treatment of status epileptics,intensive therapy,2004

1. Trattamento dello stato di
male:
Il punto di vista del
rianimatore.
Claudio Melloni
Anestesia e Rianimazione
Ospedale di Faenza

2. Tossicità acuta da farmaci o brusca
sospensione
• Sindr.da astinenza:alcool(6% associate a
les.intracranica(40),Bdz,oppiacei (11)
• Abbassamento livelli plasmatici ,up regulation del
sist.glutamergico.... (46)
• Occasionalmente le convulsioni da
astinenza potrebbero costituire la I
indicazione della dipendenza

3. Convulsioni indotte da farmaci:1
• In general, medications rank low as precipitants
of seizures. The large Boston Collaborative Drug
Surveillance Program evaluating the records of
32,812 inpatients (ward and ICU) found druginduced seizures to occur in only 0.08% of the
group, or approximately 0.5% of patients with
neurologic side effects (20,47,48).
Nevertheless, drugs with convulsant properties
may precipitate seizures in high-risk inpatients
and thus be particularly a problem in the ICU
setting (49).

4. Schema delle modificazioni
neurofisiologiche:parte I
Aum richieste
O2 cerebrali
Aum CBF
Aum. Attività
autonomica
Aum PA
Aum glicemia
Sudorazione
Salivazione
iperpiressia

5. Schema delle modificazioni
neurofisiologiche:parte II
Fallimento
Autoregolaz.
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemica
Dissociazione
Elettro EEG/ meccanica convuls
Diminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richieste

6. Mortalità
• overall mortality 21%(Rochester)
– Logroscino G, Hesdorffer DC, Cascino G, Annegers
JF, Hauser WA. Short-term mortality after a first episode of
status epilepticus. Epilepsia 1997;38:1344-1349
– Most of these deaths (89%) occurred in those with an acute
symptomatic aetiology, especially anoxic encephalopathy or
cerebrovascular disease.
– When analysed for other factors, only age (>65 years) and
sex (male) contributed significantly to the risk of death; this
appeared to be independent of aetiology. In the overall
analysis, however, length of status epilepticus was not an
independent predictor of mortality. Whether it is the
underlying aetiology itself or the status epilepticus that has a
major influence on mortality cannot be determined from this
study.

7. Mortalità da CSE & NCSE
90
Generalized
SE
80
70
60
48 patients with
serious medical illnesses
but without prior epilepsy;
%
40
30
20
10
0
coma after
convulsive SE
critically ill elderly
50
10 elderly patients with
stroke, tumors,
head injury,
electroconvulsive therapy
, and metabolic derangements
3 died from infection.
42 pts
Epilepsy,
stroke
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994

8. Morbilità e mortalità
• Morte: 10 -35% (Hauser, 1983; DeLorenzo et
al., 1996)
• Morbilità cognitiva e neurologica :10 - 35%
(Hauser, 1983; Dodrill and Wilensky, 1990;
DeLorenzo et al., 1996; Cascino et al., 1998)
• Epilessia cronica (30% dei bambini che si
presentano inizialmente in status) (Shinnar et
al., 1992)
• SE ricorrente (15 - 20% dei bambini ) (Shinnar et
al., 1992).

9. Morbidità legata al trattamento:depressione
respiratoria
45
40
35
30
%
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
25
20
15
10
5
0
depr resp

10. Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs Irgantua
Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for
generalized convulsive status epilepticus. N Engl J Med 1998;339:792-8.
35
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
30
25
20
%
15
10
5
0
ipotensione
ipoventilazione
disturbi ritmo
cardiaco

11. prognosi

12. Prognosi:SE vs NCSE
• Necessità di una attenta stratificazione
• studies drawn from the intensive care setting
(Drislane and Schomer, 1994; DeLorenzo et al.,
1998; Litt et al., 1998) are faced with the
markedly greater task of determining the
selective consequences and morbidity of the
superadded insult of the epileptic electrical
activity combined with the medical and
neurologic problems that sent the patient to the
intensive care setting or resulted in coma in the
first place

13. Prognosi 2:
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
• 1. Generalized SE in nonconvulsing, well-oxygenated animals produces
brain damage (Wasterlain et al., 1993). In paralyzed, oxygen-ventilated
baboons with over 3 hours of electrographic seizure activity, there was
neuronal necrosis in the hippocampal neocortex even when systemic
complications and no convulsions were seen (Meldrum et al., 1973).
Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that
included infarction of the substantia nigra (Nevander et al., 1985).
• 2. Focal seizures can induce neuronal necrosis (Wasterlain et al., 1993).
Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical
stimulation of the afferent pathway for 2 to 24 hours (Sloviter, 1983) with
similar changes seen with intraventricular glutamate or aspartate injection
(Sloviter and Dempster, 1985).
• 3. Limbic seizures can cause brain damage: Cholinomimetics, kainic
acid, and other methods to produce limbic SE can result in neuronal
necrosis in the hippocampus, amygdala, piriform and entorhinal cortices, the
thalamus, lateral septum, substantia nigra, and neocortex (Olney et
al., 1974, 1983; Strain and Tasker, 1991).

