British Journal of Clinical Pharmacology
`
`DOI:10.1111/j.1365-2125.2007.02931.x
`
`Anticonvulsant therapy for status epilepticus
`
`Kameshwar Prasad, Pudukode R. Krishnan,1 Khaldoon Al-Roomi2 & Reginald Sequeira3
`Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India, 1Department of Clinical
`Neurosciences, Salmaniya Medical Complex, Ministry of Health, 2Department of Family and Community Medicine and 3Clinical
`Pharmacology and Therapeutics, The Arabian Gulf University, Manama, Kingdom of Bahrain
`
`Correspondence
`Dr Kameshwar Prasad, Room no.
`704, Department of Neurology,
`Neurosciences Centre, All India
`Institute of Medical Sciences,
`New Delhi 110 029, India.
`Tel: + 91 11 2659 3497
`E-mail:
`drkameshwarprasad@yahoo.co.in
`
`.............................................................................................................................
`
`Keywords
`anticonvulsant therapy, management,
`meta-analysis, status epilepticus
`
`.............................................................................................................................
`
`Received
`2 November 2006
`Accepted
`25 March 2007
`Published OnlineEarly
`18 April 2007
`
`Aims
`than
`is more effective or safer
`To determine whether a particular anticonvulsant
`another or placebo in patients with status epilepticus, and to summarize the available
`evidence from randomized controlled trials, and to highlight areas for future research
`in status epilepticus.
`
`Methods
`Randomized controlled trials of participants with premonitory, early, established or
`refractory status epilepticus using a truly random or quasi-random allocation of
`treatments were included.
`
`Results
`Eleven studies with 2017 participants met the inclusion criteria. Lorazepam was better
`than diazepam for reducing risk of seizure continuation [relative risk (RR) 0.64, 95%
`confidence interval (CI) 0.45, 0.90] and of requirement of a different drug or general
`anaesthesia (RR 0.63, 95% CI 0.45, 0.88) with no statistically significant difference in
`the risk of adverse effects. Lorazepam was better than phenytoin for risk of seizure
`continuation (RR 0.62, 95% CI 0.45, 0.86). Diazepam 30 mg intrarectal gel was better
`than 20 mg in premonitory status epilepticus for the risk of seizure continuation (RR
`0.39, 95% CI 0.18, 0.86).
`
`Conclusions
`Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and
`carries a lower risk of continuation of status epilepticus requiring a different drug or
`general anaesthesia. Both lorazepam and diazepam are better than placebo for the
`same outcomes. In the treatment of premonitory seizures, diazepam 30 mg intrarectal
`gel
`is better than 20 mg for cessation of seizures without a statistically significant
`increase in adverse effects. Universally accepted definitions of premonitory, early,
`established and refractory status epilepticus are required.
`
`Introduction
`Status epilepticus is defined as a condition in which
`there is either >30 min of continuous seizure activity, or
`two or more sequential seizures without recovery of full
`consciousness between the seizures. Status epilepticus is
`a medical emergency and is associated with an overall
`mortality of 8% in children and 30% in adults [1]. About
`5–10% of people develop permanent vegetative state or
`
`Br J Clin Pharmacol
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`640–647
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`640
`
`cognitive difficulties. Approximately 12–30% of adults
`with a new diagnosis of epilepsy present with status
`epilepticus [2]. Status epilepticus may be convulsive
`(with limb stiffness and jerking) or nonconvulsive
`(without limb stiffness and jerking). Though convulsive
`status epilepticus is associated with a higher mortality
`and morbidity than nonconvulsive status epilepticus,
`both require prompt and effective treatment. However,
`AQUESTIVE EXHIBIT 1112 Page 0001
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`© 2007 The Authors
`Journal compilation © 2007 Blackwell Publishing Ltd
`
`

`

`regimen is not clear
`the most effective treatment
`from the literature. We conducted a systematic review of
`all the randomized controlled trials that could be identi-
`fied to summarize the existing evidence and to highlight
`areas requiring further research.
`In this review we followed Shorvon’s classification of
`status epilepticus, which divides it into early, established
`and refractory stages [3]. Early status epilepticus consists
`of the first 30 min of the epileptic state, during which
`physiological mechanisms compensate for the greatly
`enhanced metabolic activity. Established status epilepti-
`cus is defined as the stage beyond 30 min, where the
`status continues despite early-stage treatment. It is during
`this phase that physiological compensation mechanisms
`begin to fail. If seizures continue for 60–90 min after the
`initiation of therapy, it is the stage of refractory status. We
`included trials that recruited people with status epilepti-
`cus as well as those that recuited people experiencing
`a cluster of seizures or a prolonged seizure.
