Emergency handling of acute seizures and condition epilepticus

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  1. Robert C Tasker
  1. Department of Paediatrics, University of Cambridge Schoolhouse of Clinical Medicine, Cambridge CB2 2QQ, United kingdom

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    This article discusses some of the bug related to protocols for emergency anticonvulsant treatment of acute seizures and status epilepticus with particular emphasis on the utilize of benzodiazepines in children presenting to accident and emergency departments.

    Definitions

    Infants and children tin have both convulsive and non-convulsive forms of prolonged seizures. This commodity addresses merely convulsive episodes of status epilepticus, which is strictly defined every bit 2 or more seizures occurring consecutively without an intervening menses of full recovery of consciousness, or equally recurrent epileptic seizures lasting for more than 30 minutes.1 Unfortunately, such a precise definition of status epilepticus, although useful for epidemiological analysis and evaluation of therapeutic interventions, conceals a sometimes frenetic arroyo to acute care and the urgency experienced by clinicians when confronted with a convulsing child, irrespective of how long the episode has lasted. It therefore seems more advisable to take a pragmatic view and consider status epilepticus equally the astringent terminate of a continuum encountered during the progressive evolution of an unrelenting seizure, which heralds a potentially life threatening sequence of complications in key, metabolic, and systemic physiology (table 1).2-5 This somewhat looser approach is reflected in the paediatric literature where seizure episodes of considerably less than thirty minutes have been considered as condition epilepticus.6 7

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    Table 1

    Systemic physiology, metabolic, as well as central changes, and derangements during prolonged seizures2–5

    Clinical perspective

    Both the clinical context and natural history of astute seizures and condition epilepticus are very of import considerations when evaluating choice of anticonvulsant treatment. In many parts of the world status epilepticus in childhood is often associated with fever, although there is wide variation in the proportion of patients who have this symptom (25–50%).viii-10

    In the Great britain, condition epilepticus (defined as a 30 minute episode) is an exceptional occurrence. For example, Verity et al reported in 19939 that only 37 of 14 676 children from a long term accomplice study had an episode of status epilepticus past their 10th birthday. Similarly, Smithet al reported in 199610 only 12 episodes of status epilepticus (lasting longer than 30 minutes) in 254 seizure episodes occurring in children presenting to an accident and emergency department over one year; this was from a surrounding population of 70 000 children.

    Clinical strategy

    Smith et al'south district general hospital study10 also illustrated another important feature of astute seizures in children: 80% of them did not require any anticonvulsant treatment in the emergency section. Therefore, given that most acute seizures in children finish spontaneously, usually during transit to hospital, we should presume that if a child is however convulsing on arrival in the emergency department the seizure will continue unless treated. How apace such handling should be carried out then becomes an important issue. Condition epilepticus in the 1990s has a relatively low morbidity and mortality directly attributable to the seizure itself,8 9 and an overexuberant arroyo with anticonvulsants may expose patients to the unnecessary iatrogenic risks of respiratory low and hypotension. One commentator has raised the important question "Does the morbidity of the treatment of seizures in the emergency room to preclude condition now exceed the morbidity of the status epilepticus itself?".eleven In the absence of whatever clear clinical data to respond this question fully, the onus on those involved with acute seizure treatment is to ensure that it is administered safely and in a standardised fashion that is understood by all emergency personnel involved.

    Emergency supportive treatment

    Anyone who is still convulsing on arrival in the emergency department should receive immediate, bones, supportive treatment.

    AIRWAY AND OXYGENATION

    Hypoxaemia can be both the cause and the consequence of a seizure. In severe episodes bradycardia and hypotension may complicate the seizure. To begin with, the head and neck should be positioned to keep the airway open and, if necessary, the airway should be suctioned to ensure patency. If feasible, an oral airway can be inserted—although this should simply be done if there is no likelihood of trauma to the oral fissure and teeth—and oxygen should exist administered by nasal cannula or mask and bag-valve-mask ventilation. If the need for respiratory assistance persists after the patient has been supported by bag-valve-mask, endotracheal intubation should be considered. Nevertheless, administering an anticonvulsant is a top priority because managing the airway and assisting respiration are much easier afterwards the convulsion has stopped. If persistent convulsive action causes hypoventilation necessitating endotracheal intubation, seizure activity tin can exist stopped temporarily with a loftier dose of a curt acting barbiturate or midazolam, and patient ventilation dysynchrony can exist abolished with a neuromuscular blocking agent.

