Trattamento dello stato di
male:
Il punto di vista del
rianimatore.
Claudio Melloni
Anestesia e Rianimazione
Ospedale di F...
Tossicità acuta da farmaci o brusca
sospensione
• Sindr.da astinenza:alcool(6% associate a
les.intracranica(40),Bdz,oppiac...
Convulsioni indotte da farmaci:1
• In general, medications rank low as precipitants
of seizures. The large Boston Collabor...
Schema delle modificazioni
neurofisiologiche:parte I
Aum richieste
O2 cerebrali

Aum CBF

Aum. Attività
autonomica
Aum PA
...
Schema delle modificazioni
neurofisiologiche:parte II
Fallimento
Autoregolaz.
cerebrale
Diminuz
CBF
Aum
ICP

Ipotensione
s...
Mortalità
• overall mortality 21%(Rochester)
– Logroscino G, Hesdorffer DC, Cascino G, Annegers
JF, Hauser WA. Short-term ...
Mortalità da CSE & NCSE
90

Generalized
SE

80
70
60

48 patients with
serious medical illnesses
but without prior epileps...
Morbilità e mortalità
• Morte: 10 -35% (Hauser, 1983; DeLorenzo et
al., 1996)
• Morbilità cognitiva e neurologica :10 - 35...
Morbidità legata al trattamento:depressione
respiratoria
45
40
35
30
%

diazepam
lorazepamWyeth
loraz Walker
loraz Levy

2...
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs Irgantua
Treiman DM, Meyers PD, Walton NY, e...
prognosi
Prognosi:SE vs NCSE
• Necessità di una attenta stratificazione
• studies drawn from the intensive care setting
(Drislane a...
Prognosi 2:
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
• 1. Generalized SE in nonconvulsing, well-oxygenated a...
La prognosi finale dipende dalla eziologia!!!

The possible relationships among seizure etiology,
nonconvulsive status
epi...
Fattori che influenzano la prognosi nello
SE(anche NCSE)
• Causa dello stato
epilettico
• Durata dello stato
• Trattamento...
Chin RFM,Verhulst L,Neville BGR,Peters MJ,Scott RC.
Inappropriate emergency management of status epilepticus
in children c...
complicazioni
Complicazioni sistemiche dello status epilepticus

SNC

cardiova Resp
s

metaboli
co

altro

Ipossia/anos
sia

IM

Apnea/i...
Complicazioni dello SE
• Durata convulsioni > 1 hr:predittore indipendente di poor outcome
(mortality odds ratio di quasi ...
Complications of SE
• Aminoff MJ, Simon RP. Status epilepticus:
causes, clinical features and consequences in 98
patients....
•

•

•
•
•
•

Neuroprotective effects of acidosis
???

some studies that suggest that hypoxia, acidosis and hypoglycaemia...
Effetti collaterali della fenitoina ev
• Lesioni dei tessuti molli,con o senza
stravaso:”Purple Hand,,> 40 casi ,con parec...
Allen FH, Runge JW, Legarda S, et al. Multicenter open-label
study on safety, tolerance, and pharmacokinetics of
intraveno...
Introduzione alla peculiarità
dell’ambiente intensivistico
Convulsioni in ambiente intensivo

• Sepsi
• Cause mediche :
• Anormalità metaboliche(30-35%) (11):
– Iponatremia,ipocalce...
Problemi peculiari all’ambiente
intensivistico
•
•
•
•
•
•

Polifarmacologia
Insuff renale
Insuff epatica
Induzione enzima...
Trattamento dello stato di
male
Allora:
• Terapia immediata
• Aggressiva
• Supporto vitale di base:

• A:Airway
• B:reathing
• C:Supporto circolatorio
Status epilepticus:filosofia del trattamento

Disaccoppiamento
CMRO2/CBF
Glucosio
Tiamina 100 mg

Funzione resp

Funzione ...
Indagine conoscitiva su 127 TI NCH europee
Dauch WA, Schutze M, Guttinger M, et al. Posttraumatic seizure prevention - res...
Rischio convulsivo
Alldredge BK, Gelb AM,Isaacs S M,Corry MD,Allen F,Ulrich SK, Gottwald
MD,O'Neil N, Neuhaus JM, Segal MR,Lowenstein DH.
Com...
Alldredge BK, Gelb AM,Isaacs S M,Corry MD,Allen F,Ulrich SK, Gottwald
MD,O'Neil N, Neuhaus JM, Segal MR,Lowenstein DH.
Com...
Veterans Affairs Status Epilepticus
Cooperative Study Group, Treiman et al.