`The primary objective of the review was to synthesize
`the available evidence from randomized controlled trials
`(RCTs): (i) to determine whether a particular anticon-
`vulsant is more effective or safer in controlling status
`epilepticus compared with another drug or placebo, and
`(ii) to highlight areas for future research.
`
`Methods
`RCTs using a truly random or quasi-random allocation
`of treatment were included in this review if they
`included people with premonitory (cluster of seizures or
`a prolonged seizure), early, established or refractory
`status epilepticus. Both convulsive and nonconvulsive
`status epilepticus were considered. Studies comparing
`any anticonvulsant drug against placebo or another anti-
`convulsant drug were included. Our intention was to
`carry out separate analyses for premonitory stage, early
`status epilepticus, established and refractory status
`epilepticus. However, the definitions used in the differ-
`ent studies were both variable and often unclear, which
`precluded stage-specific analysis.
`For published trials the following electronic databases
`were searched:
`
`1 Cochrane Epilepsy Group Specialized Register (July
`2005).
`2 Cochrane Central Database of Controlled Trials
`(CENTRAL) (The Cochrane Library, Issue 2, 2005).
`3 MEDLINE (1966 to August 2004) (using the highly
`sensitive search strategy for identifying RCTs [4].
`4 EMBASE (1966 to January 2003).
`
`The search terms used included the following text
`words: status, epilepticus, anticonvulsant therapy and
`
`Anticonvulsant therapy for status epilepticus
`
`names of the drugs in combination with any of the above
`words. The outcome terms were also combined with
`‘status’ for searching. All resulting titles and abstracts
`were scanned and any relevant articles were followed
`up.
`Two review authors independently selected the trials
`to be included in the review. Any disagreements were
`resolved by seeking an independent opinion of the third
`review author. Two review authors assessed the method-
`ological quality of each trial. The trials comparing the
`same drugs were combined, whereas those comparing
`different drugs were analysed separately.
`RR (relative risk) or RD (risk difference) reductions
`were calculated by means of the statistical software pro-
`vided by the Cochrane Collaboration (RevMan version
`4.2.7). We tested for heterogeneity between trial results
`for each outcome using c2 test. If the test for heteroge-
`neity was statistically nonsignificant, then the results
`from the different trials were combined to obtain a
`summary estimate of effect [and the corresponding con-
`fidence interval (CI)] using a fixed-effect model. We
`preferred RR for our analyses, but for some outcomes
`there were zero events in all the arms of some studies. In
`such situations RD was used to ensure inclusion of the
`data in the meta-analysis.
`
`Results
`Eleven studies had 2017 participants. Of the 11 studies
`included in this review, five studied participants with
`premonitory status [5–9], one established [10], one
`refractory [11] and two mixed status epilepticus [12, 13].
`Two studies did not clearly define the status [14, 15].
`Seven studies included only adults [5, 6, 8–10, 12, 13]
`and four only children [7, 11, 14, 15]. The type of status
`epilepticus included varied from study to study: four
`generalized tonic-clonic [5, 9, 10, 14] and four mixed [6,
`11–13]. Three studies [7, 8, 15] did not describe the type
`of status epilepticus.
`All studies except three (two intrarectal and one intra-
`muscular midazolam in one arm) used intravenous
`administration of drugs. Fourteen different comparisons
`were available, but only three (lorazepam vs. diazepam,
`both administered intravenously; diazepam plus pheny-
`toin vs. phenobarbital, administered intravenously; diaz-
`epam intrarectal gel vs. placebo gel) included more than
`one study to permit a meta-analysis. The remaining 11
`comparisons had only one study.
`All participants were followed up only during their
`hospital stay. No study had postdischarge follow-up. All
`studies had cessation of status epilepticus and adverse
`effects as outcomes. Death was an outcome in five
`comparisons. Other outcomes studied were requirement
`AQUESTIVE EXHIBIT 1112 Page 0002
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`K. Prasad et al.
`
`for ventilatory support (seven comparisons) and con-
`tinuation of status epilepticus requiring another drug
`or general anaesthesia (five comparisons). Five studies
`used similar-looking placebo or comparison drugs. Use
`of placebo in random sequence with the drug conceals
`the randomization. In addition, two studies used sealed
`envelopes to conceal allocation in the randomization
`process, but whether the envelopes were opaque and
`serially numbered was unclear from the study reports.