    GLUCOSE

    Hypoglycaemia is a rare cause of prolonged seizures in children. However, all patients should have prompt measurement of blood glucose. If hypoglycaemia (claret glucose < 3 mmol/50) is documented or if it is impossible to obtain the measurement, intravenous glucose (v ml/kg) should be administered as 10% glucose.

    BLOOD PRESSURE

    Hypotension tin potentiate or exacerbate any derangement in cerebral physiology and function. Systolic claret pressure should be maintained at normal levels. If at that place is no evidence of daze, minimal isotonic fluids of 2–iii ml/kg/h should be given initially.

    Anticonvulsant treatment

    In the convulsing patient, initial supportive, therapeutic, and diagnostic measures demand to be conducted simultaneously. The goal of anticonvulsant treatment is the rapid termination of clinical and electrical seizure activity by the prompt administration of appropriate drugs in acceptable doses, with attention to the possibility of complicating apnoea, hypoventilation, and other metabolic abnormalities.

    PROLONGED SEIZURES AND ANTICONVULSANT RESPONSIVENESS

    The concept of acute seizures and status epilepticus beingness on a continuum is useful in regards to administering anticonvulsant treatment. For example, using diazepam in controlled experimental studies of prolonged seizures has established that the longer the duration of a seizure episode before treatment (ranging from 7–130 minutes) the more difficult it is to terminate, and the more likely information technology is that diazepam will catechumen an overt motor episode into another subtle or electroencephalographic form of seizure activity.12 As like findings have been reported in homo,13 the demand for rapid, definitive handling of acute seizures, irrespective of whether 30 minutes has elapsed, is underscored.

    ANTICONVULSANT PROTOCOL

    In that location is a dearth of bear witness in children that one detail anticonvulsant protocol is best for treating acute seizures. There is need for a formal systematic review of the literature to identify what would be the appropriate strategy for future investigation. A clear path or treatment programme however is necessary now, and indeed has been recommended for effective and consistent direction.14 One such arroyo is that used past the "Advanced Life Back up Group" in their recommendations for avant-garde paediatric life support (fig1).15 While endorsing wholly this specific arroyo, not to the lowest degree considering it is taught widely and has been adopted as a national standard of intendance, the main trouble with this arroyo is the fourth dimension information technology might have to stop a seizure if official recommendations are adhered to. For example, 25 to 30 minutes of seizure activity may have elapsed before either phenytoin or phenobarbitone is given: five minutes earlier the showtime dose of diazepam, and then five minutes to see if diazepam is effective, then the second dose of diazepam, then v minutes to see if this dose is effective, then a dose of paraldehyde, then 15 to 20 minutes to encounter if this is effective, etc. We shall therefore consider other emerging strategies using only benzodiazepine agents (figs 1 and2),xvi which may simplify our approach to astute emergency seizure treatment.

    Figure 1

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    Effigy 1

    Timing for the Advanced Paediatric Life Back up (APLS) "standard" anticonvulsant protocol for status epilepticusxv alongside a potentially challenging approach using simply "benzodiazepines". The time line highlights a problem with the APLS arroyo: information technology may be 25 minutes before progressing to phenytoin or phenobarbitone. *Do non utilize if the child is known to be on regular phenytoin.

    Figure 2

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    Figure two

    Chemical construction and pharmacokinetic backdrop of diazepam, lorazepam, and midazolam illustrating some of the similarities between these benzodiazepine GABAA agonists. Developed pharmacokineticsxvi: Fived, volume of distribution; T½α, distribution half life; T½β, elimination half life; Cl, clearance. All three drugs are metabolised in the liver and excreted via the kidney. All three take significant protein binding (> 88%).

