Persistent status epilepticus (SE) is a common neurological emergency with a high mortality and disability rate. According to foreign literature, the morbidity and mortality rate is 3%-33%. The mortality rate of SE in southwestern China is 15.8%. Early standardized drug treatment and systematic and comprehensive life support can prevent irreversible brain damage and important organ function damage caused by prolonged convulsions, and become the key to change the poor prognosis of SE.
I. Definition
Status epilepticus (SE): In 1981, the International League Against Epilepsy (ILAE) Classification and Terminology Committee defined SE as: a convulsive seizure lasting long enough, or repeated convulsive seizures without recovery of consciousness between seizures. 2001, the lLAE Classification and Terminology Committee modified the definition of SE as: a seizure lasting longer than the type seizure duration in most patients, or recurrent seizures in which central nervous system function does not return to normal baseline in the interictal period.
As clinical trials and basic research continued, the limit of SE seizure duration was gradually shortened from the earliest 30 min to the operational definition suitable for clinical application proposed by Lowenstein et al. i.e., each convulsive seizure lasting more than 5 min, or more than 2 seizures in which consciousness is not fully recovered in the interictal period.
Convulsive status epilepticus (CSE): CSE is the most acute and severe of all sustained seizure types, manifesting as sustained limb tonicity, clonus, or tonic-clonicity with impaired consciousness (including blurred consciousness, drowsiness, lethargy, and coma).
Subtlestatus epilepticus (SSE): a type of non-convulsive seizure continuity (non-convulsivestatus epilepticus (NCSE)), often occurs in the late stages of CSE seizures and manifests as varying degrees of impaired consciousness with (or without) microfacial muscles, oculomotor muscles, and The EEG shows persistent epileptic discharge activity.
Refractory status epilepticus (RSE): When adequate doses of first-line anti-SE drugs, such as benzodiazepines followed by another anti-epileptic drug (AEDs), fail to terminate the convulsive seizures and EEG epileptic discharges, it is called RSE.
Super-refractorystatusepilepticus (super-RSE): presented by Shorvon at the 3rd London I Innsbruck SE Symposium in 2011: When narcotic medication for SE exceeds 24h (including the process of narcotic maintenance or dose reduction), clinical convulsive seizures or EEG epileptiform discharges still cannot be terminated or recur, it is defined as super-RSE.
Recommendations
1. Lowenstein’s operational definition of SE is recommended for early initiation of initial treatment of AEDs (level A recommendation).
2) Recommend CSE definition to emphasize the importance of rapid treatment follow-up (level A recommendation).
3. Recommend SSE definition to enhance clinical observation and EEG monitoring and to guide subsequent drug therapy (level A recommendation).
4. recommend the definition of RSE to enhance pharmacological treatment and life support (level A recommendation).
5. Recommend the definition of super-RSE to explore effective treatment methods (Grade A recommendation).
II. Termination of CSE
The goal of treatment for CSE is to rapidly terminate clinical convulsive seizures and EEG epileptic discharges. a 1998 US multicenter randomized controlled trial (RCT) study that included 384 patients with CSE showed that lorazepam (0.1 mg/kg IV), or diazepam (0.15 mg/kg IV) followed by phenytoin sodium (18 mg/kg IV), or phenobarbital (15 mg/kg IV), or phenytoin sodium (18 mg/kg IV), with control rates of 64.9%, 55.8%, 58.2%, and 43.6% for the above four initial drug regimens, respectively, with similar control rates for lorazepam, diazepam injection followed by phenytoin sodium, and phenobarbital (P=0.12) (level 2 evidence).
A 2001 US multicenter RCT study that included 205 patients with CSE showed control rates of 59.1% and 42.6% for lorazepam (2 mg IV) and diazepam (5 mg IV), respectively (level 2 evidence).A 2006 Indian RCT study that included 68 patients with CSE showed that valproic acid (30 mg/kg IV) and phenytoin sodium (18 mg/kg IV) resulted in control rates of 66% and 42%, respectively (p=0.046) (level 2 evidence).
