intravenous phenobarbital for alcohol withdrawal and convulsions

ORIGINAL CONTRIBUTION alcohol, withdrawal, treatment; phenobarbital, alcohol withdrawal

Intravenous Phenobarbital for Alcohol Withdrawal and Convulsions

In a prospective, uncontrolled study, 62 alcoholic patients received IV phenobarbital (IV-PB) to treat the alcohol withdrawal (AW) syndrome. Initially 260 mg of IV-PB were administered followed by 130 mg every 30 minutes to an end point of light sedation. A mean loading dose of 598 (+ 192) mg of lV- PB resulted in a mean increase in the serum PB level of 13.9 (+_ 4.7) ~g/mL. Thus, the serum PB level rose 1.65 ~g/mL for each mg/kg of IV-PB administered to these adult patients in AW. Forty-six of 48 tremulous patients (96%) showed improvement in their AW tremors. None of the 38 patients who presented with A W seizures had another commlsion during a mean observation period of three hours and 47 minutes. Transient ataxia or over- sedation occurred in three of 62 patients (5%) and was exacerbated by con- current ethanol, ch'azepam, or phenytoin (six of 17), who were excluded from the study. We conclude that IV-PB is a safe and efficacious therapy for mild to moderate AWS, and IV-PB may prevent A W seizures. [Young GP, Rores C, Murphy C, Dailey RH: Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med August 1987;16:847-850.]

INTRODUCTION Emergency physicians frequently treat the chronic alcoholic for acute alco-

hol withdrawal (AW). There are many pharmacologic agents available to treat this syndrome. The benzodiazepines have become the drugs of choice during the past ten years, although "the benzodiazepines are by no means ideal . . . agents in (the) treatment of most of the symptoms" of AWJ Because it is loosely bound to brain tissue, diazepam maintains its anticonvulsant effect for only about 20 minutes.2 On the other hand, oral diazepam accumulates during chronic therapy when used for its sedative effect, especially in patients with liver disease. 3 Thus, large, frequent oral dosing of diazepam on an outpatient basis can be harmful to alcoholic patients.

We thought that IV phenobarbital (IV-PB) might be an excellent drug for the treatment of AW. First, there is cross-tolerance between barbiturates and ethanol. 4 Second, PB has a wide margin of safety when used for hypnosedative withdrawal 5 - - the doses that are efficacious for treating withdrawal symptoms do not produce significant central nervous system depression. Third, because of its long duration of action (half-life of approximately 90 hours), 6 serum PB concentrations remain stable for long periods after single loading doses; therefore, patients are not required to take oral PB for AW after discharge.

Fourth, IV-PB has a rapid onset of action (approximately 15 minutes), 7 so monitoring of the clinical effects of PB loading doses is practical. Finally, at therapeutic serum concentrations, PB has an anticonvulsant efficacy similar to that of diazepam or phenytoin. 8

A clinical trial was undertaken to ascertain whether IV-PB could safely suppress the manifestations of acute AW and allow AW patients to be safely discharged from the ED. We were able to establish the relationship between the amount of IV-PB administered and the resultant serum PB level.

METHODS We conducted a prospective, uncontrolled clinical trial using the Student t

test. Entered into our study were adult (older than 21) patients who presented in acute AW, defined as tremulousness, convulsions, hallucinations, or delir-

Gary P Young, MD* Christopher Rotes, MD* Charles Murphy, MDt Robert H Dailey, MD* Oakland, California

From Highland General Hospital, Oakland, California;* and the Division of Emergency Medicine, University of California, San Francisco, California.t

Received for publication April 21, 1986. Revisions received October 13, 1986 and December 29, 1986. Accepted for publication February 4, 1987.

Address for reprints: Gary P Young, MD, Emergency Medicine, Highland General Hospital, 1411 E 31st Street, Oakland, California 94602.

16:8 August 1987 Annals of Emergency Medicine 847/35

IV PHENOBARBITAL Young et al

ium occurring in a chronic alcoholic in the setting of abstinence from ethanol without any other probable cause IFignre).