    Benzodiazepine agents

    PREHOSPITAL TREATMENT

    The efficacy of intravenous diazepam for the treatment of status epilepticus is well recognised with termination of episodes in some 80% of cases.17 However, condom is a significant business as apnoea and respiratory depression are common complications.18 Therefore, except in known cases of recurrent prolonged seizures, drug treatment in the U.k. has traditionally been reserved for administration after arriving in hospital. If, as already discussed, diazepam is not but effective treatment just as well ameliorate when administered earlier, why not give it earlier arriving at hospital—providing it can be carried out safely? In support of this statement is a recent American retrospective, instance-control, study by Alldredge et al.vii Using a definition of status epilepticus as seizures lasting longer than 15 minutes, these authors found (in 45 convulsive episodes) that prehospital treatment with intravenous diazepam (0.2 mg/kg) or rectal diazepam (0.half dozen mg/kg) past paramedical staff significantly shortened the duration of condition epilepticus (mean for prehospital 32 minutes v mean for emergency section hour; p = 0.007) and reduced the likelihood of recurrent seizures in the emergency department (58%v 85%; p = 0.045). This report found no deviation between the effectiveness of rectal and intravenous diazepam. This experience seems to confirm the experimental data already described,13 merely is such an approach safe?

    The possible complication of respiratory depression from rectal diazepam has been considered in some depth in the treatment of repeated febrile convulsions.19 Respiratory depression from rectal diazepam (0.two–0.five mg/kg) is rare amid children studied to date, probably because of the slower rise in serum diazepam concentrations compared with that achieved afterward intravenous administration. The clinical consequence from rectal diazepam occurs in approximately five minutes and pinnacle serum concentrations are achieved vi–x minutes after assistants.20 21 Knudsen22 reported no respiratory complications in 376 children treated with rectal diazepam. (The upper limit of the 95% confidence interval for 0/376 is 8 per 1000 cases.) A literature review of 13 papers on rectal diazepam by Siegler in 199023 identified only three cases of reversible respiratory low in 843 cases. Some patients, notwithstanding, may exist at more hazard of respiratory depression—for example, those with serious comorbidity and those on regular anticonvulsants or with chronic central nervous system abnormalities.23 In these patients a lower rectal dose of 0.25 mg/kg is advised.

    Therefore, the literature supports the utilise of a single prehospital dose of rectal diazepam, although attendants should be aware of the possibility of respiratory depression and be able to support animate if necessary.

    Offset LINE Hospital TREATMENT

    A child who is even so convulsing on arrival in hospital can be assumed to have had a seizure lasting at least 10 minutes and therefore will require emergency treatment. Some children may have already received rectal diazepam. In this phase of management the issues are whether diazepam is the treatment of pick and, if it is, should it be used more than in one case. Although the precise serum diazepam concentration required for a therapeutic consequence is not known, concentrations of 150–336 ng/ml are associated with arrest of seizure action.24 These are achieved with a unmarried dose of rectal diazepam,20 22 which questions the notion that further doses would exist of benefit in those whose seizure has not come under command—unless of course administration of the beginning dose has been unreliable or if a second episode has occurred. Few studies in children have looked specifically at the effectiveness of serial doses of diazepam when the first dose has failed to control the seizure. However, some information on this question tin can be learnt indirectly from a contempo prospective written report reported by Appletonet al.25 Of 53 patients presenting with acute seizures to an emergency section, 28 responded to a unmarried dose of rectal or intravenous diazepam (0.3–0.4 mg/kg). In the 25 who required a second dose, 17 also needed additional anticonvulsant drugs. This may have been because of the local protocol, simply it does suggest that in those who do not respond to an initial dose of diazepam, the second dose is also likely to be ineffective. Therefore, if giving diazepam twice is questionable, is in that location a better alternative?

