Lorazepam in the Treatment
`of Refractory Neonatal Seizures
`A Pilot Study
`Anita Deshmukh, MD; William Wittert, MD; Eugene Schnitzler, MD; Henry H. Mangurten, MD
`
`\s=b\Seven neonatal patients with severe
`seizures unresponsive to conventional
`therapy were treated
`anticonvulsant
`with lorazepam. Immediate cessation of
`seizure activity occurred in all patients
`within five minutes. Although seizures
`recurred in two infants eight hours later,
`severity diminished.
`frequency and
`There were no apparent significant side
`effects attributed to the medication.
`(AJDC 1986;140:1042-1044)
`"Defractory seizures are often a diffi¬
`cult management problem in the
`neonatal patient. Seizure activity
`requires appropriate treatment
`to
`minimize mortality and to reduce
`neurologic sequelae.1 The successful
`management of refractory neonatal
`seizures depends on the use of drugs
`with rapid onset of action, long dura¬
`tion, and minimal side effects. There¬
`fore, phénobarbital sodium and pheny¬
`toin sodium are usually the drugs of
`first choice.1 Diazepam, a benzodi-
`azepine, has also been used in neonatal
`patients for many years for the treat¬
`ment of seizures. Its use, however, is
`limited by its short duration of action
`and occasional reports of cardiovascu¬
`lar and/or respiratory complications.2
`Recent literature suggests that loraze¬
`pam, a new longer-acting benzodiaze-
`pine, is both effective and safe in the
`management of status epilepticus in
`adults and older children.35 To our
`knowledge, comparative data docu¬
`menting the safety and efficacy in neo¬
`nates are unavailable to date. We con-
`Accepted for publication June 16, 1986.
`From the Division of Pediatrics (Dr Wittert),
`Sections of Pediatric Neurology (Dr Schnitzler)
`and Neonatology (Drs Deshmukh and Mangur-
`ten), Lutheran General Hospital, Park Ridge, Ill.
`Reprint requests to Neonatology Office, Lu-
`theran General Hospital, 1775 W Dempster St,
`Park Ridge, IL 60068 (Dr Mangurten).
`
`ducted a pilot study of seven critically
`ill infants with refractory seizures to
`investigate the safety and potential
`efficacy of lorazepam. The study was
`approved by the Institutional Review
`Board of the hospital.
`METHODS
`
`Seven infants with severe refractory sei¬
`zures were studied (Table). The group con¬
`sisted of two male and five female infants,
`varying in gestational age from 30 to 43
`weeks. Birth weights ranged from 1540 to
`4224 g. Five infants were full-term and two
`were preterm.
`The seizures in all of these infants were a
`result of severe perinatal asphyxia and
`hypoxic-isehemic encephalopathy; one in¬
`fant also incurred an intraventricular hem¬
`orrhage.
`Infants with seizures secondary
`to hypoglycemia or electrolyte distur¬
`bances were excluded, as were infants with
`congenital malformations of the brain. In¬
`fants were selected for the study only if
`they experienced severe asphyxia neo-
`natorum. None of these infants had a five-
`minute Apgar score exceeding 5 (Table).
`All infants were evaluated and treated for
`presumptive sepsis; all cultures of blood
`and cerebrospinal fluid were subsequently
`negative for bacterial growth. The age of
`onset of seizures ranged from less than 1 to
`72 hours. All patients had clinically docu¬
`mented seizures of the multifocal clonic and
`subtle types.
`Initial treatment consisted of appropri¬
`ate intravenous loading doses of phéno¬
`barbital and phenytoin sodium, each at
`15 mg/kg per dose, within the range (15 to
`20 mg/kg) previously recommended.6 Some
`subsequently
`authorities
`have
`recom¬
`mended a loading dose of 20 mg/kg for
`each.2 Therapeutic levels of phénobarbital
`(20 to 30 mg/L) were documented in all
`seven infants. Therapeutic levels of pheny¬
`toin sodium (10 to 20 mg/L) were docu¬
`mented in five of the seven infants. In the
`
`other two infants,
`the phenytoin levels
`were subtherapeutic when lorazepam was
`administered. Infants were enrolled in the
`study if seizures persisted after loading
`doses of these drugs.
`After obtaining informed consent from
`the parent(s), infants received lorazepam in
`a dose of 0.05 mg/kg per dose given in¬
`travenously over two to five minutes. This
`dose was based on an extrapolation of the
`In three of
`standard adult dose of 4 mg.
`electroencephalogram
`infants,
`seven
`(EEG) monitoring was done before, dur¬
`ing, and after lorazepam injection.
`In all
`infants, EEG monitoring was done within
`24 hours after lorazepam administration.