We excluded from our study patients with PB allergies; patients older than 60; pregnant or breast-feeding women; those with severe central nervous system disease; and patients with moderately severe cardiac, pul- monarg, renal, or hepatic disease. We did not exclude patients with documented alcoholic liver disease (ALD) unless it was complicated by acute alcoholic hepatitis or hepatic encepha- lopathy. We also excluded patients with acute drug intoxication (includ- ing those who appeared clinically in- toxicated in the presence of a positive blood alcohol BA level), or patients who had BA levels above 0.1 mg/dL, and patients who received diazepam or phenytoin for their AW.

In addition to the above informa- tion, the following data were col- lected: level of consciousness, weight, and orthostatic vital signs. Blood pressure, pulse, and respiratory rate were recorded before and after each dose of IV-PB. An IV line was started with normal saline, and blood samples were obtained for baseline PB and BA levels, glucose, electrolytes, creatinine, BUN, total bilirubin, serum glutamic oxalacetic transaminase or aspartate aminot rans fe rase , a lkal ine phos- phatase, and prothrombin time. All patients were placed on an ECG moni- tor.

All patients received an initial infusion of 260 mg of IV-PB (two 130-mg ampules administered over five minutes) while awaiting the results of the baseline PB level. The laboratory turn- around time for PB levels averaged about 60 minutes. None of our AW patients had an initial PB level above 10 p~g/mL, so each of our study patients received addit ional 130-mg boluses of IV-PB until the clinical end- point of light sedation was reached or some adverse effect was noted, such as worsening of the baseline CNS status (eg, worsening agitation, disorienta- tion, confusion, or dysarthria), respiratory depression requiring ventilatory support, hypotension (systolic blood pressure < 100 mm Hg), or a dys- rhythmia requiring treatment. A final PB level was drawn 30 minutes after the last IV-PB dose. All patients were observed in the ED for a minimum of one hour after the last IV-PB dose. The final level of consciousness, changes

TABLE. Dosage of IV-PB and the final serum PB levels in each of the A W patient subgroups

IV-PBt Dosage Patient Subgroups (mean loading dose Final Serum PB (no. of patients)* in mg and mg/kg) Level (~g/mL)$

Tremulous (48) 624 8.5 ' 14.0

Seizures (38) 576 8.3 13.8

ALD§ (21) 561 8.2 13.7

Total AW (62) 598 8.4 13.9

*The sum of the number of patients in the three subgroups is greater than the total number of 62 patients in alcohol withdrawal because up to 24 patients belonged in more than one subgroup.

I-Intravenous phenobarbital. !:All of the baseline phenobarbital levels were zero. §Alcoholic liver disease,

in the signs of AW, side effects, complications, and any other administered drugs were entered on the study data sheet.

Two of the authors reviewed all of the ED charts and the old medical records of every patient. We received ap- proval for this research from our county's human subjects protection committee.

RESULTS Sixty-two of 84 patients given IV-PB

for AW qualified for the study. Twenty- two were excluded because they had positive blood ethanol screens or they received diazepam or phenytoin in addition to their IV-PB.

These 62 patients, 55 men and seven women, had a mean age of 42 years and mean weight of 70 kg. The mean loading dose of IV-PB given these patients was 598 mg or 8.4 mg/ kg. None of these 62 patients had a detectable PB level on admission. Their mean final serum PB level was 13.9 ~g/mL. Thus, the serum PB level rose approximately 1.65 txg/mL for each mg/kg of IV-PB administered. Comparing our data from each of the different subgroups of AW patient (those with tremulousness, seizures, or ALD) revealed no appreciable dif- ference (P > .5) in the response of the serum PB concentration to the administration of IV-PB (Table).

Our clinical goal was safe discharge of the patient in AW from the ED. Fifty-seven of our 62 patients (92%) were able to be discharged after an average ED stay of three hours and 47 minutes. On review of their medical

charts, none of these 57 returned to our ED within the next week following treatment. For the purposes of follow-up, we relied on the chart review because of logistical difficulties and because our ED takes care of the vast majority of alcoholic patients in our county.

