Lorazepam in Status Epilepticus Jonathan E. Walker, MS, MD, Richard W. Homan, M D , Michael R. Vasko, PhD, Isaac L. Crawford, PhD, Rodney D. Bell, MD, and William G. Tasker, M D
Lorazepam, a dichloro-3-hydroxy-1,4-benzodimepine, has been shown to be a potent anticonvulsant in animal models of epilsepsy and has minimal depressant effects on respiration and circulation in humans. The effects of this compound were studied in status epilepticus. Twenty-five patients were given intravenous lorazepam during status epilepticus of varying cause. Four or 8 mg of the drug controlled status in 22 of the 25 patients. Although single seizures recurred in 5 of the 22 patients, none experienced recurrence of status during a prolonged follow-up period. Transient respiratory arrest occurred in 1 patient, but no other significant complications were observed. Studies of plasma drug levels suggest that most patients attain good seizure control at concentrations between 30 and 100 ng per milliliter. Clinical observations indicate that repetitive injections are not required for continuing control of seizures in patients whose seizures are initially controlled. Lorazepam appears to be an effective and safe drug for treatment of status epilepticus, with a duration of control longer than that achieved with diazepam. Walker JE, Homan RW, Vasko MR, et al: Lorazepam in status epilepticus. Ann Neurol 6:207-213, 1979
Methods a n d Materials
Status epilepticus is a serious and often lifethreatening emergency. Ideally, the best drug for treating status should act rapidly, produce minimal o r no side-effects, and have a prolonged duration of action. Drugs currently available for use in status epilepticus fail one o r more of these criteria. Phenobarbital is often effective in controlling the seizures only at doses that impair consciousness and depress respiration. Paraldehyde has a short duration of action, may produce laryngospasm, and may cause heart failure and pulmonary edema [15]. Phenytoin has a relatively slow onset of action even after intravenous injection, may produce cardiac arrhythmias, and is effective in stopping seizures in only 50 to 60% of patients [12]. Diazepam, though initially effective and relatively safe [ I l l , is rapidly redistributed and has an effective initial half-life of only two to four hours [lo]. As a result, repeated injections or constant infusions are required for prolonged control of seizures. Lorazepam is a newer benzodiazepine which has been shown to be a potent anticonvulsant in animal studies [S] and produces minimal cardiac o r respiratory depression in humans [2, 41. Preliminary studies have suggested that it is a potent and safe anticonvulsant in children with absence status epilepticus [ 13, 141. W e have evaluated lorazepam in adults and children with various types of status epilepticus, and our results suggest that it is superior to agents currently approved for use in this condition.
Results Table 1 delineates the important demographic data and individual responses to lorazepam for the patients involved in the study. Ages ranged from 5 to 81 years, and a variety of different seizure patterns was encountered. Most of the patients were known to have epilepsy and were taking one or more an-
From the Neurology Service, Veterans Administration Medical Center, and the Department of Neurology, University of Texas Health Sciences Center, Dallas, TX.
Address reprint requests to Dr Walker, Neurology Service, Veterans Administration Medical Center, 4500 S Lancaster Rd, Dallas, TX 75216.
Twenty-five patients were entered into this clinical trial. Patients were accepted if they had experienced at least three partial o r generalized seizures within a 15-minute period without full recovery of neurological or mental function or if they had shown continuous seizure activity for a minimum of 10 minutes. Seizures were classified according to the recommendations of Gastaut [ 5 ] . Patients with both partial and generalized status epilepticus were included. Patients with alcohol withdrawal seizures, hypoglycemia, o r hypocalcemia were excluded. Informed consent was obtained from the patients’ parents o r relatives. Lorazepam, 4 mg, was diluted with 1 ml of normal saline and given by slow intravenous injection over a 2-minute period. If seizures persisted for 15 minutes after the first injection, a second 4 mg injection was given. Phenytoin or phenobarbital was administered intravenously if seizures persisted for another 15-minute interval. Blood pressure, pulse, and respiration were recorded every 15 minutes for two hours. Blood samples were obtained ever): 15 minutes for two hours following the final injection of lorazepam. The blood was centrifuged at 1,800g for 5 minutes and the plasma removed and frozen until assay. Concentrations of drug were assayed using the electron-capture gas-liquid chromatography assay of Knowles et al [9].
Accepted for publication Mar 26, 1979.
0364-5134/79/090207-07$01.25 @ 1979 by Jonathan E. Walker
207
Table I . Clinical Characteristics and Response to Lorazepam i n 25 Patients with Status Epilepticus
Anticonvulsants Used for Status Prior to LorazeDam
Dose of IV Lorazepam (mg)
Carb, 400 mg
...
4
Phen, 300 mg; PB, 90 mg; Prim, 500 mg
...
4
Phen, 400 mg; PB, 120 mg 0
...
4
Phen, 1,800 mg over 24 hr
8
Phen, 300 mg Phen, 400 mg; PB, 120 mg; Prim, 1,250 mg 0
... ...
4 4
...
4
0
...
