Management of Status Epilepticus (PART 3)

ANESTHETIC CONSIDERATION IN SE:(1)
After all standard therapy has failed or has been determined to have unacceptable side effects most neurology textbooks recomend consulting an anesthesiolo
gist for administration of general anesthesia to manage SE.Under these situations what anesthetic should be given ?
Unfortunately no controlled clinical studies have been conducted to adequately answer this question.
Anesthetic drugs that have been used successfully to stop SE include barbitutates,benzodiazepine,propofol,etomidate ketamine,isoflurane,enflurane,and halothane. 
If general anesthesia is needed to manage SE a patient outcome is thought to corelate more with the underlying diseases than the success in terminating seizures.

One factor in this is the delay in beginning general anesthesia caused by the need to first try less potent drugs and the logistic problems in starting an anesthetic in an intensive care unit.
Prolonged used of high dose of barbiturate (i.e.for days or weeks) has been associated with barbiturate tolerance which may exacerbate the underlying seizure problem.
In one case report,isoflurane was used to facilitate the withdrawal of barbiturate.In addition,the neurochemical effects of such prolonged anesthetic used can result in substantial increases in brain glycogen after only a few hours. Moreover the potential for prolonged volatile anesthesia to be organotoxic or to induce tolerance is unknown.

The effects of isoflurane,thiopental,ketamine and midazo 
lam were assessed in rats undergoing mercaptopropionic acid induced or flurothyl induced seizures. 
Midazolam resulted in less damaged in the substantia nigra after seizures.
No protective effect was suggested with isoflurane or thiopental and although a protective effect was suggested with ketamine,it was statistically unsignificant.  
Unfortunately this study revealed nothing about the anes
thetic effects or seizure induce damage in the lymbic system.The ketamine data however are supported by other reports of anticonvulsant or neuroprotective of ketamine in the lymbic system during seizures in rodents. 
For the reasons previously given the therapeutic approach in choosing an anesthetic agent for SE should first involve increasing dosis of benzodiazepine or barbiturate. 
Only after this therapy failed should volatile anesthetic drugs be considered.

Volatile anesthetics have the advantage of allowing continuous realtime titration to maintain a spesific blood anticonvulsant level based on entidal gas monitoring.
In one patient the monitoring of end tidal volatile anesthetic concentration facilitated titration of the anti
convulsant anesthetic against EEG.
In another patient,isoflurane use facilitated withdrawal of a prolonged barbiturate infusion on which the patient was thought to be dependent.
Thus volatile anesthetics may have a role in closely titrating anticonvulsant therapy for seizures in situation where a general anesthesia is to use as little as possible while observing the patient closely for cessation of seizure and for hemodynamic compromise.

Such patient must be intubated and mechanical ventilated .
Optimally continuous EEG shoul be monitored through anesthetic procedure.If thiopental is used 50 to 500 mg iv can be given as a loading dose in adult,followed by an iv infusion,the infusion rate initially should be higher
and then should be decreased as indicated by EEG.
After the loading dose the infusion rate could be set initially at 500-1000 mg/h and then decreased as indicated to the lowest rate feasible.
Repeated boluses,100-500 mg,might be needed initially to mantain close titration.
If isoflurane is used it should be started at 0,2-0,3% inspired concentration (6L/min gas flow initially) and inreased over 10 to 20 min as indicated by EEG and hemodynamic tolerance.

Determining the end point to guide drug titration can be difficult. For example,burst occuring within a burst suppression pattern on EEG can resemble epileptic discharges.
The decision about seizure control and EEG interpretation should be jointly with the refering neurologist or epileptologist.
After seizures are controlled and if the source is still unclear reversible causes should be sought and corrected,
after which,anesthesia should be stopped. 
Otherwise the anesthetic dose should be decreased periodically to permit assessment. 
If seizures continue to recur on anesthetic discontinuation the next decision is wether to continue anesthesia considering the many unknown effects,bioethical concerns and logistic and economic issues of prolonged anesthetic administration compared with drawing life support. Nothing,the trend toward end tidal concentrations at which seizures recur,a real time seizure thresold,over such 
assessment may contribute to such decision.