A 2011 Indian RCT study enrolling 79 patients with CSE showed control rates of 76.3% and 75.6% (P=1.00) for levetiracetam (20 mg/kg IV) and lorazepam (O.1 mg/kg IV), respectively (level 2 evidence).A 2012 US prehospital multicenter noninferiority study enrolling 893 patients with CSE showed that midazolam (20 mg/kg IV) and lorazepam (O.1 mg/kg IV) had control rates of 76.3% and 75.6% (P=1.00), respectively (level 2 evidence). RCT study showed control rates of 73.4% and 63.4% for midazolam (10 mg intramuscular) and lorazepam (4 mg intravenous), respectively (P<0.01), suggesting similar efficacy (level 2 evidence).
Alternative AEDs are available after failure of initial treatment with benzodiazepines. a 2007 Indian RCT study that included 100 patients who failed to control CSE with diazepam (0.2 mg/kg) 2 times intravenously showed control rates of 88% and 84% with valproic acid (20 mg/kg) and phenytoin sodium (20 mg/kg) intravenously, respectively (p>0.05) (Level 2 evidence).
A 2011 Chinese RCT study that included 66 patients who failed to control CSE with diazepam (0.2 mg/kg) administered twice intravenously showed that the control rates for valproic acid (30 mg/kg) maintained intravenously followed by intravenous pumping (1-2 mg.kg-1.h-1) and diazepam (0.2 mg/kg) maintained intravenously followed by intravenous pumping (4 mg/h) were were 50% and 56% (P=0.652) (level 2 evidence).
The 2010 European guidelines recommend lorazepam, or diazepam followed by phenytoin sodium, and the 2012 US guidelines recommend lorazepam, or diazepam, or midazolam, or levetiracetam, or phenobarbital, or valproic acid as the initial treatment.
Recommendations
1. Initial treatment is preferred to lorazepam 0.1 mg/kg (1-2 mg/min) intravenously. If lorazepam is not available, diazepam 10mg (2-5mg/min) followed by phenytoin sodium 18mg/kg (<50mg/min) intravenous infusion can be chosen. If phenytoin sodium is not available, either diazepam 10mg (2-5mg/min) IV followed by 4mg/h IV pump, or valproic acid 15-45mg/kg (<6mg. kg-1. min-1) IV push followed by 1-2mg. kg-1. h-1 IV pump, or phenobarbital 15-20mg/kg (50-100mg/min) Intravenous injection, or levetiracetam 1000-3000mg intravenously, or midazolam 10mg intramuscularly (when intravenous access cannot be established; Grade B recommendation).
2. If the preferred drug fails, other AEDs may be followed (level D recommendation).
Immediately after termination of CSE, the same or similar intramuscular or oral medications, such as phenobarbital, valproic acid, levetiracetam, clonazepam, etc., should be administered for transition; note that the replacement of oral medications should reach steady-state blood levels (5-7 half-lives), and intravenous medications should be continued for at least 24 h during this period. The dose should be gradually reduced according to the results of blood concentration monitoring of the replacement drugs (Grade A recommendation).
4. In addition, EEG monitoring is recommended during CSE treatment to guide drug therapy (Class A recommendation).
III. Discontinuation of RSE
Once the initial treatment fails, 31%-43% of patients will enter RSE, and 50% of them may become super-RSE. At this time, in addition to the immediate intravenous infusion of anesthetic drugs, the necessary life support and organ protection must be provided to prevent irreversible brain damage and vital organ function damage due to prolonged convulsions.