`The remaining studies did not mention any attempt to
`conceal randomization. Studies with similar-looking
`placebo or comparison drug were assumed to be blinded,
`but six studies did not have blinding of carers or
`outcome assessors.
`Eleven studies included in this review had 2017 study
`participants. Data extraction was difficult because of
`heterogeneity in the definition of status epilepticus and
`the type of data presented. We sought studies with the
`same types of interventions to combine in a meta-
`analysis, but such studies were few. We could combine
`data from seven studies over eight different outcomes.
`Even here, the definitions used by different authors
`varied and we assumed that the type of participants were
`similar. We present the remaining studies separately.
`The results are presented according to the compari-
`sons used (Tables 1 and 2).
`
`Lorazepam IV vs. diazepam IV (Figure 1)
`There were three studies with 289 participants [5, 12,
`14]. Data were available for 264 patients and outcome of
`death was available in two studies ([5, 12]; for 203
`participants). There was no statistically significant dif-
`ference in deaths between the two groups (5/103 vs.
`3/100 participants; RD 0.02; 95% CI -0.04, 0.08).
`Compared with diazepam, lorazepam had a statistically
`significant lower risk of seizure continuation (32/130
`vs. 51/134 participants; RR 0.64, 95% CI 0.45, 0.90) and
`of continuation of status epilepticus requiring a different
`drug or general anaesthesia (32/130 participants vs.
`52/134; RR 0.63, 95% CI 0.45, 0.88). There was a sta-
`tistically nonsignificant trend favouring lorazepam for
`reducing requirement for ventilatory support (12/130 vs.
`17/134 participants; RR 0.73; 95% CI 0.36, 1.49) and
`adverse effects (7/130 vs. 11/134 participants; RD -0.03,
`95% CI -0.10, 0.03).
`
`Diazepam gel vs. placebo gel
`There were two studies with a total of 165 participants
`[6, 8]. The risk of seizure continuation was significantly
`less with diazepam gel compared with placebo gel
`(24/77 vs. 63/88 participants; RR 0.43, 95% CI 0.30,
`0.62). For adverse effects there was a strong but statis-
`
`642
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`63:6
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`Br J Clin Pharmacol
`
`trend towards the placebo gel
`tically nonsignificant
`(29/77 vs. 22/88 participants; RR 1.50, 95% CI 0.94,
`2.37).
`
`Diazepam plus phenytoin i.v. vs. phenobarbital i.v.
`There were two studies with a total of 222 participants
`[9, 10]. For the outcomes of death and requirement for
`ventilatory support, data were available in only one
`study (36 participants). There was no statistically sig-
`nificant difference between the two groups for the fol-
`lowing outcomes: requirement for ventilatory support
`(6/18 vs. 6/18 participants; RR 1.00, 95% CI 0.40, 2.52);
`adverse effects (57/113 vs. 55/109 participants; RR 1.00,
`95% CI 0.77, 1.30) and death (0/18 vs. 0/18 participants;
`RD 0.00, 95% CI -0.10, 0.10). For risk of seizure con-
`tinuation, the test for heterogeneity was significant and
`the type of status epilepticus studied was different,
`hence the two studies were analysed separately for this
`outcome. There was a weak statistically nonsignificant
`trend favouring phenobarbital in one of the studies [10]
`(8/18 vs. 2/18 participants; RR 4.00, 95% CI 0.98,
`16.30). In the other larger study [9], there was no statis-
`tically significant difference between the two groups for
`risk of seizure continuation (42/95 vs. 38/91 partici-
`pants; RR 1.06, 95% CI 0.76, 1.47).
`
`Adverse events (Figure 2)
`three
`For the comparison lorazepam vs. diazepam,
`studies [5, 12, 14] could be combined. There was no
`statistically significant difference between the two drugs
`for respiratory failure/depression (RR 0.78, 95% CI
`0.35, 1.74), or hypotension (RD 0.01, 95% CI -0.06,
`0.08). We were able to combine two studies [9, 10] for
`the comparison diazepam + phenytoin vs. phenobarbital.
