How do status epileptic seizures stop? Take a look at the latest Chinese expert consensus

Status epilepticus is one of the most critically ill conditions involving multiple disciplines in the clinic, and although its treatment is comprehensive, rapid termination of the onset of status epilepticus is the key to

Scope of Consensus

➤ Comprehensive SE: Confusion between two seizures does not return to normal or one seizure lasts more than 5 minutes (absence seizures need to exceed 10 to 15 minutes), focal seizures with conscious disorders lasting more than 10 minutes can be diagnosed as SE, and the duration of focal seizures with unconscious disorders is still in

➤Refractory status epilepticus (RSE): RSE is defined as the inability to terminate seizures after 2 to 3 anti-SE seizure drugs (usually benzodiazepines followed by another or two antiepileptic drugs) and an epileptiform discharge

➤ Super RSE: After treatment with more than two anti-SE drugs after RSE, the seizure continues or although effective but recurs after discontinuation, called super RSE, this type of SE often requires special treatment to be managed

Caution: The panel considers SE to be an acute seizure associated with a variety of complications that generally do not require long-term treatment after seizure termination, while epilepsy is a chronic brain condition that requires long-term treatment

Commonly used anti-SE drugs

At present, the drugs that can be used for anti-SE mainly include new anti-epileptic drugs such as lorazepam, diazepam, clonazepam, phenobarbital, valproic acid, propofol, pentabarbital, ketamine or sodium thiopenta, phosphophenytoin, levetiracetam and other new anti-epileptic drugs, phenytoin, lidocaine, and midazolam There are 14 other categories, which need to be selected according to different therapeutic purposes

Selection of commonly used treatments

Treatment is recommended in the following order: diazepam or lorazepam→ clonazepam→ phenobarbital, valproic acid, levetiracetam→ midazolam→ propofol→ ketamine → combined →ketogenic diet → subhypothermic → electroshock therapy

Clinical application

➤ Diazepam injection

Diazepam is a widely used and recognized antiepileptic drug at home and abroad, and its efficacy is accurate and well known
to the majority of medical staff.
In recent years, Western developed countries have recommended the use of lorazepam instead of diazepam, but at present there is no lorazepam in China, so it is recommended to still take diazepam as the first choice
.

(1) Indications: Suitable for the first treatment of SE and patients who do not meet the RSE standard and are not resistant to benzodiazepines and have no contraindications, it is not recommended to be used for SE
in hepatic encephalopathy and Lennox-Gastaut syndrome.

(2) Medication route: intravenous medication, pre-hospital emergency can also be administered through non-intravenous routes, such as rectal administration, etc.
, but should not be injected intramuscularly
.

(3) Dosage: Adult SE intravenous administration can consider the first dose of 10~20mg intravenous slow bolus; If ineffective, intravenous bolus can be re-injected after 5 minutes; If effective (seizures stop), intravenous infusion (12 h) with 80 to 100 mg of diazepam in 5% glucose solution; If the medication is effective, but the recurrence is maintained, 10 to 20 mg of diazepam can be reinjected; If treatment is ineffective, the drug should be discontinued and replaced with other recommended drugs
.

(4) Precautions for medication: intravenous medication needs to be slowly bolstered, no more than 2mg per minute, pay attention to the impact on the patient's respiratory and cardiovascular function, and if necessary, use respiratory stimulants such as colamine and lobergin to counter its respiratory depressive effect
.

➤ Clonazepam

Clonazepam and diazepam are the same benzodiazepines, as γ-aminobutyric acid (GABA)-A receptor agonists, can bind to the α and γ subunits of GABA-A, induce conformational changes of GABA-A receptors, promote cell hyperpolarization, and thus inhibit the central nervous system
.
Debruyne et al.
analyzed 167 SE attacks in 118 patients admitted to the Department of Neurology at the University of Roste from 2000 to 2009 and found that clonazepam was more effective than dedicamam, levetiracetam, sodium valproate, midazolam, etc.
in terminating convulsive SE, so Rundfeldt et al.
recommended clonazepam as the first choice for
initial treatment when convulsive SE in infants and children lasted for more than 5 minutes.