A systematic evaluation (retrospective cohort study or case report) of 193 patients with RSE in the United States in 2002 showed that the seizure recurrence rate (8%) was lower with pentobarbital (loading dose 13 mg/kg IV, maintenance dose 0.25-5.28 mg.kg-1.h-1) administered for 1-6 h than with midazolam (loading dose 0.2 mg/kg IV, maintenance dose 0.04-0.40 mg.kg-1.h-1) and propofol (loading dose 1 mg/kg) IV, maintenance dose 0.94-12.32 mg.kg-1.h-1 (23%; P<0.01);
The rate of seizure recurrence after 6 h of pentobarbital administration (12%) was lower than that of midazolam and propofol (42%; p<0.01); the rate of medication change (change to another AEDs after failure of preferred anesthetic treatment) was lower for pentobarbital (3%) than for midazolam and propofol (21%; p<0.01); the rate of seizure recurrence with a suppressive pattern of EEG after 6 h of anesthetic injection (4%) was lower than that of clinical convulsions only controlled seizure recurrence rate (53%; P<0.01) (level 2 evidence).
A 2011 Swiss RCT study that included 24 patients with RSE showed that propofol (loading dose of 2 mg/kg IV and continuous IV pump maintenance) and barbiturates (pentobarbital 5 mg/kg or thiopental 2 mg/kg IV and continuous IV pump maintenance) drugs targeting an EEG burst suppression (suppression of 5-l5s) pattern and lasting 36-48 h The control rates were 44% and 22%, respectively (P=0.40), and the difference in efficacy between the two drugs was not statistically significant (level 2 evidence).
EEG in a burst suppression pattern or isotonic pattern is often used as a target for depth of anesthesia, making continuous EEG monitoring particularly important (level 4 evidence). There are no studies on the choice of transition drugs after RSE termination.
Recommendations
1. midazolam (0.2 mg/kg IV, followed by continuous IV pumping of 0.05-0.40 mg. kg-1. h-1) or propofol (2-3 mg/kg IV, with the possibility of additional 1-2 mg/kg until seizure control, followed by continuous IV pumping of 4-10 mg. kg-1h-1; level B recommendation) is recommended.
2. Although pentobarbital has evidence of efficacy, it is not routinely recommended in view of adverse drug reactions (Grade A recommendation).
3. The recommended target for EEG monitoring is the cessation of EEG epileptiform discharges and maintenance for 24-48 h (Grade A recommendation).
4. Immediately after the termination of RSE, oral AEDs such as levetiracetam, carbamazepine (or oxcarbazepine), valproic acid and other single or combined medications should be administered. The replacement of oral drugs should reach steady-state blood concentrations (5-7 half-lives), and intravenous medication should be continued for at least 24-48h before the intravenous infusion of anesthetic drugs can be gradually reduced according to the blood concentration of the replacement drugs (Class A recommendation).
IV. Termination of super-RSE
Super-RSE is under active exploration and research because the commonly used anesthetic drugs cannot terminate convulsive seizures.
Ketamine anesthetics: It has been reported in the literature that ketamine was effective in 12 cases and failed in 8 cases of 20 patients with super-RSE (level 4 evidence). The greatest advantage of ketamine is the low adverse effects of cardiovascular depression, but there may be neurotoxicity (level 4 evidence). It can be tried when treatment with commonly used anesthetic drugs is ineffective or when serious cardiovascular adverse effects cannot be avoided.
Inhaled anesthetics: isoflurane or ether halothane has been reported in the literature to be effective in 27 and failed in 3 of 30 patients with super-RSE (level 4 evidence). The biggest advantage of isoflurane and ether halothane is that they are easy to control. They can be tried when treatment with commonly used anesthetic drugs is ineffective, provided that the risks of treatment, especially serious adverse effects such as neurotoxicity, are weighed (level 4 evidence).
Immunomodulators: corticosteroids (intravenous methylprednisolone 19 for 3-5 d) have been reported in the literature to be effective in 31 and failed in 6 of 37 patients with super-RSE (level 4 evidence), but their optimal dose, duration and efficacy are unclear; intravenous immunoglobulin (0.4 mg. kg-1. d-1 for 3-5 d) was effective in 43 patients with super- RSE, 10 were effective and 33 failed (level 4 evidence); plasma exchange (1.0-1.5 times the plasma volume, once every other day, 5-6 times in a row) was effective and 2 failed (level 4 evidence) in 14 patients with super-RSE. If immune-mediated mechanisms are considered to be involved in super-RSE, immunomodulatory therapy may be tried.