Summary :
Status epilepticus can be defined as a condition in which prolonged or recurrent seizures or epileptic events persist for more than 30 minutes.
SE is most often seen with drug withdrawal (including antiepilepticmedication and alcohol),drug intoxication
metabolic disarray and structural lesion from stroke,tumor,
abscess and trauma.

Morbidity and mortality from SE are related to three factors 
1.the damage to the CNS caused by the acute insult 
    precipitating the SE.
2.systemic stress from repeated seizures.
3.the injury from repetitive electrical discharges with the 
   CNS.

The most important clinical factors determining outcome are etiology, and the time from onset of SE until treatment is initiated.
The worst prognosis is found in those in whom status results from a serious intracranial process such as encephalitis, 
stroke or cerebral hemorhage.The best prognosis is seen in patients without structural lesions.

Generalized convulsive status epilepticus is considered  
a neurologic emergency.
To prevent brain damage seizure must be stopped as soon as possible optimally within 30 minutes of onset.
Initial treatment of SE starts with basic life support.
In addition the management of SE is best carried out using a predetermined protocol.
After all standard therapy has failed or has been deter mined unacceptable side effects neurology textbooks recomend consulting anesthesiologist for administration of general anesthesia to manage status epilepticus.

Reference :
1.Koffke Andrew W et all: Status Epilepticus,Anesthesia for 
   Epileptic Patients ;Cottrell E James;Anesthesia and 
   Neurosurgery;4th edit,Mosby Company,St Louis, 
   London,Philadelphia,2001,pp 477-8.

2.Trop Davy,Oliver Andre:The Problem of Status Epilepti
    cus,Albin S M;Textbook of Neuroanesthesia ,The McGraw 
    Hill Company,Newyork,1997,pp.684-7.

3.Chang JW,Bleck P Thomas:Status epilepticus;Stone DJ
   Sperry JR;the Neuroanesthesia Handbook,Mosby,St louis
   Baltimore,1966.pp.452-5

4.Namara MC Brian,Boniface J Simon:The EEG in Status   
   Epilepticus;Matta F Basil;Textbook of Neuroanesthesia 
   and Critical Care,Greenwich Medical Media Ltd,London
   2000,pp.78-80.

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Management of Status Epilepticus (PART 2)

MANAGEMENT OF TONIC- CLONIC  SE:(1,2)
Time from initiation
of observation and
treatment (min)          Procedure
=================================================
        0                         Assesss cardiorespiratory function
                                   as the presence of tonic clonic sta
                                   tus is verified.If ensure of diagnosis
                                   observe one tonic-clonic attack and
                                   verify the presence of unconcious
                                   ness after the end of the tonic clo
                                   nic attack.Insert oral airway and ad
                                   minister 02,if necessary.Insert an in
                                   travenous catheter.Draw venous 
                                   blood to determine anticonvulsant
                                   levels,glucose,BUN,electrolytes,and
                                   complete blood count stat.Draw ar
                                   terial blood for stat pH,PO2,PCO2,
                                   HCO3-.Monitor respiration,blood 
                                   pressure,and electrocardiograph.
                                   If possible monitor encephalograph.


        5                         Start iv infusion with NS contain- 
                                   ing with B complex. Give a bolus    
                                   injection of 50 ml of 50% glucose.


     10                          Infuse 1 mg lorazepam over 5 mi  
                                  nutes also give fosphenytoin to a
                                  total of 17 mg/kg(level >20 mcg
                                  per ml). If hypotension develops
                                  slow infusion rate.Phenytoin 50
                                  mg/ml in propyleneglycol may be
                                  placed in a 100 ml volume control
                                  set and diluted with normal saline.     
                                  the rate of infusion should be 
                                  watched. Alternatively phenytoin  
                                  may be injected slowly by iv.


    20                         If seizures persist give 1mg lorazepam 
                                 intravenously.


    30                         If seizures persist consider pseudo 
                                seizures if no CNS infection or   
                                trauma.Otherwise, phenobarbital 20 
                                mg/kg iv no faster than 100 mg/min  
                                until seizures stop or to a loading of 20 
                                mg/kg(level > 40 mcg/ml).