(1) Indications: The intensity of action of clonazepam is 10 times
that of diazepam.
Although some scholars advocate clonazepam as the first choice for SE, considering the wide recognition and clinical experience that needs to be accumulated, it is still advocated as a secondary choice
after the failure of treatment with diazepam.

(2) Route of medication: intravenous medication
.

(3) Dosage: Adult SE can consider 1~2mg intravenous slow bolus, if 10~15min is ineffective, it can be repeated once, if it is still ineffective, the drug needs to be discontinued, and other recommended drugs
are selected.
In patients who are effective after intravenous bolus, 1 to 2 mg of intravenous bolus can be used to maintain it every 12 hours, and discontinuation can be considered for
1 to 2 days after the seizure is stopped.

➤ Valproic acid

(1) Indications: mainly applicable to benzodiazepines-resistant SE, because it has no significant effect on the patient's consciousness, it is particularly suitable for non-convulsive SE patients
.

(2) Route of medication: intravenous medication
.

(3) Dosage: Adult SE patients can consider 20 to 40 mg / (kg.
d) intravenous bolus, and the first dose is doubled
.
First according to 3 ~ 6mg / (kg.
min) intravenous bolus 20 ~ 40mg / kg, and then with the same dose of intravenous infusion, the next day according to 20 ~ 40mg / (kg.
d) intravenous infusion, for continuous treatment of 2 to 3 days effective, after the patient's seizures stop, after the recovery of consciousness, can be changed to oral therapy (sequential therapy) to control the long-term onset of epilepsy; If ineffective, discontinue use and choose other recommended drugs
.

(4) Precautions: (1) Valproic acid treatment of SE requires the first dose to be doubled, and it is difficult to achieve the expected effect by instilling a small dose for a long time; (2) When using valproic acid, it is necessary to pay attention to its special contraindications, such as seizures in mitochondrial encephalomyopathy, etc.
, and under normal circumstances, it is not recommended to use SE caused by genetic diseases, seizures caused by hepatic encephalopathy, and other diseases
that are obviously not suitable for application.

➤ Phenobarbital

(1) Indications: mainly adapted to SE after the failure of treatment of diazepam and clonazepam, especially for children SE may be more effective
.

(2) Route of medication: intravenous medication
.

(3) Dosage: Adult SE patients can consider first slow intravenous bolus 10 ~ 15mg / kg (speed 50 ~ 100mg / min), after effective 100 ~ 200mg / time, twice a day intramuscular injection maintenance, for 1 ~ 2 days, if ineffective, stop the drug, choose other recommended drugs
.

(4) Precautions: (1) Domestic phenobarbital for clinical application has two kinds of injections for intramuscular injection and intravenous use, but most manufacturers produce dosage forms that are only for intramuscular injection, so it is necessary to carefully check before use to avoid ultra-manual medication; (2) Although there are a large number of reports of the use of phenobarbital for the treatment of SE in foreign countries and the accumulation of rich clinical experience, the lack of intravenous dosage forms for a long time in China is limited, so there is almost no accumulation of large sample studies, and it is necessary to be cautious
when choosing this drug.

➤ Levoetiracetam

(1) Indications: mainly suitable for SE after the failure of treatment of diazepam and clonazepam and the combination of multiple drugs in patients with ineffective drug therapy, the literature reports that it may be effective
for epileptic status epileptic persistent status (ESES) in children's sleep.

(2) Route of medication: intravenous medication
.

(3) Dosage: Adult SE patients can consider 1000~1500mg intravenous bolus, the dosing speed is 2~5mg/(kg.
min), if the seizures have not stopped or EEG suggests persistent epileptiform discharge, RSE should be considered, and the dose
can be added.
After the effect, the infusion can be sustained by 0.
05 to 2 mg/(kg.
h), the load is 1500 to 3000 mg/day, the maximum dose is 4500 mg, and if it is ineffective, the drug is discontinued and other recommended drugs
are selected.
Combination drugs are mainly used in combination with benzodiazepines for the treatment of super RSE
.
In combination with benzodiazepines, the recommended dose of levetiracetam is 2500 mg slowly intravenously (>5 min) in two ways, namely the addition of levetiracetam on the basis of failure of benzodiazepine therapy, or simultaneous application
with benzodiazepines.