4
Diabetic cerebrovascular accident
Phen, 300 mg; Carb, 400 mg
...
4
Idiopathic
Phen, 400 mg; PB, 120 mg
...
Idiopathic
Phen, 400 mg; PB, 120 mg
D Z , 10 mg
8 (second dose 2 hr after first) 4
Increased intracranial pressure; glioma Idiopathic
Phen, 300 mg; PB, 90 mg
D Z , 20 mg
4
Phen, 300 mg; PB, 90 mg
4
Febrile, no cause found
0
8
Diabetic, hypertensive, cryptococcal meningitis Mulriple head trauma
Phen, 300 mg; Pb, 90 mg
4
Patient No. and
Seizure
Etiological
A O P (iit-1
npsrrintinn
Diapnosis
Prescribed Daily Dose of Maintenance Anticonvulsants
PATIENTS WITH GENERALIZED STATUS EPILEPTICUS
-~ 1,6
Generalized tonicclonic
2 , 18
Generalized tonicclonic Generalized, then continuous lip smacking, left adversion Generalized tonicclonic Generalized myoclonic Generalized clonic Generalized tonicclonic
3 , 30
4, 31
5, 33 6, 37 7,37
8, 63
Generalized tonicclonic
9, 63
Generalized tonicclonic
Cerebellar astrocytoma (postop) Idiopathic, mentally retarded Idiopathic
Idiopathic Postanoxic encephalopathy Idiopathic Posttraumatic
Diabetic with frequent hypoglycemia Diabetic with frequent hvDoalvcemia . . .,
Phen, 180 mg; PB, 180 mg
~
PATIENTS WITH PARTIAL STATUS EPILEPTICUS
10,40
11,47
12,48 13, 5 1
14, 58
15,67 16,67
17,68
Unresponsive; focal motor, head down and left; left ankle, knee, hip Unresponsive; focal motor, right hand and arm Unresponsive; focal motor, right arm; lip smacking Lethargic; focal motor, right arm, face, hand, and tongue Alert; focal motor, left arm, leg, and face; jerks, left adversion Confused; focal motor, left face, arm, and leg Obtunded; focal onset, right face; twitching; +generalized Confused; focal motor
0
208 Annals of Neurology Vol 6 NO 3 September 1979
Phen, 100 mg over 48 hr
4
Seizure Response
Latency of Seizure Control (min)
Stopped
5
12
None
Stopped
5
>72
None
Stopped
4
>48
None
...
...
Stopped
10
2
None
...
...
Stopped
3
>72
None
...
Stopped Stopped
2
>72 >72
None None
...
1
Decreased bilateral parasagittal spikes ... Left temporal spikes ceased
Stopped
4
>72
None
...
...
Stopped
4
>72
None
...
...
Stopped
2
24
None
...
...
Stopped
120
>48
None
...
...
Stopped
15
>48
None
...
...
Continued
...
...
None
...
...
Stopped
3
6
None
...
...
Stopped
22
>72
None
...
...
Stopped
1
48
None
...
Stopped
2
72
None
Abolished rhythmic bilateral frontal sharp and slow wave activity
Duration of Control (hr)
Adverse Effects
Duration of Adverse Effects
Effects on EEG
Diffuse spike and wave stopped
...
Walker et al: Lorazepam in Status Epilepticus 203
Patient No. and Age ( y r )
Seizure Lkscription
Etiological Diagnosis
PATIENTS W I TH PARTIAL STATUS EPILEPTICUS
18, 68
19, 78
20, 81
2 1 , 10
Prescribed Daily Dose of Maintenance Anticonvulsants
Lethargic, focal motor, left arm and leg C omatose, focal motor, left arm, leg, and face Obtundeci, focal motor, right arm, leg, anJ face Stupor; left focal motor; lip smacking
Anticonvulsants Used for Status Prior t o Lorazepam
Dose of IV Lorazepam (mg)
(cont.)
Cerebrovascular accident
Phen, 400 mg, PB, 90 mg
Idiopathic
0
Subdural hematoma
Phen, 300 mg, PB, 90 mg
Idiopathic
Carh, 400 mg; Phen, 200 mg; PB, 60 mg
8
...
4
...
4
...
4
Phen, 1,000 mg:, PB, 130 mg; DZ, 12.5 mg Phen, 300 mg/day x 3 days; PB, 120 mg/day x 3 days; CZ, 4 mg/day x 1 day
8
PATIENTS WIT11 ILfISCEI.I.ANEOIJS TYPES OF STATUS EPILEPTICUS
22, 5
Stupor, bilateral myoclonic jerks A kinetic episodes followed by stupor
23,6 24, 3 2
25, 48
Comatose (electrical status) Multifocal myoclonus
Phen = phenyroin; PB erhosuximjde.
=
Idiopathic Idiopathic, Lennox-Gastaut syndrome Vasculitis ?