`Lorazepam was considered to be effective
`on the basis of
`immediate cessation of
`clinical seizure activity and suppression of
`seizure activity in EEG, when available.
`The clinical and laboratory data that
`were collected and monitored included the
`following:
`(1) vital signs,
`including blood
`pressure, up to 24 hours after lorazepam
`administration; (2) serial observations and
`descriptions of seizure activity; (3) baseline
`laboratory data, including a complete blood
`cell count, platelets, and 20-factor auto¬
`mated blood chemistry analysis profile, and
`phénobarbital and phenytoin levels. These
`data were obtained serially for 72 hours
`following lorazepam administration. Blood
`gases were monitored as dictated by the
`clinical condition. No infant received a sec¬
`ond dose of lorazepam. Maintenance doses
`of phénobarbital and phenytoin, however,
`were begun 12 hours after loading doses of
`these drugs.
`Either computed tomography of
`the
`brain or cranial ultrasound was performed
`in six infants. The ultrasound of patient 3
`revealed grade II intraventricular hemor¬
`rhage. Results of imaging studies in the
`remainder of the infants were normal.
`RESULTS
`Following the administration of
`lorazepam,
`temperature, blood près-
`
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`Clinical Data
`
`Birth
`Weight,
`g
`3580
`
`Gesta¬
`tional
`Age, wk
`42
`
`Patient
`1
`
`Apgar
`Scores
`at 1, 5, and
`10 min
`2, 5t
`
`Etiology
`of
`Seizures*
`HIE
`
`Age at
`Onset of
`Seizures, h
`4V2
`
`2, 4, 5
`
`HIE
`
`<1
`
`2640
`
`1540
`
`39
`
`30
`
`4120
`
`42-43
`
`2807
`
`36-37
`
`0, 2, 4
`
`0,0,0
`0,3*
`
`0, 3
`
`2,4,7
`
`2830
`
`38-39
`
`2,4,4
`
`4224
`
`40 +
`
`0,2,5
`
`Response
`No recurrence of seizures
`for 24 h after lorazepam
`except occasional
`lipsmacklng at 12 h
`No recurrence of seizures
`for 24 h after
`lorazepam except
`llpsmacking
`occasional
`No seizures for 24 h after
`lorazepam
`
`Bicycling movements
`recurred 8 h after
`lorazepam
`
`Bicycling movements
`recurred 8 h after
`lorazepam
`No recurrence of seizure
`activity for 24 h after
`lorazepam
`
`Recurrence of multifocal
`clonic seizures 12 h
`after lorazepam
`
`Short-term Outcome
`Discharged from hospital on 13th d
`of life on regimen of
`phénobarbital; neurologic
`examination results abnormal
`Discharged from hospital on
`regimen of phénobarbital on
`46th d of life; neurologic
`examination results abnormal
`Discharged from hospital on
`regimen of phénobarbital on
`78th d; neurologic examination
`results abnormal
`Life support discontinued 4 d after
`lorazepam administration; died
`within 5 min; postmortem
`examination revealed
`encephalomalacia
`Died at 19 d of age following acute
`renal failure and multiple organ
`infarcts
`Discharged from hospital on 16th d
`of life on regimen of
`phénobarbital; neurologic
`examination results abnormal
`Discharged from hospital on 70th d
`on regimen of phénobarbital;
`neurologic examination results
`abnormal; prolonged stay
`necessitated by plastic surgery
`for extensive slough of buttocks
`
`HIE
`IVH
`
`IVH
`HIE
`
`HIE
`
`HIE
`
`HIE
`
`72
`
`*HIE Indicates hypoxlc-ischemlc encephalopathy; IVH, Intraventricular hemorrhage.
`fTen-minute Apgar score not available.
`^Fifteen at 20 minutes.
`
`sure, and pulse remained stable in all
`infants. In the three patients who re¬
`quired assisted ventilation before
`lorazepam administration, no deterio¬
`ration of their respiratory status was
`observed, ie, they did not require in¬
`In the
`creased respiratory support.
`remaining four infants who were not
`receiving mechanical ventilatory as¬
`sistance, no respiratory or cardiovas¬
`cular compromise was noted.
`In five patients, a complete blood
`cell count and platelet count remained
`stable. Two infants required blood
`transfusions for conditions believed to
`be unrelated to lorazepam administra¬
`tion. One infant required a blood trans¬
`fusion to replace blood drawn for fre¬
`quent analysis of blood gases and other
`laboratory determinations. A second
`infant required a blood transfusion be¬
`cause of bleeding secondary to dis¬
`seminated intravascular coagulation.
`No changes or deterioration was noted
`in the values of serum electrolytes,
`calcium, glucose, or protein or liver
`
`and renal functions during the 72-hour
`monitoring.