Of the five patients (8%) requiring admission to the hospital, four had frank delirium tremens, defined as severe tremulousness, hallucinations, confusion, and hyperactivity of the autonomic nervous system. These four (6.5%) were the only AW patients who failed to respond to IV-PB. One patient was admitted for pneumonia, although his tremulousness responded to IV-PB.

Forty-eight (77%) of the total number of 62 AW patients were markedly tremulous and 38 (61%) had con- vulsed. Thus, 24 of the total number of 62 patients had both tremors and seizures. Forty-six of the 48 tremulous patierits (96%) were improved, and 23 (48%) had no detectable tremor on discharge. None of the 38 patients with AW seizures were observed to convulse during an average ED stay of almost four hours (Table).

Adverse reactions ascribed to IV-PB were documented in four (6%) of the 62 patients. Alter his last bolus of IV- PB (total dose of 520 mg), one patient had an asymptomatic blood pressure fall to 90/60 mm Hg, which rose without intervention within 30 minutes. Three patients were kept in the ED one to three hours after their last IV- PB bolus: one was ataxic (total dose of 650 mg) and two were lethargic (doses

36/848 Annals of Emergency Medicine 16:8 August 1987

Tremulous only 24

Seizure only 14

Tremors and seizure 24

Total in AW 62* "21 of these patients also had evidence of alcoholic liver disease.

of 390 and 780 mg). None of these patients required admission. Ataxia was a common clinical feature in patients (six of 17 patients) who were excluded from the study because they had received concomitant diazepam or phenytoin.

DISCUSSION Initial PB Dosing and Blood Levels

There have been only two previous studies of the dosage of IV-PB necessary to achieve a therapeutic serum PB concentration in human beings.9, lo In one study, neonates in status epilepticus receiving IV-PB loading doses of 15 to 20 mg/kg achieved a mean peak serum PB concentration of 19.4 ~g/mL. Thus, the ratio of serum PB level (in ~g/mL) to dose of IV-PB (in mg/kg) approximated uni ty in these neonates receiving a continuous rapid- rate infusion. 9

In the other study, seven adult inpa- tients in barbi turate wi thdrawal received a slow continuous W-PB infusion at a rate of more than 2 mg/kg/hr until they slept but were arousable. The mean peak serum PB level was 26 ~g/mL after the pa t i en t s received nearly 1 g of W-PB over a mean duration of eight hours. The authors found the total PB dosage to be predictive of the peak serum PB level. The ratio of peak serum PB concentration (ixg/rnL) to dose (mg/kg) of PB following the infusion was 1.5 in the seven barbiturate-dependent pat ients and in one control patient. This control patient required less than half as much W-PB (7.8 mg/kg) to achieve sedation (at a serum PB level of 11.7 ~g/mL). lo This is consistent with an older study that demonstrated that for an equivalent state of sedation, epileptics on chronic PB therapy had 1.5 to 2 t imes the serum PB level of patients admitted for acute barbiturate intoxication.11

Another study reported the use of

FIGURE. The subgroups of the total number of 62 AW patients entered into the study

oral PB to treat hypnosedative withdrawal, s Oral PB was given to 21 patients at 120 mg/hr or 2 mg/kg/hr. The mean total PB loading dose was 23.4 mg/kg (or 1,440 mg) and the mean peak PB level was 35.9 ~g/mL. The serum PB level (~g/mL) to oral dose (mg/kg) ratio was again 1.5. 5 We observed a similar blood level to dose ratio (1.65) in our adult patients in AW.

Phenobarbital Therapy of Alcohol Withdrawal

Because alcohol and barbiturates are cross-tolerant sedatives, the literature on the treatment of barbiturate withdrawal is relevant to the treatment of AW wi th PB. For the t r ea tmen t of " l i fe- threatening" barbi turate withdrawal, one author recommends that patients receive an initial loading dose of 1.75 mg/kg of IV-PB over five minutes. 8 But a dose of 1.75 mg/kg in a 70-kg patient would be only about 130 mg, which would result in a very low serum PB level (2 to 3 ~g/mL). Rather, we recommend the IV-PB regimen for AW used in our study. In the study of oral PB therapy for hypnoseda t i ve wi thd rawa l m e n t i o n e d above, s patients requiring less than 7 mg/kg or 500 mg were thought not to be phys- ically dependent on barbiturates.