Chronic renal failure
0
phenobarbital; Carb = carbamazepine Prim
ticonvulsant drugs. Four patients had no past history of seizures or anticonvulsant therapy. Nine patients had generalized status epilepticus and 12 had focal motor status epilepticus. Of the patients with focal motor status epilepticus, 11 experienced alteration of consciousness while only 1 remained alert. Seizures stopped in 22 of the 25 patients within minutes following the first or second injection of lorazepam. Isolated seizures recurred in 2 of 9 patients with generalized seizures, in 2 of 12 with focal motor seizures, and in 1 patient with bilateral myoclonic jerks. Status epilepticus did not recur in any of these patients over a follow-up period of several weeks. The majority of the patients (16 of 25) remained seizure free for at least forty-eight hours without additional intravenous medication. Seizures were not controlled in 3 patients. O n e (Patient 25) was a 48-year-old man with chronic renal
210
Phen, 180 mg; Carh, 400 mg PB, 60 mg; CZ, 4 mg; Etho, 500 nig 0
Annals of Neurology
Vol 6
=
primidone; DZ
=
diazepam; C Z
=
8
clonazepam; Etho
=
failure whose multifocal myoclonus had previously failed to respond to phenytoin, phenobarbital, and clonazepam. Another (Patient 23) was a 6-year-old child with repetitive akinetic episodes who was given only a single dose of lorazepam. The third was a 51year-old man (Patient 13) with a large glioma of the left hemisphere whose seizures were not controlled until his intracranial pressure was brought to normal using dexamethasone and mannitol. He also received only a single injection of lorazepam. Electroencephalograms were recorded in 9 patients during and following administration of lorazepam. In 7, prolonged abolition or marked reduction of paroxysmal activity was noted. In 1 (Patient 22), despite a satisfactory clinical response and plasma lorazepam concentration of 100.2 ng per milliliter, right frontal spike activity persisted with only a slight reduction in frequency. In Pa.tient 25, who had
No 3 September 1979
Seizure Response
Latency of Seizure Control (min)
Duration of Control (hr)
Adverse Effects
Stopped
6
>72
None
Stopped
2
>72
Respiratory arrest
Stopped; patient remained in coma
30
72
None
Stopped
4
24
Stopped
5
24
Continued
...
Seizures did not recur; patient awoke gradually Continued
Duration of Adverse Effects
Effects on EEG
4 min
...
Intermittent hallucinations; mild ataxia, 12 hr
12 hr
Abolished bilateral spike and slow wave activity
8 hr
...
Intermittent hallucinations None
Slight reduction of right frontal spiking Decreased spike frequency
...
>72
None
...
...
...
None
multifocal myoclonus secondary to chronic renal failure, the multiple foci of spike discharge were unaffected by lorazepam. The electroencephalographic response of Patient 21 to lorazepam is depicted in the Figure. Prior to administration of lorazepam, the patient’s clinical manifestations included intermittent focal motor seizures of the left upper extremity, intermittent lip smacking, and persistent stupor. The electroencephalogram revealed asymmetrical bilateral 2.5 Hz spike- and slow-wave activity (Figure, A). Four minutes after the start of the lorazepam infusion, clinical seizure activity had ceased, and the electroencephalogram revealed diffuse slowing (Figure, B). Although the clinical situation did not permit a careful and prolonged pharmacokinetic study, some indication of the relationship between plasma concentration and seizure control was obtained. Table 2 indicates the plasma lorazepam concentration at 15 minutes and 120 minutes following completion of
...
Decreased spike frequency None
the lorazepam injection in 10 patients whose seizures were clinically controlled with a single dose of lorazepam. The minimum effective concentration at 15 minutes was 30.5 ng per milliliter. The average concentration for the 10 patients was 60.1 ng per milliliter at 15 minutes and 51.7 at 120 minutes, reflecting the relatively long half-life. Two patients whose seizures were controlled following a second injection of lorazepam had plasma lorazepam concentrations of 160.0 and 118.9 ng per milliliter, respectively, at 15 minutes. Two patients not controlled with a single injection had concentrations of 34.3 and 89.5 ng per milliliter at 15 minutes, while the only patient not controlled with two injections had a concentration of 125.7 ng per milliliter 15 minutes following the second injection. The only major adverse effect in this series occurred in Patient 19, who had transient respiratory arrest without further complications. There was no obvious explanation for this occurrence. The patient
Walker et al: Lorazepam in Status Epilepticus 211
Table 2.Pkasnia Concentration of Lormeparti Lorazepam Conccntration ( ngiml )
Patient No.
2
6 8 9 10 12 17
19 21 22
Average
1 5 Min after 1niection
81.5 76.8 65.6 33.7 70.0
30.5 30.9 40.5 7 1.3 100.2 GO. 1
120 Min after Injection
52.8 57.6 52.8 48.5 39.8
39.7 28.3 55.5 48.5 93.1 5 1.:
did not have chronic respiratory impairment, and the lorazepam concentration at 15 minutes was only 40.5 ng per milliliter.