    Choices from phenobarbitone, phenytoin, and lorazepam as candidate alternative drugs for status epilepticus have been debated in the literature.16 26 27 Lorazepam, a hydroxylated benzodiazepine (fig 2), is an effective anticonvulsant with a response latency comparable to that of diazepam, and it has the advantage of a longer duration of anticonvulsant consequence than diazepam.27Although there are few studies comparing lorazepam with established standards, it has been recommended as one of the commencement line agents for status epilepticus for the above reasons.27 One preliminary study25 compared lorazepam with diazepam for the treatment of acute convulsions and status epilepticus in 102 children in a prospective, open (odd and even dates) trial. Sixteen children had to be excluded and of the remaining 86, convulsions were controlled in 76% of patients treated with a single dose of lorazepam (0.05–0.ane mg/kg) and 51% of patients treated with a unmarried dose of diazepam. Significantly fewer patients treated with lorazepam required additional anticonvulsants to end the seizure. Respiratory depression occurred in 3% of lorazepam treated patients and 15% of diazepam treated patients. No patient who received lorazepam required access to the intensive care unit for either respiratory depression or refractory condition epilepticus, whereas all 8 of the patients with diazepam related respiratory depression were admitted for intensive care. Importantly, rectal and parenteral lorazepam were equally efficacious.

    Despite these favourable aspects of lorazepam, there are still indications for the other agents. Lorazepam appears to be less constructive in patients chronically treated with other benzodiazepine anticonvulsants and in those who volition need the drug more than in one case.27 In both of these instances phenobarbitone appears to be superior,26 28 although at that place is niggling comparative clinical data for these agents and phenytoin. In practice, choice between anticonvulsants appears to relate to age and aetiology. In infants, the metabolism of phenobarbitone is more predictable than the metabolism of phenytoin. Phenytoin has a office when there is business about impaired cerebral function and the need for clinical assessment of neurology.

    REFRACTORY SEIZURES

    Refractory status epilepticus has been defined as a seizure that is unresponsive to an adequate dose of a start line parenteral anticonvulsant28; or a seizure that is unresponsive to at to the lowest degree two doses of diazepam intravenously or rectally in succession followed by phenytoin/phenobarbitone or both (20 mg/kg) given over xxx minutes equally an infusion, or failure to respond to the latter solitary or in combination15 28-xxx; or a seizure that continues for threescore to ninety minutes after the initiation of treatment.1 This lack of consistency in definition is of import when ane considers the handling and its consequences. Traditionally, for the most severe cases of condition epilepticus induction of general anaesthesia has been recommended using a brusk acting barbiturate such as thiopentone (four–8 mg/kg bolus followed by infusion of up to 10 mg/kg/h) along with supportive endotracheal intubation and mechanical ventilation.15 29 An alternative, effective approach has been to use, if necessary, repeated bolus doses of intravenous phenobarbitone (10 mg/kg) every xxx minutes, without reference to a predetermined maximum level or dose, after one dose of intravenous diazepam has failed to control a seizure.28 A number of questions arise—for instance, at what bespeak is consecration of amazement overexuberant? Is information technology really necessary to wait 60 to 90 minutes earlier deciding that standard anticonvulsants are ineffective? When is it inevitable that standard anticonvulsants are unlikely to work—later on the second dose of diazepam, subsequently the second drug, or after the third drug? Some of these issues have been addressed already. The main disadvantage of thiopentone relates to its loftier lipid solubility and slow metabolism, which results in a prolonged period of intensive care back up earlier a child is completely awake and cooperative in one case handling has been stopped.29 Similarly, prolonged intensive care will be necessary when using the very high dose phenobarbitone strategy.28

