description of pitfalls in their acute diagnosis and management in the emergency department . Emerg Med Clin North Am 2011 ; 29 ( 1 ): 73 \200\223 81 . 3. Febrile seizures : clinical practice guideline for the long-term management of the child with simple febrile seizures . Pediatrics 2008 ; 121 ( 6 ): 1281 \200\223 6 . 24. Benbadis SR , Allen Hauser W . An estimate of the prevalence of psychogenic non-epileptic seizures . Seizure 2000 ; 9 ( 4 ): 280 \200\223 1 . oxford textbook of epilepsy and epileptic seizures 342 43. Lipka K , Bulow HH . Lactic acidosis following convulsions . Acta 25. Benbadis SR , Agrawal V , Tatum WO . How many patients with Anaesthesiol Scand 2003 ; 47 ( 5 ): 616 \200\2231 8 . psychogenic nonepileptic seizures also have epilepsy? Neurology 2001 ; 57 ( 5 ): 915 \200 \223 7 . 44. Michael GE , O \200\231Connor RE . The diagnosis and management of seizures and status epilepticus in the prehospital setting . Emerg Med Clin North Am 2011 ; 29 ( 1 ): 29 \200 \223 39 . 26. Benbadis SR , Siegrist K , Tatum WO , Heriaud L , Anthony K . Short- term outpatient EE G video with induction in the diagnosis of psychogenic seizures . Neurology 2004 ; 63 ( 9 ) : 1728 \200\223 30 . 45. Lowenstein DH , Bleck T , Macdonald RL . It \200\231s time to revise the de \201 nitio n of status epilepticus . Epilepsia 1999 ; 40 ( 1 ): 120 \200\223 2 . 46. First Seizure Tr ial Group (FIR.S.T. Group) . Randomized clinical trial on the ef \201 cacy of antiepilepti c drugs in reducing the risk of relapse after a \201 rst unprovoked tonic-clonic seizure . Neurology 1993 ; 43 ( 3 Pt 1 ): 478 \200\223 83 . 27. Chung SS , Gerber P , Kirlin KA . Ictal eye closure is a reliable indicator for psychog enic nonepileptic seizures . Neurology 2006 ; 66 ( 11 ): 1730 \200\223 1 . 28. Syed TU , Arozullah AM , Suciu GP , Toub J , Kim H , Dougherty ML , et al . Do observer and self-reports of ictal eye closure predict psychogenic nonepileptic seizures? Epilepsia 2008 ; 49 ( 5 ): 898 \200\223 904 . 29. LaFrance WC , Jr . Psychogenic nonepileptic seizu res . Curr Opin Neurol 47. Kim LG , Johnson TL , Marson AG , Chadwick DW . Prediction of risk of seizure recurrenc e after a single seizure and early epilepsy: further results from the MESS trial . Lancet N eurol 2006 ; 5 ( 4 ): 317 \200\223 22 . 2008 ; 21 ( 2 ): 195 \200\223 201 . 30. Azar NJ , Tayah TF , Wang L , Song Y , Abou-Khalil BW . Postictal breathing pattern distinguishes epileptic from nonepileptic convulsive seizures . Epilepsia 2008 ; 49 ( 1 ): 132 \200\223 7 . 48. Hopkins A , Garman A , Clarke C . The \201 rst seizure in adult life. Value of clinical features, electroencephalography, and computerized tomographic scanning in predict ion of seizure recurrence . Lancet 1988 ; 1 ( 8588 ): 721 \200\223 6 . 31. Rossetti AO , Kaplan PW . Seizure semiology: an overview of the \200\230inverse problem \200\231 . Eur Neurol 2010 ; 63 ( 1 ): 3 \200\223 10 . 49. Berg AT . Risk of recurrence after a \201 rst unprovoked seizure . Epilepsia 32. Reuber M , Pukrop R , Bauer J , Helmstaedter C , Tessendorf N , Elger CE . 2008 ; 49( Suppl 1) : 13 \200\223 8 . Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients . Ann Neurol 2003 ; 53 ( 3 ): 305 \200\223 11 . 50. Marson A , Jacoby A , Johnson A , Kim L , Gamble C , Chadwick D . Immediate versus defe rred antiepileptic drug treatment for early epilepsy and single seizures: a randomized cont rolled trial . Lancet 2005 ; 365 ( 9476 ): 2007 \200\223 13 . 33. Nogueira RG , Sheth KN , Duffy FH , Helmers SL , Brom \201 eld EB . Bilateral tonic-clonic seizures with temporal onset and preservation of consciousness . Neu rology 2008 ; 70 ( 22 Pt 2 ): 2188 \200\223 90 . 51. Berg AT , Shinnar S . The risk of seizure recurrence following 34. Holtkamp M , Othman J , Buchheim K , Meierkord H . Diagnosis of a \201 rst unprovoked seizure: a quantitative review . Neurology 1991 ; 41 ( 7 ): 965 \200\223 72 . psychogenic nonepileptic status epilepticus in the emergency setting . Neurology 2006 ; 66 ( 11 ): 1727 \200\223 9 . 52. Kho LK , Lawn ND , Dunne JW , Linto J . First seizure presentation: do 35. Reuber M , Baker GA , Gill R , Smith DF , Chadwick DW . Failure to recognize psychogeni c nonepileptic seizures may cause death . Neurology 2004 ; 62 ( 5 ): 834 \200\223 5 . multiple seizures within 24 hours predict recurrence? Neurology . 