Discussion Lorazepam given intravenously is a potent, effective, and safe agent in status epilepticus. More important clinically than its potency is the fact that at doses which controlled seizures, it had little or no depressant effect on respiration o r circulation. Repeated injections o r continuous infusion were not required. Blood concentrations were maintained at relatively high levels for at least two hours following intravenous injection. These observations accord with more detailed previous studies [ 6 ] .Practically, this means that most patients given lorazepam d o not need repeated injections or continuous infusions to maintain seizure control. O u r electroencephalographic data suggest that lorazepam prevents the spread of seizure activity and suppresses focal discharges. Investigations strictly comparable to ours have not been conducted with traditional anriconvulsants used in status epilepticus. T h e studies of Wallis e t a1 [12] and of Nicol et a1 [ 111 utilized similar protocols and patient populations. In Table 3, we compare the results in our study with their results. Both benzodiazepines appear preferable to phenytoin since they initially control seizures in a higher percentage of patients and are associated with fewer and less severe side-effects. Lorazepam seems preferable to diazepam since it produces more sustained seizure control and has a lower incidence of cardiorespiratory depression and lingual airway obstruction [ l , 3 , 71. Therefore, lorazepam appears to be superior to
212
Annals of Neurology
Vol 6 No 3
September 1079
Table 3. Comparison of Lorazepam with Other Drugs Commonly Used for Initial Therapy of Status Epilepticus Patient Population by Type Study
Drug Used
Wallis et a1 [ 121, Phenytoin, 1,000 mg 1968
Criteria Three or more seizures per hour
Nicol et a1 [ l 11, Diazepam, Not stated 1969 6-150 mg
of Status Epilepticus
31 Total
10 Generalized 13 Partial 8 Serial 41 Total 13 Generalized 23 Partial 3 Petit ma1
Present study
Lorazepam 4-8 mg
Three or more seizures in 15 min
8 Alcohol withdrawal 25 Total 10 Generalized 12 Partial 2 Myoclonus 1 Akinetic
Initially
% Controlled at 24 Hr (without additional anticonvulsants)
Not stated (usually takes 30-60
52 40
5% Controlled
minutes or
longer) 96 86 100
62 50 14 54
Probably contraindicared in elderly patients with heart disease
cardiopulmonary arrest and death, 1
patient;
patient Lingual obstruction,
2 patients
52
100 90 92
76 80 83
50 0
0
88
so
8.
9. Supported by a grant from Wyeth Laboratories.
10.
References 1. Bell DS: Dangers of treatment of status epilepticus with diazepam. Br Med J 1:159, 1969 2. Comer W H , Elliott HW, Nomof N , et al: Pharmacology of parenterally administered lorazepam in man. J Int Med Res 1:216, 1973 3. Doughty A: Unexpected danger of diazepam. Br Med J 2:239, 1970 4. Elliott HW, Nomof N, Navarro G , et al: Central nervous system and cardiovascular effects of lorazepam in man. Clin Pharmacol Ther 12:468-481, 197 1 5. Gastaut H: Clinical and EEG classifications of seizures. Epilepsia lO:suppl:S2-S28, 1969 6. Greenblatt DJ, Comer WH, Elliott HW, et al: Clinical pharmacokinetics of lorazepam: 111. Intravenous injection. J Clin Pharmacol 17:490-494, 1977 7. Greenblatt DJ, Koch-Weser J: Adverse reactions to intrave-
Comment
Apnea and shock, 1
67 75
100
currently used drugs for the treatment of status epilepticus.
Adverse Effects
Transitory respiratory arrest (4 min), 1 patient
Repeated injections or constant infusion usually required; cardiopulmonary effects common No other instances of arrest reported in literature; little cardiac effect; usually single injection of 4 mg suffices for >24 hr
nous diazepam. Report from Boston Collaborative Drug Surveillance Program. Am J Med Sci 266:261-266, 1973 Greenblatt DJ, Shader RI: Benzodiazepines in Clinical Practice. New York, Raven, 1974, chap 1, p 12 Knowles JA, Comer WH, Ruelius HW: Disposition of 7-chlor0-5-(o-chlorophenyl)-1,3/dihydro-3-hydroxy-2H-1,4benzodiazepin-2-one in humans. Arzneim Forsch 2 1:10551059, 1971 Mattson RH: Benzodiazepines, in Woodbury DM, Penry JK, Schmidt R D (eds): Antiepileptic Drugs. New York, Raven, 1972, pp 497-518 Nicol CF, Tutton JC, Smith BH: P a r e n t e d diazepam in status epilepticus. Neurology (Minneap) 19:332-343, 1969 Wallis W, Kutt H, McDowell F: Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology (Minneap) 18:513-525, 1968 Waltregny A, Dargent J: Preliminary study of p a r e n t e d lorazepam in status epilepticus. Acta Neurol Belg 75:219229, 1975 Waltregny A, Dargent J: Preliminary report: p a r e n t e d lorazepam in induced epileptic states in man. Acta Neurol Belg 76:173-179, 1976 Woodbury D, Fingl E: Drugs effective in the therapy of the epilepsies. In Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. Fifth edition. New York, Macmillan, 1975, chap 13, pp 201-226 ~~
11. 12.