Forty-five of our 62 AW pat ients (73%) required at least 520 mg of IV- PB to suppress their AW symptoms. More IV-PB can be adminis tered if necessary for acute AW: three of our AW patients received 910 rng and two required 1,040 mg, all five w i t h o u t complications. The authors of the oral PB studyS concluded that because vir- tual ly all pat ients do well w i t h o u t supplemental dosing, blood level mea- surements are not essential to load patients with oral PB. We drew a baseline and a final semrn PB level from all patients only for purposes of this study.

Barbiturates probably are effective in the treatment of AW. Pentobarbital prevents the convuls ions and death that occurred in a control group of un- treated dogs in del i r ium tremens. 12 There are only two published com- parisons of barbi turates wi th other drug therapies for acute AW in human beings. In the first, Kaim and Klett 13 reported that chlordiazepoxide, paral-

dehyde, perphenazine, and pentobarbital produced favorable results in the t r ea tment of "uncompl ica ted" delirium tremens. Only one of the 41 pentobarbital patients "failed to respond adequate ly ." Interest ingly, the pentobarbital patients were the only subgroup w i thou t a convuls ion during therapy. In the second study, Smith 14 retrospectively analyzed the medical records of 2,000 patients in AW and determined that oral primidone (My- soline®), which is metabolized to phenobarbital, was superior to phenytoin, cl-tlordiazepoxide, and phenothiazines in the prevention of AW seizures.

Phenobarbital Therapy of AW Convulsions

None of our patients seized after receiving at least 260 mg of IV-PB. Thus, considering the results of the studies cited in the previous paragraph, barbiturates seem to be effective in the prevention of AW convulsions. In addition, barbiturates are effective in the chronic therapy of idiopathic epilep- sy. s AW patients can present in status epilepticus. But the literature on par- enteral PB for the treatment of status epi lept icus is conf l ic t ing. Th e IM route has been recommended in doses as low as 90 to 120 mg every four to six hours; Is however, the ratio of peak serum PB concent ra t ion (~g/mL) to single oral or IM dose (mg/kg) of PB is also approximately 1.5 to 1.16,17 Thus, 90 to 120 mg of IM-PB would result in very low serum PB levels (2 to 3 ~g/ mL). Furthermore, therapeutic serum PB levels are not reached for at least one hour fol lowing IM-PB doses of over 10 mg/kgj6A z

Recommendations for the dosage of IV-PB to treat status epilepticus range from a max imum dose of 1,000 mg at a rate of 60 mg/rnin 18 to a dose of 20 mg/kg2, 9 at a rate of 100 m g / m i n . Using our data, only the larger dose (20 mg/kg) of IV-PB would guarantee the high therapeutic serum PB level (above 30 ~g/mL) necessary to treat status epilepticus. None of our patients presented in status epilepticus.

Our s tudy design requires corn- ment . First, there were no placebo controls. Second, the assignment of patients to be given W-PB was not ran- dom. Third, many patients were excluded or withdrawn from the study because of inadequate physician com- p l i ance w i t h the s t u d y p r o t o c o l . Fourth, it is possible that some of our s tudy pa t ien t s relapsed after treat-

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IV PHENOBARBITAL Young et al

m e n t w i t h IV-PB and e i t he r r e so r t ed to e thano l or requi red fu r the r care at ano the r ED. Because of logis t ical diffi- cul t ies , w e did n o t r eques t t h a t pa- t i en t s r e tu rn to our ED for fol low-up nor did we a t t e m p t t e l e p h o n e follow- up. However, our faci l i ty is the pr ima- ry source of med ica l care for a lcohol ic p a t i e n t s in our county, and n o n e of our s tudy pa t i en t s r e t u rned for fu r the r care at our ED w i t h i n t he fo l lowing week.