`In two infants who re¬
`quired umbilical artery catheteriza¬
`tion, serial blood gas monitoring after
`lorazepam administration revealed no
`deterioration in acid-base balance or
`oxygénation.
`The onset of action of lorazepam was
`rapid, with immediate cessation of sei¬
`zure activity in five minutes.
`In one
`infant, bicycling movements recurred
`eight hours after lorazepam adminis¬
`tration, but the severity diminished.
`In another infant, recurrence of subtle
`seizures with buccolingual activity re¬
`curred eight hours after lorazepam
`administration, but the frequency and
`duration decreased.
`Electroencephalographic monitor¬
`ing before lorazepam administration in
`patients 3, 5, and 6 demonstrated
`burst suppression patterns and elec¬
`trographic seizures in the form of
`rhythmic theta and delta activity or
`multifocal sharp waves. Within min¬
`utes of the administration of lorazepam
`
`in patient 3, there was a marked gener¬
`alized suppression of the background
`activity with cessation of electro¬
`graphic seizures. A follow-up tracing
`three hours later in this patient contin¬
`ued to demonstrate marked back¬
`ground suppression.
`In patient 1, an EEG was obtained
`before receiving lorazepam and a fol¬
`low-up tracing was performed 24 hours
`later. The initial EEG showed burst
`suppression and ictal patterns in the
`form of multifocal high-voltage spikes
`and rhythmic delta activity. The next
`day the EEG was improved, with mul¬
`tifocal epileptogenic activity but no
`electrographic seizures. Two weeks
`later, this patient's tracing was normal
`for conceptual age.
`Due to urgent clinical considera¬
`tions, EEG monitoring could not be
`obtained during lorazepam adminis¬
`tration in the other three patients.
`Tracings obtained within 24 hours
`were all abnormal due to background
`disorganization,
`suppression,
`and
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`focal or multifocal epileptogenic activ¬
`ity.
`In patient 4,
`the record was se¬
`verely suppressed and the question of
`electrocerebral silence was raised.
`This patient's tracing reverted to a
`burst-suppression
`pattern
`severe
`three days later.
`COMMENT
`Adult human data indicate that
`lorazepam has a half-life of 13 to 15
`hours, rapidly penetrates the central
`nervous system, and produces minimal
`cardiovascular and respiratory de¬
`pression in normal subjects.7,8 Our pre¬
`liminary data indicate that lorazepam
`appears to be a safe and effective ad¬
`junct
`to traditional anticonvulsant
`medications in the management of re¬
`fractory neonatal seizures. No car¬
`diorespiratory embarrassment was
`noted in any neonate receiving loraze¬
`pam. Furthermore, there were no in¬
`stances of anemia, neutropenia, or
`thrombocytopenia that could be at¬
`tributed to lorazepam administration.
`In all patients, serum electrolyte, cal¬
`cium, glucose, albumin, globulin, cho¬
`lesterol, and triglycéride levels, and
`hepatic and renal functions remained
`improved following
`unchanged or
`lorazepam administration.
`(Improve¬
`ments in biochemical values correlated
`with recovery from asphyxia.) In two
`instances following lorazepam admin¬
`istration,
`the serum phénobarbital
`increased into the toxic range.
`level
`Both of these levels returned to normal
`within 72 hours after withholding phé¬
`nobarbital therapy. Such fluctuations
`are common in severely ill neonates
`with variable hepatic function. Addi¬
`tional controlled studies may clarify a
`possible relationship between elevated
`
`phénobarbital levels and lorazepam.
`One milliliter of the lorazepam prep¬
`aration used
`contains
`2 mg of
`lorazepam,
`the drug
`0.18 mL of
`solubilizer, polyethylene glycol 400 in
`glycol,
`propylene
`and
`the
`pre¬
`servative, 2.0% benzyl alcohol. The
`former has caused hyperosmolality in
`infants receiving 10 mL of a multi¬
`vitamin preparation containing 30%
`propylene glycol.9 The largest dose of
`lorazepam used in this study, 0.20 mg,
`required 0.1 mL of the solution, con¬
`taining 0.018 mL of the solubilizer,
`approximately 1/500 the volume in the
`above-mentioned report. Benzyl alco¬
`hol has caused a fatal toxic syndrome
`in preterm infants who received ap¬
`proximately 100 to 400 mg/kg/d of the
`substance.1011 Since the largest total
`dose received by any infant
`in this
`study was 2 mg, the occurrence of this
`syndrome was considered unlikely.
`Another concern relates to the po¬
`tential for benzyl alcohol to displace
`bilirubin from albumin binding sites.