  60                          If seizure continue, general anesthesia  
                               with pentobarbital is instituted.


120                          If SE continue a neurologist and 
                               anesthesiologist with expertise in SE    
                               should be consulted. Advice from a 
                               regional epilepsy center on the 
                               management of intractable SE also 
                               should be sought Push pentobarbital      
                               until seizures stop or hypotension 
                               arises.With cessation of seizures if
                               still twitching assess EEG to rule out
                               subtle SE.


Generalized convulsive SE is considered a neurologic emergency.
Treatment to secure the airway, provide oxygen,and maintain circulation must be initiated within the first fiew minutes to prevent complications such as hypoxaemia,
systemic hypertension,tachydysrythmia.


Protocols for the treatment of convulsive SE remain somewhat individualized by institution and specialty.
Recent trends have pushed aggressive treatment beginning as soon as 10 minutes into continuous convulsive state. 
In practice this intervention can rarely be effected except in hospital. One of many approaches to control SE is shown as mention above. 
This protocol reflects the current widespread use of lorazepam titrated to effect (0,03 to 0,22 mg/kg) as a subtitute for diazepam.
Parke Davis has withdrawn phenytoin(Dilantin) in favor of the prodrug fosphenytoin(Cerebyx).This a water soluble preparation with pH of 9 is converted in 15 minutes to the active drug phenytoin by tissue phosphatases. It is equally as effective as phenytoin but without complications of the propyleneglycol solvent and higher alkalinity (pH 12).
It can be delivered intramuscularly and more stable in the iv form but it can also precipitate hypotension if adminis-
tered too rapidly.


Phenobarbital as alternative drug when seizure persist after lorazepam. Physicians are using thiopental much earlier in the treatment of SE when phenobarbital is not available.
When phenytoin and phenobarbital are ineffective, a benzodiazepine is often suggested. Midazolam and diazepam have a shorter onset time than lorazepam although lorazepam generally has a longer duration of action with a lower likelihood of severe respiratory depression making it the preferred agent of some clinicians.


Diazepam is the fastest onzet (1-3 minutes) and hystoricaly was the treatment of choice because is known as the fastest  medication to terminate seizures. However because of its lipholicity diazepam has a very short duration in CNS (10-20 min). For this reason lorazepam has replaced diazepam as the drug of choice. Its onset in only slower (2-3 min) but its anticonvulsant action typically last for more than 4 hours.
Diazepam has been reported to be effective rectally, and midazolam to be effective intramuscularly and intranasally in children.
If seizures continue to be refractory to treatment with the previously noted drugs, pentobarbital  usually can be used some times thiopental.


Alternatively,volatile anesthetics can also be used. 
Intravenous valproate (depakene) is now available which being tried in refractory status. Any of the other non iv formulated AEDs can be administered via nasogastric tube.
Propofol has been used in ambulances for patient refractory to iv benzodiazepine, given in 30 mg boluses every 30 seconds until the seizure are terminated.There may be a future role for alpha 2 agonist therapy as such drugs become clinically available. 
Dexmedetomidine confered brain protection in an animal
seizure model.


Other protocol for tonic clonic generalized SE based on stage :


Stage             General measures            AEDs  Usual route of adm
Premonitory   Continued neurolo           Diazepam 10mg iv bolus                                                                
                     gic observation,dia         max 5mg/min
                     agnostic SE by ob           Lorazepam 4mg iv bolus                                       
                     serving continued           max 2mg/min                                                    
                     seizure activity of          Midazolam 5mg iv bolus                                                                                               
                     one additional sei           max 4m/min 
                     zure.                             Paraldehyde 5- 10 ml in
                                                         5- 1 ml water or oil
                                                         by rectal First line


Early              Ensure adequate           Diazepam 10mg iv bls
(0-30 mins)     cardiorespiratory          Lorazepam 4- 8mg iv
                     function,iv line,ad-             
                     minister 02,initiate      Second line
                     regular ECG,and BP      Midazolam  5-10 mg iv
                     monitoring,draw         Phenytoin 15-18 mg/kg
                     blood for emergen-     iv loading                  
                     cy investigations,in-    dose(max.               
                     tubation may be          50mg/min.
                     considered.                Paraldehyde solution 4%                                        
                                                      in saline,50-100ml/h                                                                                  
                                                      iv solution
                                                      Lidocaine:iv bolus and
                                                      short infusion.