14. La prognosi finale dipende dalla eziologia!!!
The possible relationships among seizure etiology,
nonconvulsive status
epilepticus, and outcome
. Most patients with complex partial status epilepticus (CP
have etiologies consistent with pathway [circled digit on
(strokes, anoxia/ischemia, head trauma, encephalitis)
rather than [circled digit two].
The best example of [circled digit two] would be a patient
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels.

15. Fattori che influenzano la prognosi nello
SE(anche NCSE)
• Causa dello stato
epilettico
• Durata dello stato
• Trattamento
• Età
• Effetti dannosi sistemici
metabolici e fisiologici
(Meldrum et al., 1973;
Simon, 1985)
• Danno cerebrale
secondario all’ insulto
acuto che induce SE
(Hauser, 1983; Barry et
al., 1993)
• Danno neuronale diretto
dovuto alla abnorme
attività elettrica del SE
(Meldrum et al., 1973;
Knopman et al., 1977;
Lothman, 1990)

16. Chin RFM,Verhulst L,Neville BGR,Peters MJ,Scott RC.
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care. Journal of
Neurology, Neurosurgery & Psychiatry. 75(11):15841588, 2004 .
• > 2 dosi o dosi inadeguate di BDZ
• Depressione respiratoria
• Trattati in emergenza extraospedaliera

17. complicazioni

18. Complicazioni sistemiche dello status epilepticus
SNC
cardiova Resp
s
metaboli
co
altro
Ipossia/anos
sia
IM
Apnea/ipopnea
Disidtrataz
MOF
Edema
Ipo/ipertens
Insuff resp
Disturbi
elettr.;ipoNa,ip
erK
DIC
Emorragia
Aritmie
Polmonite ab
ingestis
Acidosi metab
Rabdomiolisi
Trombosi
venosa
Arresto
Iprtens polm
Necrosi
tub.acuta
fratture
Shock
cardiogeno
EPA
Necrosi
epatica acuta
Embolia polm
Pancreatite
acuta

19. Complicazioni dello SE
• Durata convulsioni > 1 hr:predittore indipendente di poor outcome
(mortality odds ratio di quasi 10) (4).
• Convulsioni prolungate aumentano il rischio di danno neuronale:
–
–
–
–
–
Eccitotox
Accumulo intracellulare di Ca++ e apoptosi
Riorganizzazione sinaptica epilettogenica( e gemmazione)
Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
“ Particularly vulnerable to injury are the neurons within the
hippocampus, cerebral cortical mantle, and cerebellar Purkinje cells.
Selective neuronal loss has been described within the hilar area of the
dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged
seizures, leading to the development of chronic temporal lobe epilepsy
(6).”
• Manifestazioni autonomiche:morte improvvisa
–
–
–
–
DeLorenzo RJ. Status epilepticus: Concepts in diagnosis and treatment. Semin Neurol 1990; 10:396–
405.
Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;
35:27–34.
Payne TA, Bleck TP. Status epilepticus. Crit Care Clin 1997; 13 (1):17–38.
Sloviter RS. Status epilepticus-induced neuronal injury and network reorganization. Epilepsia 1999;
40:S34–41.

20. Complications of SE
• Aminoff MJ, Simon RP. Status epilepticus:
causes, clinical features and consequences in 98
patients. Am J Med 1980;69:657-666. Bibliographic
Links [Context Link]
• 25. Wasterlain CG, Fujikawa DG, Penix L, Sankar R.
Pathophysiological mechanisms of brain damage from
status epilepticus. Epilepsia 1993;34(1):S37-S53.
Bibliographic Links [Context Link]
• 26. Singhal PC, Chugh KS, Golati DR. Myoglobinuria
and renal failure after status epilepticus. Neurology
1978;28:200-201. Bibliographic Links [Context Link]
• 27. Fisher S, Zatuchni J, Greenberg J. Disseminated
intravascular coagulation in status epilepticus. Thromb
Haemost 1977;38:909-913. Bibliographic Links [Context
Link]