`There was no statistically significant difference between
`the two interventions for the following adverse events:
`respiratory depression (RR 1.19, 95% CI 0.68, 2.07);
`hypotension (RR 0.96, 95% CI 0.64, 1.43) and cardiac
`rhythm abnormalities (RD -0.11, 95% CI -0.22, 0). The
`other studies did not have similarity of interventions to
`allow meaningful meta-analysis. In the study by Singhi
`et al. [11] comparing midazolam with diazepam, intuba-
`tion was required in 13/21 with midazolam and 16/19 in
`diazepam; hypotension was observed in 8/21 in mida-
`zolam and 9/19 in diazepam. In the study by Remy [13],
`the side-effect of sedation and in the study by McCor-
`mick [15] the adverse effect of respiratory depression
`alone were described; data regarding this are shown in
`Tables 1 and 2. Two studies [6, 8] did not give separate
`figures for different adverse events (i.e. the heading
`adverse events included all of them together).
`AQUESTIVE EXHIBIT 1112 Page 0003
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`

`

`Table 1
`Summary of comparisons
`
`Comparison or outcome
`
`Studies
`
`Participants
`
`Statistical
`method used
`(fixed model)
`
`3
`3
`3
`3
`
`2
`
`1
`1
`1
`1
`
`Anticonvulsant therapy for status epilepticus
`
`Statistically
`nonsignificant
`trend favouring
`
`Lorazepam
`Lorazepam
`
`Lorazepam
`Lorazepam
`
`Effect size, 95% CI
`
`0.64 (0.45, 0.90)
`0.73 (0.36, 1.49)
`-0.03 (-0.10, 0.03)
`0.63 (0.45, 0.88)
`
`0.02 (-0.04, 0.08)
`
`0.52 (0.38, 0.71)
`0.47 (0.21, 1.07)
`0.47 (0.21, 1.07)
`0.52 (0.38, 0.71)
`
`0.49 (0.18, 1.33)
`
`Lorazepam
`
`0.79 (0.56, 1.13)
`0.86 (0.63, 1.16)
`
`Lorazepam
`Lorazepam
`
`0.84 (0.58, 1.21)
`0.86 (0.63, 1.16)
`
`0.62 (0.45, 0.86)
`0.99 (0.72, 1.37)
`
`0.20 (0.03, 1.56)
`0.40 (0.04, 3.90)
`0.40 (0.04, 3.90)
`0.20 (0.03, 1.56)
`
`Midazolam
`Midazolam
`Midazolam
`Midazolam
`
`1.36 (0.25, 7.27)
`1.11 (0.59, 2.07)
`0.80 (0.39, 1.66)
`3.62 (0.87, 14.97)
`
`Diazepam
`
`264
`264
`264
`264
`
`203
`
`137
`137
`137
`137
`
`137
`
`192
`192
`
`188
`188
`
`198
`198
`
`27
`27
`27
`27
`
`40
`40
`40
`40
`
`RR
`RR
`RD
`RR
`
`RD
`
`RR
`RR
`RR
`RR
`
`RR
`
`RR
`RR
`
`RR
`RR
`
`RR
`RR
`
`RR
`RR
`RR
`RR
`
`RR
`RR
`RR
`RR
`
`Lorazepam i.v. vs. diazepam i.v. [5,12,14]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Adverse effects
`04 Continuation of status requiring a
`different drug or general anaesthesia
`05 Death
`Lorazepam i.v. vs. placebo i.v. [5]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Adverse effects
`04 Continuation of status requiring a
`different drug or general anaesthesia
`1
`05 Death
`Lorazepam i.v. vs. diazepam plus phenytal I.v. [9]
`01 Risk of seizure continuation
`1
`02 Adverse effects
`1
`Lorazepam i.v. vs. phenobarbital i.v. [9]
`01 Risk of seizure continuation
`02 Adverse effects
`Lorazepam i.v. vs. phenytoin i.v. [9]
`01 Risk of seizure continuation
`02 Adverse effects
`Midazolam i.v. vs. lorazepam i.v. [15]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Respiratory depression
`04 Continuation of status requiring a
`different drug or general anaesthesia
`Midazolam i.v. vs. diazepam i.v. [11]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Adverse effects
`04 Death
`
`1
`1
`
`1
`1
`
`1
`1
`1
`1
`
`1
`1
`1
`1
`
`Discussion
`Our review demonstrates that there are few reported
`randomized studies on drugs used in status epilepticus.