Established     Set second iv line         First line                 
                     (large veins)admi-        Phenytoin repeate                        
                     nister thiamine 100       7mg /kg iv.                                
                     mg iv and glucose         Phenobarbital                                    
                     D50W-50 ml iv,           10-20 mg/kg iv         
                     treat acidosis,estab      loading dose                                         
                     lished etiology,admis-  (<100mg/m)
                     sion to ICU,intubation   second line        
                     ICU,intubation has to    Diazepam iv infusion       
                     be considered,EEG/     Midazolam iv infusion
                     ECG monitoring.          Paradeldehyde iv infusion


Refractory   Full anesthesia needed    First line
(>120 min)   EEG/ECG monitoring,ar-  Pentobarbital iv/infus
                   terial line,initiate pres-   Propofol iv/infusion           
                   sor therapy when requi-        
                   red monitoring of AEDs    Second line
                   levels intracranial pres-    Isoflurane inhalation      
                   sure monitoring where 
                   appropriate.


In a patient who is actively seizing a lateral position may help prevent aspiration.The choice of iv fluids should include normal saline if phenytoin will be used because phenytoin will precipitate in glucose containing solution 


After 8 mg of lorazepam if seizures have not been aborted
use of another anticonvulsant medication is indicated.
If benzodizepine are effecive in seizure control further seizures need to be prevented with a long acting anticonvulsant.


A loading dose of phenytoin is 18-20 mg /kg ,even at the recomended rate of administration (50mg/min),hypotension is the most common side effect and mandates decreasing the infusion rate.


to be continued

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Management of Status Epilepticus (PART 1)

DEFINITION:(1,2)
Status epilepticus(SE) is a condition characterized by an epileptic seizure that are so frequently repeated or so prolonged as to produce a fixed and lasting epileptic condition.
Clinically this should be interpreted as any patient who has convulsive activity for more than 30 minutes or who has a 30 minutes of repetitive seizures without rousing to full awareness and clear mental status.
The 30 minutes interval has come from recent animal and human studies that show significant neuronal damage occuring after this time.


Therefore,to prevent brain damage, seizure should be terminated as soon as possible optimally within 30 minutes of onset.
Repeated events associated with impaired conciousness should be considered to represent SE when the recurrence rate does not permit return of conciousness. Non convulsive SE can be considered "electromechanical dissociation" of the CNS where electrographic seizures have no overt clinical manifestation except a diminished mental status.


EPIDEMIOLOGY AND ETIOLOGY:(2,3)
It occurs more frequently in children and in the elderly and in patients with structural cerebral  pathology.The most commonly reported form of SE is tonic-clonic (or convulsive status),which accounts for about 40 to 50% of the total. In the USA alone,convulsive status affects more than 50.000
people each year and in a great proportion of patients the episode of SE represents the initial manifestation of their epilepsy (12 to 18%).


SE occurs relatively frequently during the neonatal period often due to metabolic infectious disorders.It is more common in mentally retarded patients probably because of diffuse cerebral abnormality. The annual incidence of SE in general population is estimated to be about 450 to 650 cases per 1000.000 persons in the USA and SE accounts for
1 to 5% of all hospital admissions for epilepsy.


The frequency of status is greatest in children and most episodes occur before 5 years age.In the first year 75% of episodes of SE were in the context of an acute illness whereas this number falls to 28% in children over 3 year of age.In older children and adults frequent causes of SE
include poor anti epileptic drugs compliance,or drug withdrawal (31%),ethanol related status(28%),drug toxicity or abuse and withdrawal(9%) CNS infections(8%),metabolic disorders(14%),cerebrovascular diseases(10%),cerebral tumor(7%),trauma(10%),fibrile SE(12%),almost exclusively found in children.No etiology is identified in about 20% of events resulting in a diagnosis of idiopathic or cryptogenic SE.