21. •
•
•
•
•
•
Neuroprotective effects of acidosis
???
some studies that suggest that hypoxia, acidosis and hypoglycaemia may be neuroprotective [28,29]. To
study these phenomena further, Sasahira and coworkers [30•,31•] looked at a rat model of status epilepticus
based upon repeated bicuculline injections, and using heat shock protein as an indirect measure of neuronal
injury. Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 7.55
to 7.17. This resulted in a shorter seizure duration and less neuronal damage [30•]. Using multiple regression
analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent
effect of acidosis [30•]. Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood
flow, and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on
receptors or transmitter release is unknown.
A further study from the same group [31•] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on
neuronal damage in the same model compared with normoxic controls. There was no difference in neuronal
injury detected, suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus. The
authors rightly conclude, however, that the implications of their findings for the treatment of status epilepticus
are unclear, as more severe hypoxia could result in additional ischaemic injury to the brain.
28. Blennow G, Brierley JB, Meldrum BS, Siesjö BK. Epileptic brain damage. The role of sysemic factors that
modify cerebral energy metabolism. Brain 1978;101:687-700. Bibliographic Links [Context Link]
29. Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates. Ischaemic cell change and its relation
to ictal physiological events. Arch Neurol 1973;28:10-17. Bibliographic Links [Context Link]
30. • Sasahira M, Lowry T, Simon RP. Neuronal injury in experimental status epilepticus in the rat: role of
acidosis. Neurosci Lett 1997;224:177-180. Bibliographic Links See [31•]. [Context Link]
31. • Sasahira M, Simon RP, Greenberg DA. Neuronal injury in experimental status epilepticus in the rat: role
of hypoxia. Neurosci Lett 1997;222:207-209. Bibliographic Links Thie paper and [30•] are excellent reports
considering the influence of physiological parameters on neuronal damage induced by status epilepticus.
[Context Link]

22. Effetti collaterali della fenitoina ev
• Lesioni dei tessuti molli,con o senza
stravaso:”Purple Hand,,> 40 casi ,con parecchie
amputazioni ( (Kilarski, 1984; Rao et al., 1988;
Hanna, 1992).
• Problemi al sito di iniezione Earnest et al. (1983):
30% su 200
• Ipotensione in > 25% dei paz.,con aritmie
– In 3/139 pazienti; 1 FA (velocità di infus 26 mg/min); 1
tachic sinusale ,1 allungamento tratto PR
– (Gellerman and Martinex, 1967; Goldschlager and
Karliner, 1967; Louis et al., 1967; Voigt, 1968).
• .

23. Allen FH, Runge JW, Legarda S, et al. Multicenter open-label
study on safety, tolerance, and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract]. Epilepsia 1994;35(Suppl 18):93
.
• Data have been published from 40 patients in status
epilepticus who received fosphenytoin at a mean infusion
rate of 92 mg/min, ranging from 24.7 to 111.3 mg/min).
Status epilepticus was terminated in 37 of 40 patients (85%)
within 30 min of receiving fosphenytoin. The rapid infusion
was well tolerated, with only mild or transient side effects.
Most of the side effects reported were attributable to the
pharmacologic effect of phenytoin and included dizziness,
nystagmus, and ataxia. Most patients in this trial received a
benzodiazepine before the infusion of fosphenytoin and no
adverse drug interactions were found.

24. Introduzione alla peculiarità
dell’ambiente intensivistico

25. Convulsioni in ambiente intensivo
• Sepsi
• Cause mediche :
• Anormalità metaboliche(30-35%) (11):
– Iponatremia,ipocalcemia,ipofosfatemia,ipoglicemia,uremia
– Alterazioni della osmolarità ,specie correzione acuta
• Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration
increased the amplitude of evoked early and late excitatory
postsynaptic potentials, a situation reminiscent of the generalized
convulsions that may follow acute reduction of glucose in diabetic
nonketotic hyperglycemia (42). :
– Ipoosmolarità induce increased nervous system excitability
by strengthening both excitatory synaptic communications in
neocortex and field effects among the entire cortical
population (41).