C O N C L U S I O N This s tudy descr ibes our exper ience

w i t h IV p h e n o b a r b i t a l , w h i c h w a s u s e d to t r e a t p a t i e n t s w i t h m i l d to m o d e r a t e a c u t e a l c o h o l w i t h d r a w a l . We found tha t t he s e r u m PB level rose 1.65 p~g/mL for each m g / k g of IV-PB a d m i n i s t e r e d to t hese adul t pa t i en t s in a c t i v e AW. IV-PB s u c c e s s f u l l y sup - pressed t r e m u l o u s n e s s due to AW, bu t W-PB did no t p reven t hosp i ta l admis- s ion of pa t i en t s in de l i r i um t r emens . N o pa t i en t s p r e sen t i ng w i t h AW s e i - zures had a convu l s ion dur ing obser- va t ion in t he ED after rece iv ing IV-PB. A d v e r s e e f f ec t s of PB t h e r a p y w e r e m i n o r and f r e q u e n t on ly in p a t i e n t s w h o were e thano l i n tox ica t ed or w h o

rece ived c o n c u r r e n t IV p h e n y t o i n or d iazepam.

REFERENCES 1. Sellers EM, Kalant H: Alcohol intoxication and withdrawal. N Engl J Med 1976;294: 757-762.

2. Delgado-Escueta AV, Wasterlain C, Treiman DM, et ah Management of status epilepticus. N Engl J Med 1982;306:1337-1340.

3. Harvey SC: Hypnotics and sedatives: Ben- zodiazepines, in Gilman AG, Goodman LS, Gilman A, (eds): The Pharmacologic Basis of Therapeutics. New York, Macmillan Publishing Co, 1980, 339-349.

4. Smith DE, Wesson DR: Phenobarbital tech- nique for treatment of barbiturate dependence. Arch Gen Psychiatr 1971;24:56-60.

5. Robinson GM, Sellers EM, Janacek E: Bar- biturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose tech- nique. Clin Pharmacol Ther 1981;30:71-76.

6. Alvin J, McHorse T, Hoyumpa A, et al: The effect of liver disease in man on the disposition of phenobarbital. J Pharmacol Exptl Ther 1975;192:224-235.

7. Harvey SC: Sedatives and hypnotics: Barbitu- rates, in Gilman AG, Goodman LS, Gilman A, (eds): The Pharmacologic Basis of Therapeutics. New York, Macmillan Publishing Co, 1980, p 349-361.

8. Buchtal F, Lennox-Buchtal MA: Phenobar- bital. Relation of serum concentration to control of seizures, in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs. New

York, Raven Press, 1971, p 335-343.

9. Painter MJ, Pippinger C, Carter G, et al: Me- tabolism of phenobarbital and diphenylhydantoin by neonates with seizures (abstract). Neu- rology 1977;27:376.

10. Martin PR, Kapur BM, Whiteside EA, et at: Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions. Clin Pharmacol Ther 1979;26:256-264.

11. Sunshine I: Chemical evidence of tolerance to phenobarbital. J Lab C]in Med 1957;50: 127-133.

12. Essig CF, Jones E, Lain RC: The effect of pentobarbital on alcohol withdrawal in dogs. Arch Neural 1969;20:554-558.

i3. Kaim SC, Klett CJ: Treatment of delirium tremens: A comparative evaluation of four drugs. Quart [ Stud Alc 1972~33:1065-1072.

14. Smith RF: Relative effectiveness of primidone (Mysoline} and diphenylhydantoin (Di- lantin} in the management of sedative withdrawal seizures. Ann N Y Acad Sci 1976;273: 378-380.

15. Tintinalli JE: Status epilepticus. [ACEP 1976;5:896-900.

16. Jalling B: Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses. Develop Med Child NeuroI 1974; 16:781-793.

17. Brachet-Liermain A, Goutieres F, Aicardi J: Absorption of phenobarbital after the intra- muscular administration of single doses in infants. J Pediatr 1975;87:624-626.

18. Nicol CF: Status epilepticus. JAMA 1975; 234:419-420.

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intravenous phenobarbital for alcohol withdrawal and convulsions

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