13.
14.
15.
Walker et al: Lorazepam in Status Epilepticus
213
Lorazepam, a dichloro-3-hydroxy-1,4-benzodimepine, has been shown to be a potent anticonvulsant in animal models of epilsepsy and has minimal depressant effects on respiration and circulation in humans. The effects of this compound were studied in status epilepticus. Twenty-five patients were given intravenous lorazepam during status epilepticus of varying cause. Four or 8 mg of the drug controlled status in 22 of the 25 patients. Although single seizures recurred in 5 of the 22 patients, none experienced recurrence of status during a prolonged follow-up period. Transient respiratory arrest occurred in 1 patient, but no other significant complications were observed. Studies of plasma drug levels suggest that most patients attain good seizure control at concentrations between 30 and 100 ng per milliliter. Clinical observations indicate that repetitive injections are not required for continuing control of seizures in patients whose seizures are initially controlled. Lorazepam appears to be an effective and safe drug for treatment of status epilepticus, with a duration of control longer than that achieved with diazepam. Walker JE, Homan RW, Vasko MR, et al: Lorazepam in status epilepticus. Ann Neurol 6:207-213, 1979
Methods a n d Materials
Status epilepticus is a serious and often lifethreatening emergency. Ideally, the best drug for treating status should act rapidly, produce minimal o r no side-effects, and have a prolonged duration of action. Drugs currently available for use in status epilepticus fail one o r more of these criteria. Phenobarbital is often effective in controlling the seizures only at doses that impair consciousness and depress respiration. Paraldehyde has a short duration of action, may produce laryngospasm, and may cause heart failure and pulmonary edema [15]. Phenytoin has a relatively slow onset of action even after intravenous injection, may produce cardiac arrhythmias, and is effective in stopping seizures in only 50 to 60% of patients [12]. Diazepam, though initially effective and relatively safe [ I l l , is rapidly redistributed and has an effective initial half-life of only two to four hours [lo]. As a result, repeated injections or constant infusions are required for prolonged control of seizures. Lorazepam is a newer benzodiazepine which has been shown to be a potent anticonvulsant in animal studies [S] and produces minimal cardiac o r respiratory depression in humans [2, 41. Preliminary studies have suggested that it is a potent and safe anticonvulsant in children with absence status epilepticus [ 13, 141. W e have evaluated lorazepam in adults and children with various types of status epilepticus, and our results suggest that it is superior to agents currently approved for use in this condition.
Results Table 1 delineates the important demographic data and individual responses to lorazepam for the patients involved in the study. Ages ranged from 5 to 81 years, and a variety of different seizure patterns was encountered. Most of the patients were known to have epilepsy and were taking one or more an-
From the Neurology Service, Veterans Administration Medical Center, and the Department of Neurology, University of Texas Health Sciences Center, Dallas, TX.
Address reprint requests to Dr Walker, Neurology Service, Veterans Administration Medical Center, 4500 S Lancaster Rd, Dallas, TX 75216.
Twenty-five patients were entered into this clinical trial. Patients were accepted if they had experienced at least three partial o r generalized seizures within a 15-minute period without full recovery of neurological or mental function or if they had shown continuous seizure activity for a minimum of 10 minutes. Seizures were classified according to the recommendations of Gastaut [ 5 ] . Patients with both partial and generalized status epilepticus were included. Patients with alcohol withdrawal seizures, hypoglycemia, o r hypocalcemia were excluded. Informed consent was obtained from the patients’ parents o r relatives. Lorazepam, 4 mg, was diluted with 1 ml of normal saline and given by slow intravenous injection over a 2-minute period. If seizures persisted for 15 minutes after the first injection, a second 4 mg injection was given. Phenytoin or phenobarbital was administered intravenously if seizures persisted for another 15-minute interval. Blood pressure, pulse, and respiration were recorded every 15 minutes for two hours. Blood samples were obtained ever): 15 minutes for two hours following the final injection of lorazepam. The blood was centrifuged at 1,800g for 5 minutes and the plasma removed and frozen until assay. Concentrations of drug were assayed using the electron-capture gas-liquid chromatography assay of Knowles et al [9].
Accepted for publication Mar 26, 1979.
0364-5134/79/090207-07$01.25 @ 1979 by Jonathan E. Walker
207
Table I . Clinical Characteristics and Response to Lorazepam i n 25 Patients with Status Epilepticus
Anticonvulsants Used for Status Prior to LorazeDam
Dose of IV Lorazepam (mg)
Carb, 400 mg
...
4
Phen, 300 mg; PB, 90 mg; Prim, 500 mg
...
4
Phen, 400 mg; PB, 120 mg 0
...
4
Phen, 1,800 mg over 24 hr
8
Phen, 300 mg Phen, 400 mg; PB, 120 mg; Prim, 1,250 mg 0
... ...
4 4
...
4
0
...
4
Diabetic cerebrovascular accident
Phen, 300 mg; Carb, 400 mg
...