26. Problemi peculiari all’ambiente
intensivistico
•
•
•
•
•
•
Polifarmacologia
Insuff renale
Insuff epatica
Induzione enzimatica:
Inibizione enzimatica
Ipo/disprotidemie…..:farmaci altamente
legati alle prot plasmatiche

27. Trattamento dello stato di
male

28. Allora:
• Terapia immediata
• Aggressiva
• Supporto vitale di base:
• A:Airway
• B:reathing
• C:Supporto circolatorio

29. Status epilepticus:filosofia del trattamento
Disaccoppiamento
CMRO2/CBF
Glucosio
Tiamina 100 mg
Funzione resp
Funzione cardiocircolatoria
Supporto supernormale

30. Indagine conoscitiva su 127 TI NCH europee
Dauch WA, Schutze M, Guttinger M, et al. Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics. Zentralbl Neurochir 1996; 57:190–5.
Profilassi con anticonvulsivi post trauma cranioencefalico
60
mai
50
sempre
sec.indicazione
40
% 30
substantial cortical
injury:
20
cerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(14,15,17).
10
0
profilassi

31. Rischio convulsivo

32. Alldredge BK, Gelb AM,Isaacs S M,Corry MD,Allen F,Ulrich SK, Gottwald
MD,O'Neil N, Neuhaus JM, Segal MR,Lowenstein DH.
Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus.
New England Journal of Medicine. 345(9):631-637, August 30, 2001.
•
Background: It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus.
Methods: We conducted a randomized, double-blind trial to evaluate intravenous benzodiazepines
administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with
prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received
intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was
given if needed.
Results: Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71
received placebo. Status epilepticus had been terminated on arrival at the emergency
department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent)
than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds
ratio for termination of status epilepticus by the time of arrival in the lorazepam group as
compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds
ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with
the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as
compared with the placebo group. The rates of respiratory or circulatory complications after the
study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for
the diazepam group, and 22.5 percent for the placebo group (P=0.08).
Conclusions: Benzodiazepines are safe and effective when administered by paramedics for outof-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.
(N Engl J Med 2001;345:631-7.)

33. Alldredge BK, Gelb AM,Isaacs S M,Corry MD,Allen F,Ulrich SK, Gottwald
MD,O'Neil N, Neuhaus JM, Segal MR,Lowenstein DH.
Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus.
New England Journal of Medicine. 345(9):631-637, August 30, 2001.
randomized, double-blind trial
to evaluate iv bdz
admin. by paramedics
for the treatment of out-of-hospital status epilepticus.
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg),
lorazepam (2 mg), or placebo.
An identical second injection was given if needed.
60
50
40
% 30
20
lorazepam
10
diazepam
placebo
0
seizures stop
complications

34. Veterans Affairs Status Epilepticus
Cooperative Study Group, Treiman et al.
Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ,
et al. A comparison of four treatments for generalized convulsive
status epilepticus. N Engl J Med 1998; 339:792-798.
randomized, double-blind trial that compared the following four
regimens commonly used for the treatment of generalized
convulsive status epilepticus: diazepam followed by phenytoin;
phenytoin alone; phenobarbital; and lorazepam. Although the doses
and infusion rates chosen for study closely reflected common clinical
practice at the time the study began, the combination of lorazepam
followed by phenytoin (the preferred regimen of many neurologists)
was not included.
This is a large, well-controlled and important clinical trial. The major
limitation in its clinical relevance is the lack of inclusion of a regimen
consisting of lorazepam followed by phenytoin.

35. Veterans Affairs Status Epilepticus Cooperative
Study Group, Treiman et al.
primary outcome measure:
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment.
Coma con scariche
SE aperto
ictali EEG
2 o + convuls senza
ripresa di coscienza
diaz
Convuls continue = > 10 min
fenitoina
fenobarbital
fenitoina
lorazepam
fenitoina
????
lorazepam

36. Veterans Affairs Status Epilepticus
Cooperative Study Group, Treiman et al.
• !st treatment successful in 55.5% of patients with a verified
diagnosis of overt status epilepticus (n=384) and in 14.9%
of patients with subtle status epilepticus (n=134).
• Comparisons between the 4 treatments showed that
lorazepam was more effective than phenytoin alone in
patients with overt status epilepticus (treatment success in
64.9 versus 43.6% of patients, respectively);
• other treatment comparisons in the overt group, and all
comparisons in the subtle group were not significantly
different, however.
• There were no significant differences between treatments in
patient outcome, rates of recurrence of status epilepticus, or
return of full consciousness over the 12-h observation
period, or in the frequency of adverse cardiac, respiratory,
or hypotensive events.