2006 ; 67 ( 6 ): 1047 \200\223 9 . 53. Hesdorffer DC , Logroscino G , Cascino G , Annegers JF , Hauser WA . Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus . Ann Neurol 1998 ; 44 ( 6 ): 908 \200\223 12 . 36. Avidan AY . Parasomnias and movement disorders of sleep . Semin Neurol 2009 ; 29 ( 4 ): 372 \200\223 92 . 37. Derry CP , Davey M , Johns M , Kron K , Glencross D , Marini C , et al . 54. Bora I , Seckin B , Zarifoglu M , Turan F , Sadikoglu S , Ogul E . Risk of recurrence a fter \201 rst unprovoked tonic-clonic seizure in adults . J Neurol 1995 ; 242 ( 3 ): 157 \200\223 63 . Distinguishing sleep disorders from seizures: diagnosing bumps in the night . Arch Neurol 2 006 ; 63 ( 5 ): 705 \200\223 9 . 38. Gallmetzer P , Leutmezer F , Serles W , Assem-Hilger E , Spatt J , 55. Shinnar S , Berg AT , O \200\231Dell C , Newstein D , Moshe SL , Hauser WA . Predictors of multiple seizures in a cohort of children prospectively followed from the time of their \201 rst unprovoked seizure . Ann Neurol 2000 ; 48 ( 2 ): 140 \200\223 7 . Baumgartner C . Postictal paresis in focal epilepsies \200\224 incidence, duration, and ca uses: a video-EEG monitoring study . Neurology 2004 ; 62 ( 12 ): 2160 \200\223 4 . 39. Hirtz D , Ashwal S , Berg A , Bettis D , Cam \201 eld C , Cam \201 eld P , et al . 56. Leone MA , Solari A , Beghi E . Treatment of the \201 rst tonic-clonic seizure Practice parameter: evaluating a \201 rst nonfebrile seizure in children: report of the q uality standards subcommittee of the American Academy of Neurology, The Child Neurology Soc iety, and The American Epilepsy Society . Neurology 2000 ; 55 ( 5 ): 616 \200\223 23 . does not affect long-term remission of epilepsy . Neurology 2006 ; 67 ( 12 ): 2227 \200 \223 9 . 57. Gowers W . Epilepsy and other chronic convulsive disorders: their causes, symptoms and treatment . London : J&A Churchill , 1881 . 40. Krumholz A , Wiebe S , Gronseth G , Shinnar S , Levisohn P , Ting T , et al . Practice Parameter: evaluating an apparent unprovoked \201 rst seizure in adults (an evidence-base d review): report of the Quality Standards Subcommittee of the American Academy of Neurolog y and the American Epilepsy Society . Neurology 2007 ; 69 ( 21 ): 1996 \200\223 2007 . 41. Gotman J , Kof \202 er DJ . Interictal spiking increases after seizures but does not afte r decrease in medication . Electroencephalogr Clin Neurophysiol 1989 ; 72 ( 1 ): 7 \200 \223 15 . 58. Hirtz D , Berg A , Bettis D , Cam \201 eld C , Cam \201 eld P , Crumrine P , et al . Practice parameter: treatment of the child with a \201 rst unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Co mmittee of the Child Neurology Society . Neurology 2003 ; 60 ( 2 ): 166 \200\223 75 . 59. Fisher RS , van Emde Boas W , Blume W , Elger C , Genton P , Lee P , et al . Epileptic seizures and epilepsy: de \201 nitions proposed by the International League Agai nst Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) . Epilepsia 2005 ; 46 ( 4 ): 470 \200\223 2 . 42. Chen DK , So YT , Fisher RS . Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy o f Neurology . Neurology 2005 ; 65 ( 5 ): 668 \200\223 75 . CHAPTER 33 Management of Status Epilepticus on the Intensive Care Unit Erich Schmutzhard and Bettina P fausler Introduction Within half an hour of generalized convulsive status epilepticus (GCSE) centra lly mediated increases in adrenaline and noradrena- line lead to highly elevated blood pres sure, increased cardiac output, and an increase of plasma glucose as well as cerebral blood \202 ow. However, with progressing GCSE progressing respiratory aci- dosis accompanies i mpairment of respiration, aggravated by bron- chial constriction and an increase in bronchi al secretions. Beyond 60 minutes respiratory acidosis deteriorates, gas exchange being high ly impaired, partial pressure of oxygen (pO 2 ) progressively reduced, and partial pressure of carbon dioxide (pCO 2 ) increased/ retained. Hypotension, acidosis, hyper/hypoglycaemia , and hyper- pyrexia increase acute morbidity, long-term morbidity, and mor- tality (1 \200 \2233). Later