4
Idiopathic
Phen, 400 mg; PB, 120 mg
...
Idiopathic
Phen, 400 mg; PB, 120 mg
D Z , 10 mg
8 (second dose 2 hr after first) 4
Increased intracranial pressure; glioma Idiopathic
Phen, 300 mg; PB, 90 mg
D Z , 20 mg
4
Phen, 300 mg; PB, 90 mg
4
Febrile, no cause found
0
8
Diabetic, hypertensive, cryptococcal meningitis Mulriple head trauma
Phen, 300 mg; Pb, 90 mg
4
Patient No. and
Seizure
Etiological
A O P (iit-1
npsrrintinn
Diapnosis
Prescribed Daily Dose of Maintenance Anticonvulsants
PATIENTS WITH GENERALIZED STATUS EPILEPTICUS
-~ 1,6
Generalized tonicclonic
2 , 18
Generalized tonicclonic Generalized, then continuous lip smacking, left adversion Generalized tonicclonic Generalized myoclonic Generalized clonic Generalized tonicclonic
3 , 30
4, 31
5, 33 6, 37 7,37
8, 63
Generalized tonicclonic
9, 63
Generalized tonicclonic
Cerebellar astrocytoma (postop) Idiopathic, mentally retarded Idiopathic
Idiopathic Postanoxic encephalopathy Idiopathic Posttraumatic
Diabetic with frequent hypoglycemia Diabetic with frequent hvDoalvcemia . . .,
Phen, 180 mg; PB, 180 mg
~
PATIENTS WITH PARTIAL STATUS EPILEPTICUS
10,40
11,47
12,48 13, 5 1
14, 58
15,67 16,67
17,68
Unresponsive; focal motor, head down and left; left ankle, knee, hip Unresponsive; focal motor, right hand and arm Unresponsive; focal motor, right arm; lip smacking Lethargic; focal motor, right arm, face, hand, and tongue Alert; focal motor, left arm, leg, and face; jerks, left adversion Confused; focal motor, left face, arm, and leg Obtunded; focal onset, right face; twitching; +generalized Confused; focal motor
0
208 Annals of Neurology Vol 6 NO 3 September 1979
Phen, 100 mg over 48 hr
4
Seizure Response
Latency of Seizure Control (min)
Stopped
5
12
None
Stopped
5
>72
None
Stopped
4
>48
None
...
...
Stopped
10
2
None
...
...
Stopped
3
>72
None
...
Stopped Stopped
2
>72 >72
None None
...
1
Decreased bilateral parasagittal spikes ... Left temporal spikes ceased
Stopped
4
>72
None
...
...
Stopped
4
>72
None
...
...
Stopped
2
24
None
...
...
Stopped
120
>48
None
...
...
Stopped
15
>48
None
...
...
Continued
...
...
None
...
...
Stopped
3
6
None
...
...
Stopped
22
>72
None
...
...
Stopped
1
48
None
...
Stopped
2
72
None
Abolished rhythmic bilateral frontal sharp and slow wave activity
Duration of Control (hr)
Adverse Effects
Duration of Adverse Effects
Effects on EEG
Diffuse spike and wave stopped
...
Walker et al: Lorazepam in Status Epilepticus 203
Patient No. and Age ( y r )
Seizure Lkscription
Etiological Diagnosis
PATIENTS W I TH PARTIAL STATUS EPILEPTICUS
18, 68
19, 78
20, 81
2 1 , 10
Prescribed Daily Dose of Maintenance Anticonvulsants
Lethargic, focal motor, left arm and leg C omatose, focal motor, left arm, leg, and face Obtundeci, focal motor, right arm, leg, anJ face Stupor; left focal motor; lip smacking
Anticonvulsants Used for Status Prior t o Lorazepam
Dose of IV Lorazepam (mg)
(cont.)
Cerebrovascular accident
Phen, 400 mg, PB, 90 mg
Idiopathic
0
Subdural hematoma
Phen, 300 mg, PB, 90 mg
Idiopathic
Carh, 400 mg; Phen, 200 mg; PB, 60 mg
8
...
4
...
4
...
4
Phen, 1,000 mg:, PB, 130 mg; DZ, 12.5 mg Phen, 300 mg/day x 3 days; PB, 120 mg/day x 3 days; CZ, 4 mg/day x 1 day
8
PATIENTS WIT11 ILfISCEI.I.ANEOIJS TYPES OF STATUS EPILEPTICUS
22, 5
Stupor, bilateral myoclonic jerks A kinetic episodes followed by stupor
23,6 24, 3 2
25, 48
Comatose (electrical status) Multifocal myoclonus
Phen = phenyroin; PB erhosuximjde.
=
Idiopathic Idiopathic, Lennox-Gastaut syndrome Vasculitis ?