37. Treiman DM, Meyers PD, Walton NY, et al. A
comparison of four treatments for generalized
convulsive status epilepticus. N Engl J Med 1998;
339:792-798.
Percentage of successful treatment
P 0.02
grey bars, overt patients; black bars, subtle patients

38. Alldredge, Brian K.a,b; Lowenstein, Daniel H.AC .Status
epilepticus: new concepts. Current Opinion in Neurology
12,1999: 183-190

39. Da Chapman,Anaesthesia 2004

40. Marik PE,Varon J. The Management of Status
Epilepticus. Chest. 126(2):582-591, August 2004
Status epilepticus is a major medical emergency associated
with significant morbidity and mortality. Status epilepticus
is best defined as a continuous, generalized, convulsive
seizure lasting > 5 min, or two or more seizures during
which the patient does not return to baseline
consciousness. Lorazepam in a dose of 0.1 mg/kg is the
drug of first choice for terminating status epilepticus.
Patients who continue to have clinical or EEG evidence of
seizure activity after treatment with lorazepam should be
considered to have refractory status epileptics and should
be treated with a continuous infusion of propofol or
midazolam. This article reviews current information
regarding the management of status epilepticus in adults.
.

41. Schema di Marik et al

42. Claassen J,Hirsch LJ, Emerson R G,Bates
JE, Thompson TB,Mayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 ,1036-1042
•
•
•
The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years. All patients were monitored with continuous EEG (cEEG). MDZ infusion rates
were titrated to eliminate clinical and EEG seizure activity; cIV-MDZ was discontinued once
patients were seizure-free for 24 hours. Acute treatment failures (seizures 1 to 6 hours after
starting cIV-MDZ), breakthrough seizures (after 6 hours of therapy), post-treatment seizures
(within 48 hours of discontinuing therapy), and ultimate treatment failure (frequent seizures that
led to treatment with pentobarbital or propofol) were identified.
Results: All patients were in nonconvulsive SE at the time cIV-MDZ was started; the mean
duration of SE before treatment was 3.9 days (range 0 to 17 days). In addition to
benzodiazepines, 94% of patients had received at least two antiepileptic drugs (AED) before
starting cIV-MDZ. The mean loading dose was 0.19 mg/kg, the mean maximal infusion rate was
0.22 mg/kg/h, and the mean duration of cIV-MDZ therapy was 4.2 days (range 1 to 14 days).
Acute treatment failure occurred in 18% (6/33) of episodes, breakthrough seizures in 56%
(18/32), post-treatment seizures in 68% (19/28), and ultimate treatment failure in 18% (6/33).
Breakthrough seizures were clinically subtle or purely electrographic in 89% (16/18) of cases and
were associated with an increased risk of developing post-treatment seizures (p = 0.01).
Conclusions: Although most patients with RSE initially responded to cIV-MDZ, over half
developed subsequent breakthrough seizures, which were predictive of post-treatment seizures
and were often detectable only with cEEG. Titrating cIV-MDZ to burst suppression, more
aggressive treatment with concurrent AED, or a longer period of initial treatment may reduce the
high proportion of patients with RSE who relapse after cIV-MDZ is discontinued.

43. Claassen J,Hirsch LJ, Emerson R G,Bates JE, Thompson TB,Mayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 ,1036-1042

45. Claassen J,Hirsch LJ, Emerson R G,Bates JE, Thompson TB,Mayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 ,1036-1042
33 episodes of RSE treated with cIV-MDZ
80 neurologic ICU over 6 years.
All patients were monitored with continuous EEG (cEEG).
70
60
50
% 40
30
20
10
0
prima
durante
dopo
no
n
se
iz
u
se
iz
ur
es
se
iz
u
bu
pe
pe
rio
rs
rio
ts
>1
di
di
re
re
up
c
c
2
s
s
ge
la
h/
0,
<3
pr
t.d
24
5n
0
es
12
di
is
m
si
sc
ch
in
h/
on
/2
ha
24
ar
4h
ge
rg
h>
0,
e
512
12
h
h
se
iz