(4) Precautions: Although there are a large number of literature reports on the use of levetiracetam for the treatment of SE in foreign countries and a wealth of clinical experience, the domestic injection market time is not long, so there is almost no accumulation of research, and caution must be taken
when choosing this drug.

➤ Midazolam

(1) Indications: It has been found that the efficacy of the preferred midazolam for the treatment of SE is better than that of diazepam or clonazepam, but it is not widely recognized by peers, and its inhibitory effect on respiratory and the effect on blood pressure is significantly stronger than that of diazepam, and it is limited by the conditions of use (anesthetic use), so the expert team still believes that the use of midazolam for RSE may be more in line with current clinical practice
.

(2) Route of medication: intravenous medication
.

(3) Dosage: Intravenous administration of adult SE can be considered as a slow bolus injection (2 to 4 mg/min) of 0.
1 to 0.
2 mg/kg, and if it is ineffective, it can be repeated once, and if it is still ineffective, the drug can be discontinued, and other recommended drugs
are selected.
If effective, it can be pumped by 0.
1 to 0.
3 mg/(kg.
h) intravenously for 12 hours
.
Recurrence can be repeated once during maintenance
.

(4) Precautions: Midazolam has obvious inhibitory effect on respiration, and its antihypertensive effect is also more prominent, therefore, it is best to use in a neurocritical care unit and under close supervision, and mechanical ventilation is required if necessary to promote respiratory function
.

➤ Propofol

(1) Indications: There is no evidence that the efficacy of the preferred isopophenol is better than that of diazepam or clonazepam, and its inhibitory effect on respiratory and the effect on blood pressure is significantly stronger than that of diazepam, and it is also limited by the conditions at the time of use, so the indications for isopoprol are mainly RSE, which is selected when midazolam treatment fails or is not suitable for the use of
midazolam.

(2) Route of medication: intravenous medication
.

(3) Dosage: Intravenous administration of adult SE can be considered as a slow bolus injection of 1~2mg/kg intravenously, if it is ineffective, it can be repeated once, and if it is still ineffective, the drug is discontinued, and other recommended drugs
are selected.
If effective, it can be pumped by 1 to 4 mg/(kg.
h) intravenous for 10 to 12 hours
.
Recurrence may be followed by
1 additional bet during maintenance.

(4) Precautions: (1) Same as midazolam, the use of propofol is best also in the neurocritical care unit and under close supervision, and mechanical ventilation is required if necessary to promote normal respiratory function; (2) Small doses of propofol can cause SE, therefore, unless special circumstances, generally should not be lower than the recommended dose when applied intravenously; (3) High-dose, long-term use of propofol, especially when the infusion rate is greater than 100 μg / (kg.
min) may cause rhabdomyolysis, which requires attention, and regular examination of phosphocreatine kinase if necessary may be helpful
for diagnosis.
Midazolam and propofol are the drugs of choice for the treatment of RSE and are widely accepted, considering that propofol may exacerbate the occurrence of SE, so it is recommended to choose
midazolam after treatment failure.

➤ Ketamine

(1) Indications: mainly suitable for the combination of RSE and a variety of drugs after the failure of treatment with midazolam and propofol therapy
.

(2) Route of medication: intravenous medication
.

(3) Dosage: Adult SE patients can consider a loading dose of 1~3mg/kg (maximum 4.
5mg/kg), and intravenous bolus
at the maximum speed of 100μg/(kg·min).
Ketamine combination is mainly used after the treatment of first- or second-line drugs such as diazepam, lorazepam, phenytoin and other first-line drugs are ineffective
.