on, GCSE may lead to rhabdomyolysis, impeding renal function and adding to ac idosis, thus increasing morbidity and mortality (4). At the same time the blood \200\223bra in barrier is pro- gressively disrupted with increased protein in the cerebrospinal \202 uid (3, 5, 6). that with the advancement of neurocritical care and intensive care medicine in particular, these \201 gures (but especially the mortality rate directly linked to the status itself/ to intensive care manage- ment) will improve (9, 10). This chapter deals with the intensive care management of patients with SE, the indication f or admission to an intensive care unit (ICU)/neurocritical care unit, and stresses the comp lications of SE and, \201 nally, focuses on the complications of the intensive care manag ement steps/strategies. Classi \201 cation Five major subtypes of SE are potential causes of intensive care manage ment (1, 9): 1. Overt GCSE 2. Complex partial status epilepticus (CPSE) 3. Subclinical or subtle GCSE (frequently referred to as myoclonic status) However, these metabolic derangements are not the only causes of brain injury due to GSCE; even if oxygen supply, body tempera- ture, and all metabolic derangements are suf \201 cie ntly controlled, neuronal damage still occurs and continues as a direct result of electrica l seizures and neuronal depolarizations, adding to neuro- logical long-term sequelae as cog nitive impairment and memory loss (1, 6, 7). This is explained by the fact that prolonged s tatus epilepticus (SE) results in neuronal cell loss in hippocampus pyramidal layers (2). 4. Partial or focal SE 5. Absence SE (petit mal status). GCSE is the most common subtype of SE, being characterized by repetitive or continuous toni c and clonic motor activity with loss of consciousness. In the ictal electroencephalogram ( EEG), bilat- eral epileptiform discharges are seen. If allowed to progress untreated, GCSE may evolve into \200\230subtle \200\231 or subclinical GCSE; in such patients minimal twit ching movements of the eyelids, \201 ngers, or in the facial muscles may be the only clin ical manifestation of the SE (1, 9). However, the evolution of GCSE into subtle GCSE is ass ociated with worsening of coma and higher morbidity and mortality (1, 9). Subtle GCSE is hi ghly refractory to treatment car- rying a higher mortality rate than overt GCSE. In a serie s of 94 head trauma victims, 11 had subclinical seizures, six of these 11 patients were in subtle generalized convulsive status, all of them eventually died (10). Absence SE and CPSE as well as partial/focal SE are rarely admitted to the intensive care unit, thus these con di- tions are not considered further here. Intravenous anticonvulsant agents, the implementation of inten- sive care and neurocritical care, in particular, and increased aware- ness in the emergency medical community has led to decreasing morbidity and, in particular, mortality of GCSE (1, 2, 5 \200\2237). Neverthe less, any type of SE, and in particular, overt GCSE is still a major neurological emergency , and carries a mortality of up to 35 % within the \201 rst 30 days (5). In most instance s, mortality, being a function of age, duration, and etiology, is mainly related to the und erlying etiology of SE (6 \200\2238). In a meta-analysis of 12 pub- lished reports (publish ed 20 \200\22340 years ago) only 3 % of the deaths could be directly linked to the GCSE its elf. It might be surmised oxford textbook of epilepsy and epileptic seizures 344 pulse oximetry is not suf \201 cient in the emergency setting and never in the ICU setting . The immediate establishment of an intravenous line is essential, along with continuous bl ood pressure monitoring and ECG recording. Box 33.1 Algorithm \227\206 Intubation should be performed after the administration of a barbiturate bolus of 3 \200\2235 mg/kg body weight (e.g. thiopen- tal). This dosage usually allows suf \201 ci ent \200\230relaxation \200\231 to facilitate the placement of the endotracheal tube. Treatment must never be delayed in the neurological emergency setting of a GCSE. History ta king, physical examination, and pri- mary laboratory examinations (blood gas analysis, bloo d glucose) must be completed rapidly (5). If in the recommended algorithm for the treatment of a generalized convulsive status the \201 rst- and second-line anticonvulsants have no t terminated the GCSE, the patient needs urgent admission to an ICU, intubation, and arti \201 - cial ventilation. Box 33.1 lists the recommended algorithm imme- diately after the a dmission to the neuro-ICU (1, 3, 5, 9, 10). \227\206 Neuromuscular blockade should not be given in these patients; however, if absolut ely necessary, vecuronium 0.1 mg/kg body weight can be considered. \227\206 Monitor body temperature, maintain normothermia. \227\206 Pentobarbital 5 \200\22315 mg/kg body weight over 1 hour (or thi- opental 3 \200 \2237 mg/kg/hour), then continue pentobarbital 0.5 \200\2235 mg/kg/hour (or continue thiope ntal at a rate of 1 \200\2233 mg/kg/hour) until seizures are controlled. Adverse effects of barbiturate agents Depending on the dosage and duration of barbiturate t herapy, side effects include haemodynamic instability, leading to distributive shock, immun osuppression, and reduced gastrointestinal motility. All these side effects may limit the d ose and the duration of therapy with barbiturates (2) \227\206 Monitor with continuous EEG \227\206 Intra-arterial line for blood gas analysis, invasive blood pressure monitoring. \227\206 Invasive haemodynamic monitoring, e.g. PiCCO or even more invasive monitoring. Patients with cardiopulmonary instability, i.e. distributive shock, need invasive blood pre ssure monitoring, invasive and haemody- namic monitoring, e.g. PiCCO or even more invasi ve monitoring methods such as a pulmonary artery catheter (11 \200\22315). Depending on the se monitoring \201 ndings, patients on barbiturate therapy need suf \201 cient \202 ui d management, aggressive \202 uid balancing, and, in most instances, catecholamines. \227\206 Titrate the dosage of barbiturates against EEG burst sup- pression pattern. \227\206 Fluid management, aggressive \202 uid balancing, if necessary catecholamines. \227\206 Monitoring must be on high alert to recognize any incipient nosocomial infection (regular culturing of body \202 uids, reg- ular C-reactive protein, procalcitonin, white blood cell count, etc.). Haemodynamic instability potentially leading to distributive shock, reduces the cerebral pe rfusion and adds to injury of neuro- nal intracranial structures (3). It must also be borne in mind that barbiturates lead to immuno- suppression, increasing the risk of nosocomial infections, e.g. cath- eter-associated bloodstream infections, nosocomi al ventilator-associated pneumonia, urinary tract infection, and even intestinal infection (12). Therefore careful monitoring to identify as early as possible any incipient nosocomia l infection is vital. Regular culturing of body \202 uids, C-reactive protein, procalcito nin, white blood cell count, differential count on (at least) a daily basis are recommended (16). Alternatives 1. Midazolam 0.2 mg/kg body weight intravenously as a bolus, followed by 1 \200\2232 mg/kg/minute for 12 \200\22324 hours. 2. Monitor with continuous EEG and blood pressure monitor- ing in ICU setting. 3. Propofol 1 mg/kg over 6 minutes, then 1 \200\2235 mg/kg/hour. 4. Attempt to taper after 12 \200\22324 hours. Barbiturates lead to reduced gastrointestinal motility, which is particularly important in patients with haemodynamic instability, or even distributive shock, necessitating a liberal use of catecho- lamines. The effect of these catecholamines on the peripheral vascular sys tem increases the blood pressure by peripheral vasoconstriction; this effect may add to the risk of nosocomial infection since the vasoconstriction may lead to (incomplete) ischaemia in the gastrointestinal wall (3). This speci \201 cally holds true in patients on therape utic agents which reduce, per se, gas- trointestinal motility. For this reason, patients on barbiturates with reduced gastrointestinal motility who require high-dose catecho- lamines are at high risk of experiencing transmural translocation of intestinal bacteria, e.g. Gra m-negative rods (such as Enterobacteriaceae, Escherichia coli , or, even Clostridia species , etc.) (16). The intensivist must react rapidly to the clinical signs and symptoms of sept ic shock and/or a rapid increase of \200\230in \202 am- matory parameters \200\231 (C-rea ctive protein, white blood cell count, procalcitonin) with the appropriate empiric antimicr obial chemo- therapy. This requires best knowledge of the resistance pattern, in particular , of the Gram-negative bacteria seen in patients of the 5. Watch for hypotension and the propofol infusion syn- drome. 