Hypothermia: A total of 10 adult cases of hypothermia for super-RSE have been reported, all of which were effective. The theoretical basis of hypothermia treatment is neuroprotection and reduction of cerebral edema. Hypothermia (31-35°C) requires narcotic drugs, and it is the combination of hypothermia (lasting 20-61h) and narcotic drugs that allows effective control of clinical convulsive seizures and EEG epileptiform discharges. Both hypothermia and anesthetic drugs are associated with risks of adverse effects such as cardiac arrhythmias, pulmonary infections, thrombosis, intestinal paralysis, acid-base and electrolyte imbalance, but these risks are manageable at mild hypothermia (32-35°C) (level 4 evidence).
Surgery: 36 surgical cases were reported, of which 33 were effective (level 4 evidence). Surgical treatment is not recommended prematurely and may be considered when medication is completely ineffective for 2 weeks. When multiple foci of epileptic origin are present in patients with RSE, surgical treatment must be done with caution.
Ketogenic diet: 15 children and 4 adults were reported to be effective on ketogenic diet treatment in 2003 and 2010, respectively (level 4 evidence). The usual approach is to fast for 24 h and then administer a 4:1 ketogenic diet while avoiding glucose (close monitoring of blood glucose, blood B-hydroxybutyrate and urinary ketone levels). The ketogenic diet is contraindicated in patients with pyruvate carboxylase and beta-oxidation defects. Concomitant use of ketogenic diet with corticosteroids may inhibit ketone body production, and concomitant use with propofol may result in fatal propofol infusion syndrome (level 4 evidence).
Recommendations
1. Combination of multiple treatments to control super-RSE, such as ketamine anesthesia and anesthesia with inhaled drugs (with the assistance of anesthesiology), mild hypothermia, immunomodulation, surgery, and ketogenic diet, is recommended, provided that the pros and cons are weighed (level C recommendation).
2. Combination therapy and surgery patients should be closely monitored in the neuro-intensive care unit (NICU) (Grade A recommendation).
V. Life support and vital organ protection
NICU care: A large number of clinical studies have shown that patients with CSE, especially those who fail initial benzodiazepine treatment, often have a variety of serious complications due to prolonged seizures, such as hyperthermia, hypoxemia, hypercapnia, pulmonary edema, cardiac arrhythmia, hypoglycemia, metabolic acidosis and rhabdomyolysis, etc.; also the application of AEDs or anesthetic drugs can cause a variety of drug The application of AEDs or anesthetic drugs can also cause a variety of adverse drug reactions, such as respiratory depression, circulatory depression, hepatic impairment and bone marrow suppression (level 2 evidence).
Therefore, it is necessary to strengthen the monitoring of vital signs, EEG, vital organ function, and life support and organ protection for CSE patients. Relevant guidelines have been recommended: admit CSE patients to NICU or ICU to enhance monitoring and treatment.
Brain function monitoring and protection: Patients with CSE may have atypical clinical seizures (twitch limitation and amplitude reduction) in the late stages of repeated convulsive seizures or be in NCSE status after clinical seizure control, which may still affect the prognosis. Therefore, continuous EEG monitoring is necessary to detect abnormal discharges in the brain. a 2010 US survey of neurology clinicians showed that 83% of 330 physicians used continuous EEG at least once a month, and the duration of continuous EEG monitoring was usually 24h.
Continuous EEG monitoring is highly advantageous in obtaining evidence of epileptic discharges, guiding adjustment of pharmacological treatment strategies, and especially in determining whether anesthetic drug doses are meeting EEG targets. a 2013 prospective cohort study in China that included 94 patients with CSE showed that after initial treatment for CSE, there was a recurrence of interictal epileptic discharges, periodic discharges, or NCSE when monitored by continuous EEG within 6 h tendency (level 2 evidence).
Therefore, all patients with CSE should have EEG monitoring completed in the shortest possible time, for at least 48 h. Monitoring must be continued even if AEDs are reduced to allow for timely adjustment of medications and to predict seizure recurrence. In addition, other cerebral protection measures such as reduction of cerebral edema must be reinforced.