`Theoretically this could result in ker-
`nicterus at low serum bilirubin levels
`in asphyxiated and low-birth-weight
`infants who already have decreased
`bilirubin-binding capacity. Other than
`in vitro data, there is no documenta¬
`tion that benzoate enhances this risk in
`the human newborn.12 Furthermore,
`the dose of benzyl alcohol was so small
`in our study (0.5 mg/kg) that the effect
`of bilirubin displacement was consid¬
`ered insignificant.
`In all of our infants, lorazepam ad¬
`ministration was followed rapidly by
`cessation of clinical seizure activity.
`Compared with diazepam, a primary
`advantage of the drug appears to be
`the duration of seizure control follow-
`
`References
`
`ing administration.5 Lorazepam pre¬
`vented recurrence of seizure activity
`up to 24 hours after administration.
`The longer duration of seizure control
`obtained with lorazepam may be due to
`its slower tissue distribution.13
`Electroencephalographic data con¬
`firmed the cessation of seizure activity
`accompanied by a generalized sup¬
`pression of background activity. Such
`background suppression has also been
`observed after the administration of
`diazepam in neonates." The duration
`of background suppression, however,
`may be longer after lorazepam admin¬
`istration. Caution must therefore be
`exercised in cases of suspected elec-
`trocerebral silence if the patient has
`recently received lorazepam.
`CONCLUSION
`In summary, based on preliminary
`data in seven patients, lorazepam ap¬
`pears to be a safe and probably effec¬
`tive agent for the treatment of refrac¬
`Its efficacy
`tory neonatal seizures.
`appears at least comparable with that
`of diazepam. Other advantages may
`include prolonged duration of action
`and absence of cardiorespiratory de¬
`pression. We cannot recommend the
`routine use of lorazepam in the treat¬
`ment of neonatal seizures.
`Its use,
`however, may be justifiable in severely
`ill neonates with seizures refractory to
`therapy. A controlled
`conventional
`study is needed, perhaps comparing
`diazepam with lorazepam in randomly
`assigned cases and including blood
`level determinations and pharmaco-
`kinetics.
`
`Kim Walkup gave technical assistance, and
`Seymour Metrick, MD, and Alice Kowalczyk,
`PharmD, made helpful suggestions.
`
`1. Fenichel GM: Neonatal Neurology. New
`York, Churchill Livingstone Inc, 1980, chap 2.
`2. Volpe JJ: Neurology of the Newborn. Phila-
`delphia, WB Saunders Co, 1981, chap 5.
`3. Leppik IE, Derivan AT, Homan RW, et al:
`Double-blind study of lorazepam and diazepam in
`status epilepticus. JAMA 1983;249:1452-1454.
`4. Levy RJ, Krall RL: Treatment of status
`epilepticus with lorazepam. Arch Neurol 1984;41:
`605-611.
`5. Howman RW, Walker JE: Clinical studies of
`lorazepam in status epilepticus. Adv Neurol
`1983;34:493-498.
`6. Painter MJ, Pippenger C, MacDonald H,
`et al: Phenobarbital and diphenylhydantoin lev-
`els in neonates with seizures. J Pediatr 1978;92:
`
`315-319.
`7. Greenblatt DJ, Comer WH, Elliott HW,
`et al: Clinical pharmacokinetics of lorazepam:
`III. Intravenous injection: Preliminary results.
`J Clin Pharmacol 1977;17:490-494.
`8. Greenblatt DJ, Shader RI, Franke K, et al:
`Pharmacokinetics and bioavailability of
`intra-
`lorazepam in
`intramuscular, and oral
`venous,
`humans. J Pharm Sci 1979;68:57-63.
`9. Glasgow AM, Boeckx RL, Miller MK, et al:
`Hyperosmolality in small
`infants due to pro-
`pylene glycol. Pediatrics 1983;72:353-355.
`10. Brown WJ, Buist NRM, Gipson HTC, et al:
`Fatal benzyl alcohol poisoning in a neonatal inten-
`sive care unit. Lancet 1982;1:1250.
`11. Gershanik JJ, Boecler B, George W, et al:
`
`The gasping syndrome: Benzyl alcohol (BA) poi-
`soning? abstracted. Clin Res 1981;29:895A.
`12. Brodersen R: Free bilirubin in blood
`plasma of the newborn: Effects of albumin, fatty
`acids, pH, displacing drugs, and phototherapy, in
`Stern L, Oh W, Friis-Hansen B (eds): Intensive
`Care of the Newborn: II. New York, Masson
`Publishers USA Inc, 1978, pp 331-345.
`13. Greenblatt DJ, Shader RI: Drug therapy:
`Prazepam and lorazepam, two new benzodiaze-
`pines. N Engl J Med 1978;299:1342-1344.
`14. Werner SS, Stockard JE, Bickferd RG:
`Atlas ofNeonatal Electroencephalography. New
`York, Raven Press, 1977, p 19.
`
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