47. Waterhouse, Elizabeth J. 1 2; DeLorenzo, Robert J. 1 3 4 2
Status Epilepticus in Older Patients: Epidemiology and
Treatment OptionsDrugs & Aging. 18(2):133-142, 2001
•
Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant
morbidity and mortality. The most widely accepted definition of SE is more than 30 minutes of either continuous
seizure activity, or intermittent seizures without full recovery of consciousness between seizures. SE is a major
clinical concern in the elderly population, both because it has increased incidence in the elderly compared with the
general population, and because of concurrent medical conditions that are more likely to complicate therapy and
worsen prognosis in elderly individuals.
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year. With
the anticipated growth of the elderly population, SE is likely to become an increasingly common problem facing
clinicians, and an important public health issue. The elderly have the highest SE-associated mortality of any age
group at 38%, and the very old elderly (>80 years of age) have a mortality of at least 50%. Acute or remote stroke
is the most common aetiology of SE in the elderly. Nonconvulsive SE (NCSE) has a wide range of clinical
presentations, ranging from confusion to obtundation. It occurs commonly in elderly patients who are critically ill
and in the setting of coma. Electroencephalogram is the only reliable method of diagnosing NCSE.
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity. Most treatment protocols
call for the immediate administration of an intravenous benzodiazepine, followed by phenytoin or fosphenytoin.
Recent studies suggest that when this initial treatment of SE fails, little is gained by using additional standard
drugs. General anaesthetic agents (such as pentobarbital, midazolam, or propofol) should be expeditiously
employed, although these treatments have their own potential complications. Intravenous valproic acid is a recent
addition to the armamentarium of drugs for the treatment of SE, with a low risk of hypotension, respiratory
depression and hypotension, making it a potentially useful drug for the treatment of SE in the elderly. However,
further information is needed to establish its role in the overall treatment of SE.

48. Waterhouseet al.
Status Epilepticus in Older Patients: Epidemiology and
Treatment OptionsDrugs & Aging. 18(2):133-142, 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico

50. Ns proposta
Lorazepam
0.1 mg/kg
Propofol
1-2 mg/kg
Miorilassante solo
Per intubazione!
Inf cont 3-10 mg/kg/h
Pentobarbital dose carico,poi 0.1-0.4 mg/kg/min ????
Midazolam:0.1 mg/kg
Inf cont 0.01-0.05 mg/kg/h

51. fenobarbital
• 10-20 mg/kg i.v.
– Eccessiva sedazione
– Depress.resp
– Ipotensione
– Interaz farmacol
– Hl >48 hr………

52. tiopental
•
•
•
•
cumulativo
Inotropo neg….
Pentobarbital???
immunosoppressione

53. propofol
•
•
•
•
Vantaggi cinetico/dinamici:
Titolazione continua possibile
TCI:quale livello ???
Dosi; 1 mg/kg,ripetibile dopo 5’– Inf.cont 2-10 mg/kg/h
• Rapida emergenza:finestra neurologica.evitare la
brusca sospensione!!
• + rapido controllo delle convuls > barbiturici
–
Stecker. MM, Kramer. TH, Raps. EC, O'Meeghan R, Dulaney. E, Skaar. DJ. Treatment of
refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;
39: 18-26

54. AG
• Non ci sono dati che indichino quanto a
lungo i paz debbano rimanere senza
convuls prima di poter alleggerire il piano
di AG:24 h????96h ???(Treiman DM. Convulsive status
epilepticus. Current Treatment Options in Neurology 1999; 1: 359-69)
• Anest
alogenati:isoflurano>sevoflurano>desflurane
•
•
•
..
Ma :vaporizzatori
Contaminazione ambientale
Costi…..

55. Studi comparativi:1
• Midazolam> tiopental
–
Lohr A Jr, Werneck LC. Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese]. Arq Neuropsiquiatr 2000; 58:282-287.
– non-randomized comparison
– of historical data (thiopental) and prospectively
acquired data (midazolam) .
– Midazolam was no more often effective than
thiopental, but was associated with less cyanosis and
less respiratory distress in this study of 50 children.

56. Studi comparativi:2
Valproato
• . Valproate,(iv”Depacon”), has been used for the treatment of refractory SE
in children and myoclonic SE
– Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus.
Neurology 2000; 54:1201
– Uberall MA, Trollmann R, Wunsiedler U, Wenzel D. Intravenous valproate in
pediatric epilepsy patients with refractory status epilepticus. Neurology 2000;
54:2188-2189. ]
•
Valproate has also been used in SE in the elderly, and appears to be safe,
even in the presence of cardiovascular instability and hypotension: no
significant change in blood pressure, pulse or the need for vasopressors in
13 patients with SE and hypotension given a loading dose of 14.7-32.7
mg/kg Depacon intravenously
– Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients
with status epilepticus. Neurology 2000; 55:722-724
• However, there is a case report of severe hypotension in an 11-year-old
child after treatment of SE with 30 mg/kg intravenous valproate
– White JR, Santos CS. Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus. J Child Neurol 1999; 14:822823.

57. FINE
Perché non ne possiamo
più………..