Respiratory monitoring and protection: Several RCTs have confirmed that respiratory depression can occur in CSE patients during clinical seizures or initial AEDs treatment (5.5%-42.2%), and respiratory monitoring must be strengthened during drug administration, with tracheal intubation and mechanical ventilation if necessary (level 2 evidence). showed that both diazepam and phenobarbital can cause respiratory depression (5.2% and 13.0%) and require tracheal intubation and mechanical ventilation (level 2 evidence).
Patients with RSE or super-RSE are at increased risk of hospital-acquired pneumonia or ventilator-associated pneumonia due to prolonged periods of impaired consciousness and prolonged periods of tracheal intubation and mechanical ventilation as a result of persistent seizures and the use of continuous narcotics or AEDs, necessitating increased pneumonia control and pulmonary function protection. This leads to an increased risk of hospital-acquired pneumonia or ventilator-associated pneumonia, which necessitates improved pneumonia control and lung function protection.
Circulatory monitoring and protection: A 2012 US multicenter RCT of 893 patients showed that the incidence of hypotension was 2.8% (level 2 evidence) after initial AEDs in CSE patients, and a 2013 Chinese prospective cohort study of 101 patients showed that the incidence of hypotension was 7.9%-8.7% (level 2 evidence) after initial AEDs in CSE patients.
A 2011 Swiss study of 23 RCTs showed a 52.2% incidence of hypotension in RSE patients treated with anesthetics (level 2 evidence). Therefore, blood pressure must be monitored with either AEDs or anesthetic agents and, if necessary, with antihypertensive drugs.
Liver function monitoring and protection: A 2007 Indian study of 100 RCTs showed a 4% incidence of liver function abnormalities (increased alanine aminotransferase) in CSE patients treated with valproic acid (level 2 evidence). 2012 Indian study of 79 RCTs showed a 6.3% incidence of liver function abnormalities in SE patients treated with lorazepam (level 2 evidence).
A prospective cohort study of 101 patients in China in 2013 showed that the incidence of liver function abnormalities [elevated blood ammonia and/or alanine aminotransferase] in CSE patients treated with valproic acid and phenobarbital was 25% and 21.7%, but no case of hyperammonemic encephalopathy occurred (level 2 evidence). This suggests that monitoring and protection of liver function should be strengthened during drug administration.
Gastrointestinal function monitoring and protection: primary disease, post-ictal status and AEDs (or anesthetics) can trigger neurogenic gastrointestinal dysfunction. 2008 Australian clinical study of 36 critically ill patients showed that the incidence of gastric retention was 95% in patients with midazolam combined with morphine and 56% in patients with propofol (p<0.01) (level 2 evidence). Therefore, it is important to monitor the gastrointestinal motility status when applying anesthetics, control gastric residual <100 ml, and change nasogastric tube to nasoenteric tube feeding or parenteral nutrition support if necessary.
Bone marrow function monitoring and protection: A 2011 Chinese RCT of 66 patients showed that one case of myelosuppression occurred in CSE patients treated with valproic acid, but it gradually returned to normal 1 month after discontinuation without special treatment (level 2 evidence). 2012 Indian RCT of 79 patients showed that the incidence of thrombocytopenia in CSE patients treated with levetiracetam and lorazepam were l7% and 5% (level 2 evidence). Therefore, the peripheral blood picture must be monitored during drug administration, and the drug should be reduced or changed if necessary.
Monitoring and maintenance of the internal environment: Patients with CSE frequently present with disturbances in the internal environment, such as respiratory or metabolic acidosis (35%), hyperazotemia, hyperkalemia, hyponatremia, hypoglycemia or hyperglycemia, which not only directly cause neuronal damage but also other multi-organ functional damage. Therefore, it is important to monitor and maintain acid-base and electrolyte balance.