6. Monitor with continuous EEG and blood pressure monitor- ing in ICU setting. ICU management of overt GCSE Given the risk of hypotension, respiratory depression, and met abolic acidosis, high-quality monitoring is essential in the emergency management of a pati ent with SE (5). If a patient with GCSE evolves into early refractory GCSE, immediate admis sion to a monitoring unit, even better, to an ICU (preferably a neurocriti- cal care unit) is indicated (1, 3, 9, 10). Pulse oximetry is regularly recommended in the emergency settin g as well as an oxygen supply (9, 10). However, it must be stressed that pulse oximetry can never be suf \201 cient, and blood gas analysis must be done at the earliest possible poi nt of time, since the increase of pCO 2 is usually not paralleled by the decrease of the pO 2 . Therefore pure and only CHAPTER 33 management of status epilepticus on the intensive care unit 345 Cardiac arrhythmias Phenytoin and fosphenytoin, being sodium channel blockers and class 1b antiarrhythmics, can cause ventricular arrhythmias, and changes in the PR and QRS intervals . The incidence of rhythm dis- turbances might be as high as 7 % on phenytoin (1, 5). respective ICU. In the case of the occurrence of extended-spectrum beta-lactamases or carba penemase producing Gram negatives, the empiric antimicrobial chemotherapy might even necess itate the use of polymyxin B (or E), tigecycline, or similar third-line antimi- crobials (1 6 \200\22318). Impaired gastrointestinal motility, in particular, of the large intestine, may be the conse quence of or even be caused by antibi- otic-associated ulcerative colitis due to Clostridia species. Constipation does not preclude the presence of a clostridial colitis, a disease w ith mortality rates of up to 50 % , if diagnosis and appro- priate management is delayed un necessarily (3). Phlebitis, tissue necrosis Extravasation of intravenous phenytoin (high pH) may cause tissu e necrosis, leading \201 nally to what is known as the \200\230purple glove syn- drome \200\231. Fosphenytoin carries a lower risk of phlebitis and necrosis since its pH is neutr al (9, 10). Adverse effects of propofol In addition to the same problems encountered with barbiturates, propofol may, in rare instances, cause the so-called propofol infu- sion syndrome (PRIS) ( 19 \200\22322). Rhabdomyolysis Rhabdomyolysis is de \201 ned as a syndrome with myalgia and muscle weaknes s, caused by damage to muscle cells resulting in leakage of cellular contents, muscle enzym es, myoglobin, creatine, and elec- trolytes (potassium, phosphate) (26). The diagnostic mai n features are elevation of creatine kinase (CK) and myoglobin potentially leading to renal failure (26). It can be caused by prolonged tonic \200\223 clonic SE, the risk being highe r in patients treated with propofol (2, 21, 22, 25). Deranged body-temperature regulation, notably hyper- thermia, increases the risk of rhabdomyolysis (26). Furthermore, the liberal use of depolarizing muscle relaxants is a well-recognized cause of critical illness neurop athy and critical illness myopathies (26). Thus, it is conceivable that a patient with prol onged GCSE, being treated with \200\230immunosuppressant \200\231 dosages of thiopental an d/or propofol, may develop a severe sepsis syndrome which can, in term, lead to sepsis ence phalopathy, which has the potential to aggravate and propagate the SE. If this is the case and the patient continues to have a clinically overt seizure activity, the therapy of refra ctory GCSE itself, the ongoing systemic in \202 ammatory response syndrome (SIRS) or sepsi s syndrome and the ongoing GCSE may lead to rhabdomyolysis (26). Rhabdomyolysis may produce very high levels of CK and myoglobinaemia and myoglobinuria eventu- ally impairing kidney function, necessitating haemo \201 ltration or other means of extracorporeal kidney failur e treatment. Continuous haemo \201 ltration is essential to avoid acute deterioration of t he cer- ebral function due to severe electrolyte disturbance and uraemic metabolic encephal opathy, both adding to brain oedema and cer- ebral metabolic disturbance (26). Finally it s hould be stressed that any type of haemodynamic instability or distributive shock may add t o impairment of renal function, therefore kidney function must be carefully monitored from the very beginning of the treat- ment of a GCSE in an ICU. A propofol-related syndrome with metabolic acidosis, bradyar- rhythmia, and progressive myo cardial failure was \201 rst described almost 20 years and was found to carry a 30 % mort ality rate (22). The incidence of PRIS slightly exceeds 1 % (21). Postulated risk fac- tors include use of a high propofol dose ( > 83 micrograms/kg/ minute), a duration of therapy o f more than 48 hours, and con- comitant vasopressor therapy. Patients on the ketogenic diet are possibly predisposed to develop PRIS (23). Both high-dose and concomitant vasopressor therapy are frequently necessary in patients with refractory convulsive SE. However, it nee ds to be stressed that PRIS can occur soon after the initiation of propofol therapy and eve n also at rather low dose (21). In early publications, the mortality rate was high and rhab domyolysis was frequently seen. Although, the co-incidence of convulsive SE triggered rhab- domyolysis and PRIS has been reported only once (25), it is con- ceivable that patients wi th myoglobinuria or even frank rhabdomyolysis are at an increased risk of developing PRIS ( 4, 26). Therefore, careful observation is necessary when patients with refractory convulsiv e SE are treated with propofol. Side effects of any type of treatment of GCSE Hypoventilation This should not play any role since a patient with GCSE treated at the ICU should be (must be) on an arti \201 cial ven tilator. However, increased bronchial mucus production, aspirates, or bronchos- pasm might impair airways, ventilation, and even gas exchange. If necessary, invasive ventilation stra tegies must be chosen includ- ing reversal of I:E (inspiration: expiration rate), bronchosc opy, and even prone positioning (kinetic therapy) (3, 12). Immunosuppression This aspect has been detailed extensively earlier in the chapter. Every p atient with refractory SE who needs ICU management must be intubated at the earliest point of time to avoid aspiration as a contributing factor of pneumonia in a patient who potentia lly develops severe infectious disease due to his/her externally caused immunosuppressive s tate. Any structural cause of SE, such as an intracranial space-occupying lesion or maligna ncy may add to the state of immunosuppression either directly or indirectly (8). Both immun osuppression due to the SE and anticonvulsive therapy such as barbiturates, increase the li kelihood of developing pneu- monia, especially in those patients in whom intubation was del ayed and who have aspirated already. Hypotension Hypotension occurs frequently in GCSE, all treatment strategies may be associat ed with low blood pressure. The higher the dosage, the older the patient, and the more como rbidities, hypotension might create major intensive care problems. A central venous line is essential as is best possible \202 uid balancing and invasive cardiop- ulmonary monitori ng (PiCCO ) (13 \200\22315). Pressure agents should be given liberally since hypoperfusi on of the endangered brain tissue increases the risk of permanent neuronal damage, neuro- l ogical sequelae, and, even more, mortality. oxford textbook of epilepsy and epileptic seizures 346 There are also several case reports suggesting that this substance may have a role in the t reatment of refractory SE (27). Ketamine can be used in a bolus of 2 mg/kg body weight foll owed by an infu- sion of 10 \200\22350 mg/kg/minute, a dose that does not necessarily cause respiratory depression. Unlike the earlier mentioned anesthetic agents, in particular, bar biturates and propofol, ketamine has less haemodynamic effects being more likely to cause h ypertension than hypotensive shock (27). In