    A newer approach, recently delineated in children, has been to use midazolam,30 31 an imidazobenzodiazepine (fig 2). This drug has a relatively short elimination one-half life of 1.5 to 3.five hours, and preclinical and clinical analyses indicate that it shares anxiolytic, muscle relaxant, hypnotic, and anticonvulsant deportment with other benzodiazepines. Rivera et al reported the employ of midazolam in 24 children (aged 2 months to 2 years) with status epilepticus failing to respond to three repeated doses of 0.3 mg/kg diazepam, 20 mg/kg of phenobarbitone, and 20 mg/kg phenytoin.30 Intravenous midazolam given as a bolus of 0.15 mg/kg followed by continuous infusion of ane μg/kg/min (with increasing increments of 1 μg/kg/min every 15 minutes until seizure control) was successful in all cases. The average time to reach seizure control was 47 minutes (range 15 minutes to four.5 hours) with a mean infusion dose of 2.3 μg/kg/min (range 1 to 18). Afterwards stopping the infusion, the average time to full consciousness was simply over four hours (range two to viii.5). Lal Koul et alrecently reported similar findings in a further 20 children.31

    Given the structural and pharmacokinetic similarities betwixt diazepam and midazolam (fig two) and their like mechanism of activity via binding to the γ-aminobutyric acid A (GABAA) receptor, it is pertinent to question "Why should midazolam be effective when other GABAA agonists including phenobarbitone and benzodiazepines have failed?" As notwithstanding this cannot be answered from the bachelor data, simply it may relate to actions and interactions distant to the benzodiazepine bounden site on the GABAAreceptor.32 This therapeutic conundrum does nevertheless raise another important consideration—if midazolam is constructive when all drugs accept failed, would it be a ameliorate option earlier in astute seizure care? Lal Koul et al addressed this question in their report31 by using a midazolam infusion as their but treatment in eight patients who had seizure activity for at least 30 minutes. One time this handling was started, control of the seizure was achieved within 10 to lx minutes (mean 34). None of their patients required mechanical ventilation or endotracheal intubation.

    What about the potential use of midazolam every bit a beginning line anticonvulsant for all acute seizures? In the blow and emergency department in predominantly adult series, intravenous33and intramuscular34 midazolam as first line treatment for seizures accept been used effectively and safely. Galvin and Jelinek33 reported that intravenous midazolam lonely was successful in stopping seizures in all 75 patients they treated. Intramuscular midazolam is besides quickly effective: in 36 of 38 patients undergoing seizures, seven of whom were children, seizures were controlled with a mean of ane minute and 53 seconds.34 The two patients whose seizures connected despite intramuscular midazolam responded to some other benzodiazepine given intravenously.

    Decision

    Devising a protocol for the management of condition epilepticus with the optimal selection of anticonvulsant drugs is fraught with issues given the reality of clinical duty rotations and varied expertise of frontline staff. Introducing relatively new agents such as midazolam and lorazepam into an established pattern of do volition need to exist justified. Inevitably, factors other than pharmacology and therapeutics volition influence the specific approach adopted. What is right for a practice seeing head injury as the major crusade of status epilepticus may not be appropriate for those dealing with central nervous system infection every bit the leading cause. The clinical context, toll, and logistics of delivering effective treatment and care are also important. Finally, diagnostic studies and the type and timing of investigation are a concern. Some of these aspects are well summarised elsewhere.35 36 However, irrespective of regional variance in exercise, it is articulate that much thought should be given to these issues at a local level. In a recent United kingdom intensive care questionnaire written report reported by Walker et al, xiv only 12% of the respondents were aware of a local protocol for status epilepticus.

    Future direction

    Possibly not surprisingly at that place is a paucity of clinical data comparing drug regimens for status epilepticus, which means that there is even so much to larn near this emergency. As alluded to already, there is a need to formalise and ostend our current ignorance in a systematic review. Building on this cognition will inevitably require a number of specific studies concentrating on prehospital, first line, and refractory phases of drug treatment. For example: Is prehospital administration of rectal lorazepam past paramedical staff of benefit? Can midazolam exist used equally monotherapy, intranasal or rectal in the prehospital setting and then parenterally thereafter? Can we predict meliorate those patients who volition eventually show to be refractory to handling? For the present, standards such as that recommended by the Avant-garde Paediatric Life Support Group15 take been rightly adopted on a national level, but that should not detract from a constructive, investigational questioning of culling or even better, more timely approaches, which accept as their goal improved emergency care.

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