`This is evident from the fact that a search of Medline
`with the key phrase ‘status epilepticus’ restricted to the
`last 5 years yielded hundreds of reviews but only a few
`RCTs. The results are likely to be similar with EMBASE
`or any other database. It is unlikely that we have missed
`any randomized trial, because we attempted quite a com-
`prehensive search,
`including databases such as the
`Cochrane library, EMBASE and Medline. We speculate
`that the reason lies in the fact that conducting RCTs in
`
`an emergency situation is difficult, particularly when the
`patient
`is unconscious, which makes gaining rapid
`consent to join a trial difficult. The difficulty is not
`insurmountable, because trials in similar conditions such
`as stroke and meningitis are being reported in increasing
`numbers. This review highlights the need to conduct
`more randomized studies in status epilepticus. Other
`experts have also noted a lack of RCTs addressing treat-
`ment issues in status epilepticus [16, 17].
`Even with limited data, we were able to conclude the
`following: (i) diazepam is better than placebo for cessa-
`tion of seizures: there is a lower risk of requirement for
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`

`K. Prasad et al.
`
`Table 2
`Summary of comparisons (continued)
`
`Comparison or outcome
`
`Studies
`
`Participants
`
`Statistical
`method used
`(fixed model)
`
`Statistically
`nonsignificant
`trend favouring
`
`Diazepam
`
`Effect size, 95% CI
`
`0.85 (0.06, 12.01)
`0.85 (0.06, 12.01)
`0.85 (0.06, 12.01)
`0.85 (0.06, 12.01)
`
`0.73 (0.57, 0.92)
`0.39 (0.16, 0.94)
`0.46 (0.20, 1.04)
`0.73 (0.57, 0.92)
`
`0.28 (0.08, 0.98)
`
`0.43 (0.30, 0.62)
`1.50 (0.94, 2.37)
`
`Placebo gel
`
`0.39 (0.18, 0.86)
`0.90 (0.53, 1.53)
`
`4.00 (0.98, 16.30)
`1.00 (0.40, 2.52)
`1.00 (0.77, 1.30)
`0.00 (-0.10, 0.10)
`
`1.06 (0.76, 1.47)
`
`0.78 (0.59, 1.04)
`
`1.16 (0.86, 1.56)
`
`0.78 (0.57, 1.06)
`1.09 (0.81, 1.47)
`
`Phenobarbital
`
`Diazepam plus
`phenytoin
`
`Phenobarbital
`
`RR
`RR
`RR
`RR
`
`RR
`RR
`RR
`RR
`
`RR
`
`RR
`RR
`
`RR
`RR
`
`RR
`RR
`RR
`RD
`
`RR
`
`RR
`
`RR
`
`RR
`RR
`
`1
`1
`1
`1
`
`1
`1
`1
`1
`
`1
`
`24
`24
`24
`24
`
`139
`139
`139
`139
`
`139
`
`165
`165
`
`39
`39
`
`Midazolam i.m. vs. diazepam i.v. [7]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Adverse effects
`04 Continuation of status requiring a different
`drug or general anaesthesia
`Diazepam i.v. vs. placebo i.v. [5]
`01 Risk of seizure continuation
`02 Requirement for ventilatory support
`03 Adverse effects
`04 Continuation of status requiring a different
`drug or general anaesthesia
`05 Death
`Diazepam gel vs. placebo gel (rectal) [6, 8]
`2
`01 Risk of seizure continuation
`2
`02 Adverse effects
`Diazepam 30 mg rectal vs. diazepam 20 mg rectal [13]
`01 Risk of seizure continuation
`1
`02 Sedation
`1
`Diazepam plus phenytoin i.v. vs. phenobarbital i.v. [9, 10]
`36
`01 Risk of seizure continuation
`1
`36
`02 Requirement for ventilatory support
`1
`222
`03 Adverse effects
`2
`36
`04 Death
`1
`Diazepam plus phenytoin i.v. vs. phenobarbital i.v. (premonitory status) [9]
`01 Risk of seizure continuation
`1
`186
`Diazepam plus phenytoin i.v. vs. phenytoin i.v. (9)
`01 Risk of seizure continuation
`
`1
`
`196
`
`02 Adverse effects
`Phenobarbital i.v. vs. phenytoin i.v. [9]
`01 Risk of seizure continuation
`02 Adverse effects
`
`1
`
`1
`1
`
`196
`
`186
`186
`
`ventilatory support and continuation of status epilepticus
`requiring a different drug or general anaesthesia with
`diazepam; (ii) lorazepam is better than placebo for ces-
`sation of seizures and carries a lower risk of continuation
`of status epilepticus requiring a different drug or general
`anaesthesia; (iii) lorazepam is better than diazepam for
`cessation of seizures and has a lower risk of continuation
`of status epilepticus requiring a different drug or general
`anaesthesia; (iv) lorazepam is better than phenytoin for
`cessation of seizures; and (v) diazepam 30 mg intrarec-
`tal gel is better than 20 mg in premonitory status epilep-
`ticus for cessation of seizures without any statistically
`significant increase in adverse effects.