patients who need prolonged arti \201 cial ventilation the risk of ventilator-associate d pneumonia is increased (12). Accurate knowledge of the causative agents in any particular ICU is essential to avoid unnecessary, potentially harmful antimicrobial chemo- therapies and to help to choose the best possible empiric antibiotic therapy until microbiological re sults, obtained from blood or bronchial lavage cultures, are obtained (17, 18). Reduced gastrointestinal motility It is mainly the barbiturates which lead to reduced gastr ointestinal motility. This is particularly important in patients with haemody- namic instab ility, suffering from distributive shock syndrome in which high dosages of catecholamines a re needed. These catecho- lamines act on the peripheral vasculature, increasing the blood p ressure by vasoconstriction. This vasoconstriction leads to distur- bance of microcirculati on in all organs, also in the entire gut. This disturbance of microcirculation together wit h the impairment of the gastrointestinal motility, as caused by barbiturates, increases the risk of transmural translocation of intestinal bacteria, in par- ticular, Gram-negative ro ds, as Enterobacteriaceae, Escherichia coli , Klebsiella spp., but also enterococci, even C lostridia spp. or Candida spp. (17,18). Therefore, the intensivist must pay close attention to the gastrointestinal motility. One possibility is to start enteral feed- ing (via nasog astric tube) together with properistaltic substances as domperidone, distigminbromid, eryth romycin, etc. (3). Lidocaine Lidocaine is another possible alternative for the treatment of refrac- tory SE in the ICU (28). Lidocaine functions as an antiarrhythmic, stabilizing the cardiac membrane b y blocking the fast voltage-gated sodium channels. Its antiepileptic activity may also be r elated to sodium channel blockade. Several small case series have described rapid cessation of seizures following administration of a lidocaine bolus (2 \200\2233 mg/kg body weight g iven within 5 minutes); however, its effective duration is rather short. In more than half of the responders in one of the key series (28), seizures recurred within half an hour. Eit her a second (1 \200\2233 mg/kg) bolus or continuous infusion (0.06 mg/kg/minute \200\224 up to a maximum infusion rate of 5 mg/minute) will then need to be administered. The lidoca ine infusion should not be continued for more than 12 hours. Adverse effects include parado xical proarrhythmic and, rarely, proconvul- sant effects (29). Lidocaine must be avoided in patients with sig- ni \201 cant heart disease, in particular, bradyarrhythmia or conducti on block. Even worse, as lidocaine is metabolized by the liver, it should be avoided in pat ients with liver dysfunction (28, 29). The earliest possible recognition of an incipient Gram-negative sepsis caused by transmural location of intestinal germs is essential. A watchful and careful selection of antimicrobi al chemotherapeu- tic agents is essential to avoid lowering of seizure thresholds by antibi otic therapy and thus aggravating and prolonging the GCSE (3). Impaired gastrointestinal mo tility, in particular, of the large intestine may be caused by antibiotic-associated ulcera tive colitis due to Clostridia species. Imaging of the abdomen (abdominal computed tomograp hy) visualizes the distended colon and helps timing of a potentially necessary colonoscopy which allows its appropriate diagnosis. Immediate and early application of oral \200\224 i n case of systemic spread also additionally intravenous \200\224 metronida- zole is indica ted in cases where antibiotic-associated ulcerative colitis is suspected or diagnosed (17, 18). Iso \202 urane Iso \202 urane is an inhalational anesthetic. It has been given in few cas es with therapy refractory GCSE. Its use is complex and cum- bersome, since it needs the fu ll-scale equipment of inhalational anesthetic systems which usually are not available in IC Us or neuro-ICUs. Despite a successful control of GCSE, mortality remains high in those pat ients reported so far. Iso \202 urane is used in concentrations of 0.8 \200\2233 % , progr essively higher concentrations may be needed to control seizures; however, it