SE can be devided in stages :(1,2)
Premonitory stage    
Usually in patients with established  epilepsy. May last several hours. 


Early status 
This is the stage where(0-30 min)mechanism compensate
for the greatly enhanced metabolic activity(adaptative
or early compensated phase).                                          


Established status
Defines as status that has continued (30-120 min) for 30
minutes in spite of early stage treatment.Physiologic decompensation has begun (maladaptative or late decompensated phase).


Refractory status
Seizures continue after initiation of (>120 min) therapy
Prognosis is worse and there is a high mortality.                    


PATHOPHYSIOLOGY OF SE:(1)
It has been noted that during tonic clonic SE especially motor seizures are frequently restricted in their distribution. In addition focal or lateralized convulsive activity does not necessarily indicate that a localized structural lesion is responsible for the status.
At later stages in the sequence of events,motor activity diminishes or even disappears.Therefore,the end stage may consist of ongoing epileptiform discharges recorded by EEG without motor accompaniment or a form of electromecha-
nical discociation between motor events and brain dischar-
ges.Status epilepticus both convulsive and non convulsive can lead lifethreatening,systemic,metabolic,and physiolo-
gic disturbances.These factors usually account for the poor prognosis associated with this disorder. Status itself,how 
ever,independent of metabolic and physiologic disturbances may lead to lasting brain dysfunction and prolinged status may result in permanent neuronal damages.


Tonic clonic status is often preceded by a premonitoring stage during which seizure activity progressively increases from its habitual levels, resulting in clinical deterioration. 
In patients who have an acute  symptomatic events however,status often starts abruptly.
Physiologic changes in tonic clonic SE are usually divided into two phases with an early compensated phase I, and a late decompensated phase II. The transition from early to late phase occurs often about 30 min, that is why that 30 minutes is the time limit usually defined to represent SE.


During early compensated phase cerebral matabolism is greatly increased due to seizure activity but physiologic mechanism are sufficient to meet the metabolic demands and cerebral tissue is protected from hypoxia or other metabolic damages.The major physiologic changes are related to the increased CBF and metablism(hyperglycae
mia,lacticacidosis), autonomic activity cardiovascular changes(including hypertension, tachycardia,cardiac arrhythmia,hypersecretion and  perspiration,hyperpyrexia vomiting, and incontinence).
Later, if not controlled the status enters a phase of decompensation during which the increased cerebral metabolic demands cannot be fully met,resulting in hypoxia,failure cerebral autoregulation,hypoglycaemia
cerebral edema,resulting in rising ICP;altered systemic metabolic patterns (electrolyte disturbance,metabolic and respiratoric acidosis,multiorgan failure)


THE EEG AND SE (4)
The EEG is important tool in the management of both convulsive or non vulsive SE.While SE is a medical emergency and treatment should not be delayed,if an EEG is not available,clinical examination alone may result
in misdiagnosis of SE for two reasons :
First,psychogenic status,is a common cause of diagnostic confusion.
In one study 20% of patients presenting to an emergency department of a tertiary referral centre with intractable convulsive movements had psychogenic seizures.


Second,non convulsive status is under recognized and patients with non convulsive status are often mislabelled as being confused or postical.


In sedated patients treated with general anesthesia continuous EEG monitoring allows immediate recognition and treatment of seizures.
Seizure activity increases CMRO2 and causes excitotoxic cell damage. Continuous EEG monitoring facilitates adequate seizure control without over treatment in SE and reduces this risk of excitotoxic cell damage.
Mortality in SE increases with the duration of seizures.
It is therefore reasonable to assume that early detection of subclinical seizures in the ICU reduces morbidity and mortality.
Where continuous EEG monitoring is not available it is reasonable to obtain an EEG daily while the patient remains unconcious and to consider performing an EEG before making significant alterations to therapy.
Also continuous EEG monitoring is essential to titrate medications to burst suppression.


to be continued

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