Chronic renal failure
0
phenobarbital; Carb = carbamazepine Prim
ticonvulsant drugs. Four patients had no past history of seizures or anticonvulsant therapy. Nine patients had generalized status epilepticus and 12 had focal motor status epilepticus. Of the patients with focal motor status epilepticus, 11 experienced alteration of consciousness while only 1 remained alert. Seizures stopped in 22 of the 25 patients within minutes following the first or second injection of lorazepam. Isolated seizures recurred in 2 of 9 patients with generalized seizures, in 2 of 12 with focal motor seizures, and in 1 patient with bilateral myoclonic jerks. Status epilepticus did not recur in any of these patients over a follow-up period of several weeks. The majority of the patients (16 of 25) remained seizure free for at least forty-eight hours without additional intravenous medication. Seizures were not controlled in 3 patients. O n e (Patient 25) was a 48-year-old man with chronic renal
210
Phen, 180 mg; Carh, 400 mg PB, 60 mg; CZ, 4 mg; Etho, 500 nig 0
Annals of Neurology
Vol 6
=
primidone; DZ
=
diazepam; C Z
=
8
clonazepam; Etho
=
failure whose multifocal myoclonus had previously failed to respond to phenytoin, phenobarbital, and clonazepam. Another (Patient 23) was a 6-year-old child with repetitive akinetic episodes who was given only a single dose of lorazepam. The third was a 51year-old man (Patient 13) with a large glioma of the left hemisphere whose seizures were not controlled until his intracranial pressure was brought to normal using dexamethasone and mannitol. He also received only a single injection of lorazepam. Electroencephalograms were recorded in 9 patients during and following administration of lorazepam. In 7, prolonged abolition or marked reduction of paroxysmal activity was noted. In 1 (Patient 22), despite a satisfactory clinical response and plasma lorazepam concentration of 100.2 ng per milliliter, right frontal spike activity persisted with only a slight reduction in frequency. In Pa.tient 25, who had
No 3 September 1979
Seizure Response
Latency of Seizure Control (min)
Duration of Control (hr)
Adverse Effects
Stopped
6
>72
None
Stopped
2
>72
Respiratory arrest
Stopped; patient remained in coma
30
72
None
Stopped
4
24
Stopped
5
24
Continued
...
Seizures did not recur; patient awoke gradually Continued
Duration of Adverse Effects
Effects on EEG
4 min
...
Intermittent hallucinations; mild ataxia, 12 hr
12 hr
Abolished bilateral spike and slow wave activity
8 hr
...
Intermittent hallucinations None
Slight reduction of right frontal spiking Decreased spike frequency
...
>72
None
...
...
...
None
multifocal myoclonus secondary to chronic renal failure, the multiple foci of spike discharge were unaffected by lorazepam. The electroencephalographic response of Patient 21 to lorazepam is depicted in the Figure. Prior to administration of lorazepam, the patient’s clinical manifestations included intermittent focal motor seizures of the left upper extremity, intermittent lip smacking, and persistent stupor. The electroencephalogram revealed asymmetrical bilateral 2.5 Hz spike- and slow-wave activity (Figure, A). Four minutes after the start of the lorazepam infusion, clinical seizure activity had ceased, and the electroencephalogram revealed diffuse slowing (Figure, B). Although the clinical situation did not permit a careful and prolonged pharmacokinetic study, some indication of the relationship between plasma concentration and seizure control was obtained. Table 2 indicates the plasma lorazepam concentration at 15 minutes and 120 minutes following completion of
...
Decreased spike frequency None
the lorazepam injection in 10 patients whose seizures were clinically controlled with a single dose of lorazepam. The minimum effective concentration at 15 minutes was 30.5 ng per milliliter. The average concentration for the 10 patients was 60.1 ng per milliliter at 15 minutes and 51.7 at 120 minutes, reflecting the relatively long half-life. Two patients whose seizures were controlled following a second injection of lorazepam had plasma lorazepam concentrations of 160.0 and 118.9 ng per milliliter, respectively, at 15 minutes. Two patients not controlled with a single injection had concentrations of 34.3 and 89.5 ng per milliliter at 15 minutes, while the only patient not controlled with two injections had a concentration of 125.7 ng per milliliter 15 minutes following the second injection. The only major adverse effect in this series occurred in Patient 19, who had transient respiratory arrest without further complications. There was no obvious explanation for this occurrence. The patient
Walker et al: Lorazepam in Status Epilepticus 211
Table 2.Pkasnia Concentration of Lormeparti Lorazepam Conccntration ( ngiml )
Patient No.
2
6 8 9 10 12 17
19 21 22
Average
1 5 Min after 1niection
81.5 76.8 65.6 33.7 70.0
30.5 30.9 40.5 7 1.3 100.2 GO. 1
120 Min after Injection
52.8 57.6 52.8 48.5 39.8
39.7 28.3 55.5 48.5 93.1 5 1.:
did not have chronic respiratory impairment, and the lorazepam concentration at 15 minutes was only 40.5 ng per milliliter.