may be neurot oxic when used in high doses for long time periods as evidenced by progressive T2 signal hy perintensities in thalamus and cerebellum (30). Other complications Rib fractures and vertebral fractures, in particular in the elderly, ha ve been reported. Both may contribute to impairment of sponta- neous ventilation adding to the risk of pneumonia (1, 3). Hypothermia Single cases have been reported in which therapy of refractory GCSE has been co ntained by employing mild to moderate thera- peutic hypothermia, cooling the body temperatu re to 32 \200\22334 C. High-quality ICU management is necessary in these patients, as hy pothermia has a wide variety of potential complications, includ- ing coagulopathies, increa sed risk of infection, disturbance of elec- trolytes, cardiac arrhythmias, impairment of bo wel movement, reduced intestinal absorption, etc. (31, 32). Unconventional therapies Ketamine As seizures persist, gamma-aminobutyric acid (GABA) recep tors become downregulated and GABA-mediated treatments may become more and more ineffective . At this point, excitatory N-methyl-D-aspartate (NMDA) receptors and glutamate are thought to play a more important role (2). Ketamine, being a non- competitive NMDA receptor antago nist, might have a role in effec- tively treating prolonged electrographic seizures. Animal models have shown ketamine to be ineffective in early SE, but to be effec- tive in reducin g electrographic seizures after 1 hour or longer. Conclusion All therapeutic strategies require careful monitoring of both neu- rological and cardiopulmonary function, as well as regular moni- toring of routine laboratory parameters , including in \202 ammatory, renal, hepatic, and coagulation parameters. In rare cases it might CHAPTER 33 management of status epilepticus on the intensive care unit 347 be advisable to supplement the electroencephalographic and cardi- opulmonary monitoring by neuroimaging (magnetic resonance imaging, digital volumetric imaging) and invasive modern n euro- monitoring techniques such as intracranial pressure measurement (allowing cerebral pe rfusion pressure management), tissue oxygen measurement, brain temperature measurement, or even microdi- alysis with monitoring of metabolic developments (brain tissue lactate, pyruv ate/lactate ratio, glucose, glycerin, etc.). Whether the regular measurement of biomarkers of brain tissue destruction as S 100 or neuronal speci \201 c enolase add to a potential o ptimization of management needs to be studied. Substances that are used regularly in any ICU, and also in neuro- logical ICUs, that can re duce seizure threshold might be the \201 nal trigger to provoke \200\224 in an ICU \200 \224 a SE. Such substances are antibi- otics, antipsychotics and antidepressants, and these are listed in Table 33.1 . References 1. De Giorgio Ch , Faught E , Fujikawa DG , Vespa PM . Status epilepticus . In: Noseworthy JH (ed) Neurological Therapeutics, Principles and Practice ( 2nd edn), pp. 3 75 \200\223 84 . Oxford : Informa Healthcare , 2006 . 2. Robakis TK , Hirsch LJ . Literature review, case report, and expert discussion of prolonged refractory status epilepticus . Neurcrit Care 2006 ; 4 : 35 \200 \223 46 . As soon as SE is suspected, be it overt GCSE or non-convulsive status or subtle SE, continu ous EEG monitoring should be initi- ated. All type of status epileptici need to be treated aggressively. The term subtle SE has been introduced in patients with severe structural bra in damage who do not awake from coma after pro- longed intensive care medicine and who do s how subtle motor movement like eye lid twitching or a deviation noted only when eye lids ar e lifted and which frequently cannot be discovered by video-monitoring or clinical examinat ion alone. Such status epi- leptici with even waxing and waning of consciousness may go unn oticed for days. Therefore, EEG monitoring in a suspected patient should be established at the earliest possible point of time. Neurologists usually accurately diagnose convulsive SE . However, psychogenic SE can mimic the clinical manifestation of a GCSE and can even lead to intubation and use of barbiturates. 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