are superior to benzodiazepines in DT ically administered as a 10-20 mg intravenous dose given [5], but due to the risk of respiratory depression, some hourly. If no effect was achieved, diazepam was adminis- DANISH MEDICAL BULLETIN Dan Med Bul ϧϩ/Ϫ August tered more frequently, i.e. two, three or four times an Cardiovascular complications were defined as a systolic hour. The aim was to make the patient fall asleep. blood pressure < 90 mmHg or a diastolic blood pressure < 60 mmHg, cardiogenic syncope or electrocardiograph- Baseline data ically verified arrhythmia or cardiac arrest. We recorded gender, age, substance abuse, biochemical and clinical findings including blood alcohol concentra- Statistical analysis tion (BAC), withdrawal seizures and symptoms compat- Quantitative variables were analysed using analysis of ible with thiamine deficiency, i.e. cognitive disturbances, variance while categorical data were analysed by or- ocular paralysis and ataxia at gait. Previous detoxifica- dinary χ2 test or Fisher’s exact test. If multiple compari- tions were also registered (Table 1). sons led to rejection of homogeneity across groups, two-by-two tests were subsequently applied to Bonfer- Treatment effect The effect of phenobarbital and diazepam was meas- FIGURE 1 ured by length of stay and by DT duration. Mean (± standard A Medicine deviation) doses of Phenobarbital dose (mg) phenobarbital in the 5000 Alcohol withdrawal patients from the DZP Bispebjerg phenobarbital Rigs- 4500 group who did not initially show signs of DT received a hospitalet group (A) 4000 varying amount of chlordiazepoxid before diazepam was and phenobarbital Bispebjerg Hospital 3500 administered. As a measure of the total benzodiazepine group (B) at day 1, 3000 day 2 and for the dose, we defined the various diazepam equivalents as 2500 entire treatment follows: period (total). 2000 C shows the corres- 1500 ponding diazepam Diazepam equivalent = dose of diazepam (mg) + 1/10 × 1000 equivalent doses in (dose of chlordiazepoxid) (mg). the diazepam Bispe- 500 bjerg Hospital group. 0 Day 1 Day 2 Total Complications Diazepam equival- ents were calculated B Respiratory complications were defined as follows: as dose of diazepam Phenobarbital dose (mg) (mg) + 1/10 x (dose 4500 of chlordiazepoxid) 1. Respiratory depression occurred if the respiratory (mg). 4000 frequency (RF) was below 12 per minute, or if the 3500 patient had obstructed airways including apnoea 3000 2. Pneumonia 2500 3. Other respiratory complications: Coughing, low 2000 oxygen saturation, RF > 20/min., airway secretion, 1500 1000 chronic lung diseases not requiring antibiotic 500 treatment. 0 Day 1 Day 2 Total C TABLE 1 Diazepam equivalents (mg) 1200 Alcohol-related baseline data. Number of patients in the three groups who had previously been detox- ified at a hospital, had previously suffered from delirium tremens and before developing delirium 1000 tremens during the current episode had experienced a withdrawal seizure. Furthermore, the table shows the number of patients in whom the admitting physician suspected Wernicke’s encephalopathy and the measured blood alcohol concentration. 800 PB Rigshospitalet PB Bispebjerg DZP Bispebjerg (N = 53) (N = 53) (N = 88) p 600 Previously detoxified, n (%) 39 (74) 39 (74) 73 (83) NSa a Previous DT, n (%) 16 (30) 13 (25) 33 (38) NS 400 Seizures, n (%) 14 (26) 14 (26) 15 (17) NSa Wernicke’s encephalopathy, n (%) 29 (55) 24 (45) 38 (43) NSa 200 Blood alcohol concentration, g/l, 0.90 ± 1.4 0.92 ± 1.5 1.53 ± 1.5 0.049b mean ± standard deviation DT = delirium tremens; DZP = diazepam; NS = non-significant, p > 0.05; PB = phenobarbital. 0 a) χ2. b) Analysis of variance. Day 1 Day 2 Total Dan Med Bul ϧϩ/Ϫ August DANISH MEDICAL BULLETIN roni-adjusted significance levels. The hypothesis that the TABLE 2 number of DT cases per year was similar in the PB Bispe- bjerg and the DZP Bispebjerg group was tested using ex- Respiratory and cardiovascular complications. The numbers of deaths, respiratory- and cardiovascular act Poisson test. The general level of significance (p) was complications. In addition, the numbers of patients transferred to the intensive care unit and the num- ber of patients treated in respirator are presented. 0.05. If not otherwise specified, data are presented as mean ± standard deviation (SD). n (%) PB Rigshospitalet PB Bispebjerg DZP Bispebjerg (N = 53) (N = 53) (N = 88) pa Study approval Fatal outcome 2 (4) 1 (2) 1 (1) NS The study was approved by the Danish Data Protection Respiratory complications 18 (34) 21 (40) 38 (43) NS Agency. Respiratory depression 3 (6) 1 (2) 1 (1) Pneumonia 11 (20) 15 (28) 24 (27) Results Otherb 5 (9) 5 (9) 13 (15) The inclusion criteria were fulfilled by 53 cases in the Intensive care unit 8 (16) 5 (9) 12 (14) NS PB Rigshospitalet group, 53 cases in the PB Bispebjerg Respirator treatment 7 (13) 4 (8) 4 (5) NS Cardiovascular complications 5 (9) 9 (17) 9 (10) NS group and 88 cases in the DZP Bispebjerg group. The Arrhythmia 2 (4) 3 (6) 3 (3) mean (± SD) frequency of DT patients per year during Blood pressure < 90/60 mmHg 3 (6) 5 (9) 6 (7) the study period was PB Rigshospitalet 5.9 ± 1.8, PB Bis- Cardiogenic syncope 0 (0) 1 (2) 0 (0) pebjerg 12.8 ± 4.1 and DZP Bispebjerg 17.0 ± 8.7. There DZP = diazepam; NS = non-significant, p > 0.05; PB = phenobarbital. was a trend toward an increase in the incidence of DT at a) χ2. b) Respiratory complications due to other reasons were coughing, low oxygen saturation, respira- tory frequency > 20/min., airway secretion or mucus and chronic lung disease. Bispebjerg Hospital when diazepam was used compared to when phenobarbital was used (exact Poisson test, p = 0.061). An overview of respiratory and cardiovascular com- The length of the delirious period was 5.85 ± 6.3 plications in the DT patients is shown in Table 2.
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