(4) Precautions: (1) Ketamine is an anesthetic, which needs to be applied under the guidance of an anesthesiologist, which has a significant inhibitory effect on breathing, therefore, it is best to use it in a neurocritical care unit and under close supervision, and if necessary, mechanical ventilation is required to promote normal respiratory function; (2) Due to the obvious respiratory depressive effect, the US Food and Drug Administration (FDA) recommends that the use of ketamine should start with a small dose and increase it slowly; (3) Because ketamine may have central nervous system excitatory effect, although it rarely occurs, the US FDA is still not recommended for patients with severe hypertension and allergy to the drug, with coronary heart disease, cardiac insufficiency, glaucoma, arteriosclerosis, pulmonary heart disease, pulmonary hypertension, severe intracranial hypertension, pregnancy, psychiatric history Patients with hyperthyroidism, tachyarrhythmias and adrenal philophiloma should also be used with caution, and a CT scan of the skull should be performed first to exclude intracranial lesions that can cause increased intracranial pressure; (4) SE caused by alcoholism should be administered with caution; (5) The symptoms of increased skeletal muscle tone caused by ketamine need to be distinguished from
epileptic tonic-clonic seizures.

➤ Combination medication

(1) Potential advantages: SE is a multi-caused, heterogeneous disease, not only has a variety of causes, but also the mechanism is very complex
.
The combination of a variety of different mechanisms of anti-SE drugs may be more in line with the clinical reality of SE than drugs with a single mechanism, and SE is still a continuous disease process, and its pathogenesis may not be exactly the same at different times of the
attack 。 Wasterlain et al.
[24] found that with recurrent seizures and prolonged seizure time, the activity of GABA-A receptors on the postsynaptic membrane decreases, and the number and activity of N-methyl-D-aspartic acid (NMDA) receptors increases, resulting in an increase in the incidence of drug-resistant SE caused by benzodiazepines, and the combination of drugs for multiple neurotransmitters may be more advantageous, especially the combination of newly marketed anti-epileptic drugs as additives can improve the prognosis of patients [2]; Persistent seizures are sufficient to cause substantial brain damage, including neuronal injury, cerebral edema, etc.
, and early combination of anti-SE drugs with multiple mechanisms is beneficial to terminate the seizures as early as possible and improve the prognosis of
patients.

(2) Clinical application: At present, the combined application of anti-SE drugs mainly involves levetiracetam, ketamine, midazolam, phenytoin, barbiturates, steinebol and immunomodulatory drugs, but the more successful ones are ketamine, midazolam, valproic acid, levetiracetam
.

Ketogenic diet

Mainly for patients with super RSE, the dose needs to be determined
according to the composition of the ketogenic diet.

Subhypothermia treatment

Subhypothermia has an inhibitory effect on seizures, which attracts the attention of clinicians and gradually applies it to patients with RSE who
are ineffective in drug therapy or relapse after withdrawal of drugs.

(1) Indications: mainly used in patients with RSE who still cannot control their seizures after treatment with the above recommended drugs or who
have been controlled by the above-mentioned drug treatment episodes, but relapse after withdrawal of drugs.

(2) Usage method: At the same time as sufficient anti-SE drug treatment, the intravascular cryogenic cooling system is used for sub-hypothermia induction or the use of cryogenic treatment instruments (ice blanket, ice cap) for hypothermia, etc.
, and the body temperature is gradually reduced to the target temperature (31 ~ 35 °C), the seizures cease seizures or EEG outbreak inhibition for 24 to 48 h, and the rewarming rate cannot be greater than 1 °C/d
.

(3) Onset time: Under normal circumstances, the onset of effect begins 3 to 48 hours after reaching the target body temperature, and a wide range of inhibition manifestations
can be seen on EEG at this time.

(4) Precautions: (1) EEG monitoring is required during sub-hypothermia induction, treatment and rewarming, and there is no recurrence after rewarming, anti-SE drugs can be withdrawn, and if necessary, they can be changed to oral anti-seizure drugs; (2) When there is a chill during the sub-hypothermia induction process, it is necessary to stop the sub-hypothermia treatment and re-warm it at the same time; (3) Continue to use anti-SE drugs (such as phenobarbital, midazolam, etc.
) in the process of subhypothermic treatment; (4) When the temperature is less than 30 °C, it is easy to have ventricular fibrillation, coagulation dysfunction, venous thrombosis and so on
.