`
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`
`The above conclusions favour using lorazepam as the
`first-line drug in place of more commonly used diaz-
`epam. The pharmacokinetic properties of lorazepam
`also favour its use over diazepam. The anticonvulsant
`effect of a single dose of diazepam is approximately
`20 min, whereas that of lorazepam is >6 h. The shorter
`duration of the anticonvulsant effect of diazepam in spite
`of its longer elimination half-life is attributed to its lipid
`solubility and rapid redistribution to peripheral fat
`stores. The analysis of adverse events suggests that
`lorazepam is as safe as diazepam, if not more so. None
`of the analyses of adverse events shows any significant
`difference among the various interventions.
`AQUESTIVE EXHIBIT 1112 Page 0005
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`

`

`Anticonvulsant therapy for status epilepticus
`
`Comparison:
`Outcome:
`Study
`
`Lorazepam IV versus diazepam IV
`Risk of seizure continuation
`Lorazepam IV
`Diazepam IV
`n/N
`n/N
`27/66
` Alldredge 2001
`39/68
`1/27
` Appleton 1995
`5/34
`4/37
` Leppik 1983
`7/32
`134
`130
`Total (95% CI)
`Total events: 32 (Lorazepam IV), 51 (Diazepam IV)
`Test for heterogeneity: Chi2 = 1.32, df = 2 (P = 0.52), I2 = 0%
`Test for overall effect: Z = 2.56 (P = 0.01)
`
`RR (fixed)
`95% CI
`
`Weight
`%
`76.30
` 8.79
`14.91
`
`RR (fixed)
`95% CI
` 0.71 [0.50, 1.02]
` 0.25 [0.03, 2.03]
` 0.49 [0.16, 1.54]
`
`100.00
`
` 0.64 [0.45, 0.90]
`
`100
`10
`0.1
`0.01
`1
`Favours Lorazepam Favours Diazepam
`
`Comparison:
`Outcome:
`Study
`
`Lorazepam IV versus diazepam IV
`Requirement for ventilatory support
`Diazepam IV
`Lorazepam IV
`n/N
`n/N
`6/68
`7/66
` Alldredge 2001
`7/34
`1/27
` Appleton 1995
`4/32
`4/37
` Leppik 1983
`130
`134
`Total (95% CI)
`Total events: 12 (Lorazepam IV), 17 (Diazepam IV)
`Test for heterogeneity: Chi2 = 2.78, df = 2 (P = 0.25), I2 = 28.1%
`Test for overall effect: Z = 0.87 (P = 0.38)
`
`RR (fixed)
`95% CI
`
`Weight
`%
`36.05
`37.79
`26.16
`
`100.00
`
`RR (fixed)
`95% CI
` 1.20 [0.43, 3.39]
` 0.18 [0.02, 1.37]
` 0.86 [0.24, 3.18]
`0.73 [0.36, 1.49]
`
`100
`10
`1
`0.1
`0.01
`Favours Lorazepam Favours Diazepam
`
`Comparison:
`Lorazepam IV versus diazepam IV
`
`Outcome: Adverse effects
`Weight
`Study
`Lorazepam IV
`Diazepam IV
`RD (fixed)
`n/N
`n/N
`95% CI
`%
`7/68
`50.98
`7/66
` Alldredge 2001
`22.91
`0/34
`0/27
` Appleton 1995
`26.12
`4/32
`0/37
` Leppik 1983
`130
`134
`Total (95% CI)
`Total events: 7 (Lorazepam IV), 11 (Diazepam IV)
`Test for heterogeneity: Chi2 = 3.61, df = 2 (P = 0.16), I2 = 44.6%
`Test for overall effect: Z = 0.95 (P = 0.34)
`
`100.00
`
`RD (fixed)
`95% CI
` 0.00 [–0.10, 0.11]
` 0.00 [–0.06, 0.06]
`–0.13 [–0.25, 0.00]
`
`–0.03 [–0.10, 0.03]
`
`0.5
`0.25
`0
`–0.25
`–0.5
`Favours Lorazepam Favours Diazepam
`
`Comparison:
`Lorazepam IV versus diazepam IV
`