Usually metabolic acidosis improves rapidly with the termination of the attack, so premature application of sodium bicarbonate solution is not emphasized. However, in patients with continuous massive intravenous infusion of barbiturates or anesthetics with propylene glycol or methanol as the solvent, once high anion gap acidosis occurs, the possibility of propylene glycol or methanol toxicity should be considered and the drug must be stopped or changed.
Temperature monitoring and control: Patients with CSE are often accompanied by hyperthermia and result in neuronal damage and functional impairment of multiple organ systems. Therefore, core (bladder or rectal) temperature monitoring is necessary to guide the implementation of body surface cooling or intravascular hypothermia.
Blood concentration monitoring and guidance: When available, drug blood concentration monitoring should be performed in patients receiving intravenous AEDs. If the blood concentration is outside the reference range, clinical and laboratory test changes should be noted, possible adverse drug reactions should be monitored, and timely treatment should be provided.
Recommendations
1. Patients with CSE should be monitored and treated more intensively during the initial treatment in the emergency department; after the initial treatment fails, they should be admitted to NICU as soon as possible (Class A recommendation).
2. After the initial treatment of CSE patients, continuous EEG monitoring is required for at least 6 h to detect abnormal brain discharges or NCSE; for RSE patients, continuous EEG monitoring is required for at least 24-48 h during anesthetic treatment; for SE and RSE patients, continuous EEG monitoring is required during AEDs or anesthetic dose reduction; the purpose is to adjust the treatment plan in a timely manner (Grade B recommendation).
3. Strengthen other cerebral protection measures, especially the monitoring of cerebral edema and the rational application of cranial pressure-lowering drugs (Grade A recommendation).
4. Patients with CSE should be monitored for respiratory function, such as respiratory movements (frequency, amplitude and rhythm), partial pressure of end-expiratory carbon dioxide (in patients with endotracheal intubation), pulse oximetry and arterial blood gas, etc. If necessary, tracheal intubation and/or mechanical ventilation should be performed; the prevention and treatment of pneumonia should be strengthened (Grade A recommendation).
5. Patients with CSE should be monitored for circulatory function, especially blood pressure, and given vasoactive drug support therapy if necessary (Class A recommendation).
6. Patients with CSE should be monitored for liver function and treated with blood ammonia and transaminase lowering drugs if necessary (Grade B recommendation).
7. Patients with CSE should be monitored for gastrointestinal function, especially gastrointestinal motility, and be given nasal enteral tube feeding or parenteral nutrition support if necessary (level B recommendation).
8. Patients with CSE should be monitored for bone marrow function, and medication should be reduced or changed if necessary (Grade B recommendation).
9. Patients with CSE should be monitored in the internal environment to maintain water and electrolyte balance; water restriction and/or hypertonic salt supplementation should be provided for common hyponatremia, but the rate of increase in plasma osmolality should be controlled to avoid osmotic encephalopathy; premature application of sodium bicarbonate is usually not required to correct acidosis, but for acidosis caused by propylene glycol or methanol poisoning, the drug should be stopped or changed (Grade D recommendation).
10. Core (bladder or rectal) temperature monitoring is required in patients with CSE to guide the implementation of surface cooling or intravascular cooling (Grade D recommendation).
11. When available, AEDs blood concentration monitoring can be performed for CSE patients to guide the rational use of medication (Grade D recommendation).
VI. Prognosis follow-up
In 2001, a multicenter RCT of 205 patients with CSE in the United States showed that 9.3% died during hospitalization and 16.9% were discharged with neurological sequelae (level 3 evidence). 2011, an RCT of 66 patients with CSE in China showed that 10.6% died during hospitalization and 25.8% were discharged with symptomatic epilepsy (level 3 evidence).
An RCT of 79 patients with CSE in India in 2012 showed that 30.3% of patients died during hospitalization (level 3 evidence). Therefore, there is a need to follow up the prognosis of CSE patients, to explore the factors affecting prognosis, and to make recommendations to improve prognosis.
Recommendations
Immediate or long-term prognostic assessment of patients with CSE to explore factors affecting prognosis (level B recommendation)