Treatment of electroconvulsion

(1) Indications: Treatment of ineffective super RSE
with the above methods.

(2) Electroconvulsive treatment parameters: There are two ways to determine the amount of electroconvulsive therapy: fixed dose and titration dose (gradually increase the dose).

The American Psychiatric Society recommends treatment with a titrated dose, that is, the initial charge of the minimum amount that can cause a seizure, and gradually increasing the power
.
The advantage of titration dosage is that the dose is individualized – the corresponding therapeutic dose is given according to the individual convulsion threshold, which not only guarantees the therapeutic effect but also minimizes the impact on
the patient's cognitive function.
The specific treatment SE parameters are shown in Table 1
.

Table 1

(3) How to use: (1) Place the electrode on both sides; (2) A set of continuous stimuli is composed of 3 consecutive single stimuli; (3) The selection of anesthetics may affect the effect of electroconvulsion; Because propofol can attenuate the hemodynamic response caused by electroshock and provide rapid recovery, it is more suitable for use with electroconvulsion, so in the United Kingdom, propofol has become the most commonly used anesthetic drug
for electroshock therapy to implement anesthesia.

(4) Precautions: The treatment method is relatively safe, the main complication is cognitive impairment, so the following matters need to be paid attention to when implementing electroconvulsive therapy: (1) assess the condition and obtain the informed consent of the patient and his family; (2) Anesthesia is carried out by professional anesthesia personnel, anesthesia can relieve the patient's nervousness and reduce the complications that may be caused by electrical shock, such as fractures and tooth, tendon, muscle damage, etc.
; (3) Adjust the electricity, time and frequency of treatment according to the patient's response to electroconvulsive therapy and possible complications; (4) When patients have heart failure, severe heart valve disease and arrhythmias, it can increase the risk of electroconvulsive therapy and cause cardiovascular complications, so it is necessary to closely monitor the duration of seizures, EEG performance, airway patency, vital signs and complications throughout the treatment; (5) Since electroconvulsive therapy can induce convulsive and non-convulsive SE, continuous EEG monitoring after electroconvulsive therapy is necessary
.
Due to the limited clinical use of electroconvulsive therapy SE, there is currently no agreed treatment plan
.

EEG guides the treatment of SE

The treatment of SE requires EEG guidance for the following reasons: (1) The International Anti-Epileptic Federation requires that in the treatment of SE, not only the clinical seizures of SE need to be terminated, but also the epileptoid discharge on EEG is required to be terminated at the same time, many patients with convulsive SE stop clinical seizures after taking medication, but consciousness does not recover, suggesting that it is possible to turn into non-convulsive SE, and it is necessary to increase the dose to completely control the occurrence of SE, at this time, EEG examination can find the presence of non-convulsive SE, Help clinicians develop further treatment plans
.
(2) In 2015, in the diagnostic criteria for non-convulsive SE proposed by the International Anti-Epilepsy Federation, epileptiform discharge was found to be one of
the criteria that must be met by EEG examination.
(3) Many anti-SE drugs do not take effect immediately after taking the drug, but need to be observed for a period of time to know the effect of the drug, thus bringing uncertainty to further treatment, but EEG examination is very sensitive to the response to drug treatment, and changes in EEG can be seen almost soon after the medication, which in most cases can reflect the efficacy of the drug
.
(4) After the termination of the SE attack, maintenance therapy needs to be maintained for a period of time, but the specific time is inconclusive, and the return of EEG to normal after medication is the basic condition for
stopping maintenance therapy.
(5) The non-termination of the SE attack after medication may be insufficient dose, or it may be that the patient is resistant, and the dual-frequency index EEG is close to or below 40% is the maximum tolerated dose of the patient, and it is not appropriate to increase the dose
of the drug.
Therefore, when using recommended drugs to treat SE, if necessary, EEG can be performed simultaneously to improve the effect of
drug therapy.

Compiled from: Chinese Association Against Epilepsy (CAAE, China Association).
PLA Medical Journal, 2022, 47(7): 639-646.