`Outcome: Death
`Study
` Lorazepam
` Diazepam
`RD (fixed)
` Weight
` n/N
` n/N
`95% CI
` %
`3/68
`5/66
`66.12
`0/32
`0/37
`33.88
`
` Alldredge 2001
` Leppik 1983
`
`RD (fixed)
`95% CI
`0.03 [–0.05, 0.11]
`0.00 [–0.06, 0.06]
`
`103
`Total (95% CI)
`Total events: 5 (Lorazepam), 3 (Diazepam)
`Test for heterogeneity: Chi2 = 0.62, df = 1 (P = 0.43), I2 = 0%
`Test for overall effect: Z = 0.73 (P = 0.47)
`
`100
`
`100.00
`
`0.02 [–0.04, 0.08]
`
`0.5
`0
`–0.25
`0.25
`–0.5
`Favours Lorazepam Favours Diazepam
`
`Comparison:
`Outcome:
`Study
`
`Lorazepam IV versus diazepam IV
`Continuation of status requiring a different drug or general anaesthesia
` Lorazepam IV
` Diazepam IV
`RR (fixed)
` Weight
` n/N
` %
` n/N
`95% CI
`39/68
`74.71
`27/66
` Alldredge 2001
` 8.61
`5/34
`1/27
` Appleton 1995
`16.68
`8/32
`4/37
` Leppik 1983
`130
`134
`Total (95% CI)
`Total events: 32 (Lorazepam IV), 52 (Diazepam IV)
`Test for heterogeneity: Chi2 = 1.68, df = 2 (P = 0.43), I2 = 0%
`Test for overall effect: Z = 2.68 (P = 0.007)
`
`100.00
`
` RR (fixed)
` 95% CI
`0.71 [0.50, 1.02]
`0.25 [0.03, 2.03]
`0.43 [0.14, 1.30]
`
`0.63 [0.45, 0.88]
`
`Figure 1
`Lorazepam vs. diazepam intravenous: outcomes
`
`100
`10
`1
`0.1
`0.01
`Favours Lorazepam Favours Diazepam
`
`AQUESTIVE EXHIBIT 1112 Page 0006
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`
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`645
`
`

`

`K. Prasad et al.
`
`Comparison:
`Outcome:
`Study
`
`Lorazepam vs diazepam
`Adverse event: Hypotension
` Diazepam
`Lorazepam
`n/N
` n/N
` 7/66
`7/68
`1/37
`0/32
`
` Alldredge 2001
` Leppik 1983
`
`103
`Total (95% CI)
`Total events: 8 (Lorazepam), 7 (Diazepam)
`Test for heterogeneity: Chi2 = 0.20, df = 1 (P = 0.66), I2 = 0%
`Test for overall effect: Z = 0.30 (P = 0.76)
`
`100
`
`RD (fixed)
`95% CI
`
`Weight
`%
`66.12
`33.88
`
`RD (fixed)
`95% CI
`0.00 [–0.10, 0.11]
`0.03 [–0.05, 0.10]
`
`100.00
`
` 0.01 [–0.06, 0.08]
`
`0.25
`0
`–0.25
`0.5
`–0.5
`Favours lorazepam Favours diazepam
`
`Comparison:
`Lorazepam vs diazepam
`
`Outcome:n Adverse event: Respiratory failure/depression
`Study
`Lorazepam
` Diazepam
`n/N
` n/N
`7/66
`6/68
` Alldredge 2001
`1/33
`8/53
` Appleton 1995
`2/37
`1/32
` Leppik 1983
`136
`153
`Total (95% CI)
`Total events: 10 (Lorazepam), 15 (diazepam)
`Test for heterogeneity: Chi2 = 2.83, df = 2 (P = 0.24), I2 = 29.3%
`Test for overall effect: Z = 0.61 (P = 0.54)
`
`RD (fixed)
`95% CI
`
`Weight
`%
`45.04
`46.79
` 8.17
`100.00
`
`RD (fixed)
`95% CI
`1.20 [0.43, 3.39]
`0.20 [0.03, 1.53]
`1.73 [0.16, 18.20]
`0.78 [0.35, 1.74]
`
`10
`0.1
`100
`1
`0.01
` Favours lorazepam Favours diazepam
`
`Comparison:
`Outcome:
`Study
`
`DZP PHT vs PB
`Adverse event: Respiratory depression
`DZP PHT
`PB
`n/N
`n/N
`6/18
`6/18
`16/95
`12/91
`
` Shaner 1988
` Treiman 1998
`
`113
`Total (95% CI)
`Total events: 22 (DZP PHT), 18 (PB)
`Test for heterogeneity: Chi2 = 0.18, df = 1 (P = 0.68), I2 = 0%