Treiman DM, Meyers PD, Walton NY, Collins JF,...
Veterans Affairs Status Epilepticus Cooperative
Study Group, Treiman et al.
primary outcome measure:
cessation of clinical...
Veterans Affairs Status Epilepticus
Cooperative Study Group, Treiman et al.
• !st treatment successful in 55.5% of patient...
Treiman DM, Meyers PD, Walton NY, et al. A
comparison of four treatments for generalized
convulsive status epilepticus. N ...
Alldredge, Brian K.a,b; Lowenstein, Daniel H.AC .Status
epilepticus: new concepts. Current Opinion in Neurology
12,1999: 1...
Da Chapman,Anaesthesia 2004
Marik PE,Varon J. The Management of Status
Epilepticus. Chest. 126(2):582-591, August 2004
Status epilepticus is a major m...
Schema di Marik et al
Claassen J,Hirsch LJ, Emerson R G,Bates
JE, Thompson TB,Mayer SA Continuous EEG
monitoring and midazolam infusion for refr...
Claassen J,Hirsch LJ, Emerson R G,Bates JE, Thompson TB,Mayer
SA Continuous EEG monitoring and midazolam infusion for refr...
Claassen J,Hirsch LJ, Emerson R G,Bates JE, Thompson TB,Mayer
SA Continuous EEG monitoring and midazolam infusion for refr...
Waterhouse, Elizabeth J. 1 2; DeLorenzo, Robert J. 1 3 4 2
Status Epilepticus in Older Patients: Epidemiology and
Treatmen...
Waterhouseet al.
Status Epilepticus in Older Patients: Epidemiology and
Treatment OptionsDrugs & Aging. 18(2):133-142, 200...
Ns proposta
Lorazepam
0.1 mg/kg
Propofol
1-2 mg/kg

Miorilassante solo
Per intubazione!

Inf cont 3-10 mg/kg/h

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

cumulativo
Inotropo neg….
Pentobarbital???
immunosoppressione
propofol
•
•
•
•

Vantaggi cinetico/dinamici:
Titolazione continua possibile
TCI:quale livello ???
Dosi; 1 mg/kg,ripetibil...
AG
• Non ci sono dati che indichino quanto a
lungo i paz debbano rimanere senza
convuls prima di poter alleggerire il pian...
Studi comparativi:1
• Midazolam> tiopental
–

Lohr A Jr, Werneck LC. Comparative non-randomized study with
midazolam versu...
Studi comparativi:2
Valproato
• . Valproate,(iv”Depacon”), has been used for the treatment of refractory SE
in children an...
FINE
Perché non ne possiamo
più………..
Staus epilepticus ;icu;nov 2004
Staus epilepticus ;icu;nov 2004
Staus epilepticus ;icu;nov 2004
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treatment of status epileptics,intensive therapy,2004

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Staus epilepticus ;icu;nov 2004

  1. 1. Trattamento dello stato di male: Il punto di vista del rianimatore. Claudio Melloni Anestesia e Rianimazione Ospedale di Faenza
  2. 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. 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. 4. Schema delle modificazioni neurofisiologiche:parte I Aum richieste O2 cerebrali Aum CBF Aum. Attività autonomica Aum PA Aum glicemia Sudorazione Salivazione iperpiressia
  5. 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. 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. 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. 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. 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. 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. 11. prognosi
  12. 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. 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. 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. 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. 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. 17. complicazioni
  18. 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. 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. 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. 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. 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. 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. 24. Introduzione alla peculiarità dell’ambiente intensivistico
  25. 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. 26. Problemi peculiari all’ambiente intensivistico • • • • • • Polifarmacologia Insuff renale Insuff epatica Induzione enzimatica: Inibizione enzimatica Ipo/disprotidemie…..:farmaci altamente legati alle prot plasmatiche
  27. 27. Trattamento dello stato di male
  28. 28. Allora: • Terapia immediata • Aggressiva • Supporto vitale di base: • A:Airway • B:reathing • C:Supporto circolatorio
  29. 29. Status epilepticus:filosofia del trattamento Disaccoppiamento CMRO2/CBF Glucosio Tiamina 100 mg Funzione resp Funzione cardiocircolatoria Supporto supernormale
  30. 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. 31. Rischio convulsivo
  32. 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. 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. 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. 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. 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. 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. 38. Alldredge, Brian K.a,b; Lowenstein, Daniel H.AC .Status epilepticus: new concepts. Current Opinion in Neurology 12,1999: 183-190
  39. 39. Da Chapman,Anaesthesia 2004
  40. 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. 41. Schema di Marik et al
  42. 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. 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
  44. 44. 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
  45. 45. 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.
  46. 46. 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
  47. 47. 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
  48. 48. fenobarbital • 10-20 mg/kg i.v. – Eccessiva sedazione – Depress.resp – Ipotensione – Interaz farmacol – Hl >48 hr………
  49. 49. tiopental • • • • cumulativo Inotropo neg…. Pentobarbital??? immunosoppressione
  50. 50. 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
  51. 51. 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…..
  52. 52. 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.
  53. 53. 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.
  54. 54. FINE Perché non ne possiamo più………..
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