Discussion Lorazepam given intravenously is a potent, effective, and safe agent in status epilepticus. More important clinically than its potency is the fact that at doses which controlled seizures, it had little or no depressant effect on respiration o r circulation. Repeated injections o r continuous infusion were not required. Blood concentrations were maintained at relatively high levels for at least two hours following intravenous injection. These observations accord with more detailed previous studies [ 6 ] .Practically, this means that most patients given lorazepam d o not need repeated injections or continuous infusions to maintain seizure control. O u r electroencephalographic data suggest that lorazepam prevents the spread of seizure activity and suppresses focal discharges. Investigations strictly comparable to ours have not been conducted with traditional anriconvulsants used in status epilepticus. T h e studies of Wallis e t a1 [12] and of Nicol et a1 [ 111 utilized similar protocols and patient populations. In Table 3, we compare the results in our study with their results. Both benzodiazepines appear preferable to phenytoin since they initially control seizures in a higher percentage of patients and are associated with fewer and less severe side-effects. Lorazepam seems preferable to diazepam since it produces more sustained seizure control and has a lower incidence of cardiorespiratory depression and lingual airway obstruction [ l , 3 , 71. Therefore, lorazepam appears to be superior to
212
Annals of Neurology
Vol 6 No 3
September 1079
Table 3. Comparison of Lorazepam with Other Drugs Commonly Used for Initial Therapy of Status Epilepticus Patient Population by Type Study
Drug Used
Wallis et a1 [ 121, Phenytoin, 1,000 mg 1968
Criteria Three or more seizures per hour
Nicol et a1 [ l 11, Diazepam, Not stated 1969 6-150 mg
of Status Epilepticus
31 Total
10 Generalized 13 Partial 8 Serial 41 Total 13 Generalized 23 Partial 3 Petit ma1
Present study
Lorazepam 4-8 mg
Three or more seizures in 15 min
8 Alcohol withdrawal 25 Total 10 Generalized 12 Partial 2 Myoclonus 1 Akinetic
Initially
% Controlled at 24 Hr (without additional anticonvulsants)
Not stated (usually takes 30-60
52 40
5% Controlled
minutes or
longer) 96 86 100
62 50 14 54
Probably contraindicared in elderly patients with heart disease
cardiopulmonary arrest and death, 1
patient;
patient Lingual obstruction,
2 patients
52
100 90 92
76 80 83
50 0
0
88
so
8.
9. Supported by a grant from Wyeth Laboratories.
10.
References 1. Bell DS: Dangers of treatment of status epilepticus with diazepam. Br Med J 1:159, 1969 2. Comer W H , Elliott HW, Nomof N , et al: Pharmacology of parenterally administered lorazepam in man. J Int Med Res 1:216, 1973 3. Doughty A: Unexpected danger of diazepam. Br Med J 2:239, 1970 4. Elliott HW, Nomof N, Navarro G , et al: Central nervous system and cardiovascular effects of lorazepam in man. Clin Pharmacol Ther 12:468-481, 197 1 5. Gastaut H: Clinical and EEG classifications of seizures. Epilepsia lO:suppl:S2-S28, 1969 6. Greenblatt DJ, Comer WH, Elliott HW, et al: Clinical pharmacokinetics of lorazepam: 111. Intravenous injection. J Clin Pharmacol 17:490-494, 1977 7. Greenblatt DJ, Koch-Weser J: Adverse reactions to intrave-
Comment
Apnea and shock, 1
67 75
100
currently used drugs for the treatment of status epilepticus.
Adverse Effects
Transitory respiratory arrest (4 min), 1 patient
Repeated injections or constant infusion usually required; cardiopulmonary effects common No other instances of arrest reported in literature; little cardiac effect; usually single injection of 4 mg suffices for >24 hr
nous diazepam. Report from Boston Collaborative Drug Surveillance Program. Am J Med Sci 266:261-266, 1973 Greenblatt DJ, Shader RI: Benzodiazepines in Clinical Practice. New York, Raven, 1974, chap 1, p 12 Knowles JA, Comer WH, Ruelius HW: Disposition of 7-chlor0-5-(o-chlorophenyl)-1,3/dihydro-3-hydroxy-2H-1,4benzodiazepin-2-one in humans. Arzneim Forsch 2 1:10551059, 1971 Mattson RH: Benzodiazepines, in Woodbury DM, Penry JK, Schmidt R D (eds): Antiepileptic Drugs. New York, Raven, 1972, pp 497-518 Nicol CF, Tutton JC, Smith BH: P a r e n t e d diazepam in status epilepticus. Neurology (Minneap) 19:332-343, 1969 Wallis W, Kutt H, McDowell F: Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology (Minneap) 18:513-525, 1968 Waltregny A, Dargent J: Preliminary study of p a r e n t e d lorazepam in status epilepticus. Acta Neurol Belg 75:219229, 1975 Waltregny A, Dargent J: Preliminary report: p a r e n t e d lorazepam in induced epileptic states in man. Acta Neurol Belg 76:173-179, 1976 Woodbury D, Fingl E: Drugs effective in the therapy of the epilepsies. In Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. Fifth edition. New York, Macmillan, 1975, chap 13, pp 201-226 ~~
11. 12.
13.
14.
15.
Walker et al: Lorazepam in Status Epilepticus
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