`Test for overall effect: Z = 0.60 (P = 0.55)
`
`109
`
`RR (fixed)
`95% CI
`
`Weight
`%
`32.86
`67.14
`
`100.00
`
`RR (fixed)
`95% CI
`1.00 [0.40, 2.52]
`1.28 [0.64, 2.55]
`
`1.19 [0.68, 2.07]
`
`Comparison:
`Outcome:
`Study
`
`DZP PHT vs PB
`Adverse event: Hypotension
`DZP PHT
`n/N
`3/18
`30/95
`
` Shaner 1988
` Treiman 1998
`
`5
`1
`0.1 0.2 0.5
`2
` Favours DZP PHT Favours PB
`
`10
`
`PB
`n/N
`2/18
`31/91
`
`RR (fixed)
`95% CI
`
`113
`Total (95% CI)
`Total events: 33 (DZP PHT), 33 (PB)
`Test for heterogeneity: Chi2 = 0.30, df = 1 (P = 0.58), I2 = 0%
`Test for overall effect: Z = 0.19 (P = 0.85)
`
`109
`
`5
`2
`1
`0.5
`0.1 0.2
` Favours DZP PHT Favours PB
`
`10
`
`Weight
`%
` 5.94
`94.06
`
`100.00
`
`RR (fixed)
`95% CI
`1.50 [0.28, 7.93]
`0.93 [0.61, 1.40]
`
`0.96 [0.64, 1.43]
`
`Comparison:
`Outcome:
`Study
`
`DZP PHT vs PB
`Adverse event: Cardiac rhythm abnormalities
`DZP PHT
`PB
`n/N
`n/N
`1/18
`0/18
`30/91
`20/95
`
` Shaner 1988
` Treiman 1998
`
`113
`Total (95% CI)
`Total events: 20 (DZP PHT), 31 (PB)
`Test for heterogeneity: Chi² = 0.57, df = 1 (P = 0.45), I² = 0%
`Test for overall effect: Z = 1.96 (P = 0.05)
`
`109
`
`RR (fixed)
`95% CI
`
`Weight
`%
`16.22
`83.78
`
`RR (fixed)
`95% CI
`–0.06 [–0.20, 0.09]
`–0.12 [–0.25, 0.01]
`
`100.00
`
`–0.11 [–0.22, 0.00]
`
`Figure 2
`Adverse events
`
`646
`
`63:6
`
`Br J Clin Pharmacol
`
`0.5
`0.25
`0
`–0.25
`–0.5
` Favours DZP PHT Favours PB
`
`AQUESTIVE EXHIBIT 1112 Page 0007
`
`

`

`This review has demonstrated several areas requir-
`ing attention in future research in status epilepticus. A
`universally acceptable definition of premonitory,
`early, established and refractory status needs to be
`agreed upon and used consistently by investigators.
`Agreement on the definition of outcomes and method of
`data presentation is also desirable to facilitate meta-
`analysis.
`In particular,
`reports should provide the
`number of participants having each outcome and the
`denominator in analyses should be the number of par-
`ticipants rather than the number of episodes of status
`epilepticus.
`
`Competing interests: None declared.
`This paper is based on a Cochrane Review published
`in The Cochrane Library (Prasad K, Al-Roomi K,
`Krishnan PR, Sequeira R. Anticonvulsant therapy for
`epilepticus. Cochrane Database Systematic
`status
`Reviews 2005; 4: CD003723). Cochrane Reviews are
`regularly updated as new evidence emerges and in
`response to feedback, and The Cochrane Library should
`be consulted for the most recent version of the review. The
`full text, data tables, results, analyses and reference lists
`of this article are available in the Cochrane Library.
`
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`AQUESTIVE EXHIBIT 1112 Page 0008
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`647
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`