Pregabalin 25 \200\223300 ++ + +? PTSD = post-traumatic stress disorder. Curtis SP, Ng J, Yu Q, et al. Renal effects of etoricoxib and comparator nonsteroidal anti- in \202 ammatory drugs in controlled clinical trials. Clin Ther 2004; 26: 70 \200\22383. Adjuvant therapies Especially in patients with features of chronic pain or altered sleep pa tterns, tricyclic antidepressants have been used extensively. There might be a rationale fo r using these drugs in the medium- to long-stay patient where a constel- lation of pain, an xiety and depression co-exists, possibly along with a disturbed sleep pattern. There is evi dence that the usage of tricyclics, and possibly some of the drugs used to treat neuropathi c pain, may reduce the development of post-traumatic stress disorder (PTSD) in ICU survivor s. Kuhlen R, Putensen C. Remifentanil for analgesia-based sedation in the intensive care unit. Crit Care 2004; 8: 13 \200\2234. Muellejans B, Matthey T, Scholpp J, et al. Sedation in the intensive care unit with remifen tanil/propofol versus midazolam/fentanyl: a randomized, open-label, pharmacoeconomic trial. Crit Care 2006; 10: R91. Roemsing J, Moeniche S. A systematic review of COX-2 inhibitors compared with traditional N SAIDs, or different COX-2 inhibitors for post-opereative pain. Acta Anaesthesiol Scand 2004 ; 48: 525 \200\22346. Wilson W, Smedira N, Fink C, et al. Ordering and administration of se datives and analgesics during the withholding and withdrawal of life support from criticall y ill patients. JAMA 1992; 267: 949 \200\22353. http://www.anzca.edu.au/publications/acutep ain. Alternative therapies No evidence exits to support the use of alternative thera- pies in th e critically ill. In the absence of any untoward effects, however, the use of transcutaneou s electrical nerve htm 208 DH CONWAY & R BEDAIR Sedation management in ICU Drugs with sedative, analgesic and neuromuscular blocking activity are used in different co mbinations to facilitate care of the critically ill. Sedative agents alleviate anxiety, red uce the stress response and improve tolerance of ICU inter- ventions. Tolerance to benzodiazepines may occur within hours to several days of therapy, and escalat ing doses of midazolam have been reported. Benzodiazepines can also cause delir- ium (both hypo- and hyperactive forms). Propofol Propofol is a non-water-soluble propylphenol formulated as an aqueous emulsion in intralipid solution. It is a short- acting GABA agonist with sedative and hypnotic effects but no analgesic properties. The plasma level of propofol rapidly falls after discontinuati on, and recovery time is short compared with other sedatives. This is due to redis- tributi on from plasma to the tissues. With prolonged infusions, the tissues become saturated and r ecovery is longer. No changes in kinetic parameters have been reported in patients with ren al or hepatic dysfunction. Propofol improves control of ICP and decreases CBF and metabolis m. Rapid awakening from propofol makes it useful for patients in whom frequent neurological assess- ment is needed. Propofol causes a dose-dependent drop in blood pressure through re duced SVR and bradycardia. Also, the lipid base of propofol can function as a medium for ba cterial growth, and long-term or high dose infusions may result in hyper- triglyceridaemia, and some cases of pancreatitis have been reported. Propofol infusion syndrome is a rare bu t lethal complica- tion. It is reported in pediatric and occasionally in adult critical car e. There is a severe metabolic acidosis, rhab- domyolysis, haemodynamic collapse and bradyc ardia pro- gressing to asystole. This may be due to impaired fatty acid oxidation or inhibi tion of phosphorylation in the mito- chondria. Risk factors include hypoxia, sepsis, cerebr al injury and high propofol dose. Whilst propofol has experimental evidence of anticonvul- sant activity in animal models, abnormal epileptiform movement has been reported in clinica l anesthetic practice. Indications for use of sedation 1 To maintain patient comfort while being managed within critical care areas. 2 To facilitate compliance with mechanical ventilation. 3 To help control raised ICP. 4 To manage anxiety, agitation and delirium. 5 To augment analgesia through the opiate-sparing e ffect of some sedative agents. Prior to starting sedation, any underlying cause of discom- fort or agitation should be tre ated. Furthermore, the unde- sirable effects of sedative infusions should be considered, as sedative use can complicate neurological assessment, prolong the duration of mechanical ve ntilation and increase length of stay in the ICU and the hospital . The amnesic properties of some sedatives may modify post-traumatic stress (PTSD) by reducing recollection of unple asant or frightening memories. Unfortunately, overse- dation and withdrawal can contribute to PTSD symptoms. Sedative agents A number of drug classes with distinct features are available. Sedation can be administered by intermittent bolus dose or continuous infusion. IV infusions provide co nstant levels of sedation to increase patient comfort. However, their use is an independent predictor of increased length of stay in the ICU and the hospital . Determining appropriat e dosing of drugs can be dif \201 cult. The decreased protein binding and the impaired ren al and hepatic function that occur in critical illness lead to changes in half-life and vol ume of distribution. Benzodiazepines Benzodiazepines are the most commonly used sedatives. They act on benzodiaz epine receptors, which enhance the effect of -aminobutyric acid (GABA) on chloride channe ls, causing intracellular in \202 ux of chloride ions. This increases resting membrane pot ential, inhibiting excitation. They have anxiolytic, anticonvulsant, amnesic and centrally mediated muscle relaxant properties. \200 Etomidate Etomidate is now rarely used in the ICU because it is asso- ciated with adrenocor tical insufficiency and has been shown to increase mortality in critically ill patients. Butyrophenones Haloperidol has sedative effects, and boluses are used to alleviate delirium . Haloperidol infusions have been used successfully in the management of agitated patients in critical care. There is a risk of complete heart block, ventricular tachycardia and QTc prolongation \200\224with the accompanying possibility of torsades de pointes. Diazepam has a rapid onset of action, and patients gen- erally will awaken rapidly after a bolus dose. With con- tinuous infusions, the half-life and active diazepam metabolites lead to a prolonged sedative effect. Lorazepam is eliminated by conjugation to inactive glu- cu ronides. It has a slower onset of action, making it less useful for acute agitation, and a prolonged half-life, mak- ing it dif \201 cult to titrate. Midazolam has a rapid onset of action and a short half- life, making it ideal for the critically ill. Accumulation and pro longed sedative effects are reported in critically ill patients who are obese, in renal fai lure or have low serum albumin Prolonged sedative effects may also be caused by the accum ulation of the active metabolite, - hydroxymidazolam, or its conjugated salt. Phenothiazines Phenothiazines block muscarinic, 1-adrenergic, H1 histaminic, DA1 and DA2 receptors. They have antipsychotic properties that are mainly due to their DA2 receptor blo cking activity in the limbic system. Chlorpromazine 50 \200\223100mg can be administered IM , but IV bolus doses (2.5 \200\22310mg) cause severe hypotension. An infusion of 10 \200 \22320mg/h is less likely to compromise blood pressure. Central 2 agonists These include clonidine and dexmedetomidine. Dexmedetomidine is a selective 2 agonist. It has sedative and analgesic-sparing properties, and produces anxiolysis 209 CHAPTER 13.2 Sedation management in ICU to collect. A de \201 ned sedation goal, using sedation scales, can reduce length of stay. comparable with benzodiazepines. Rapid administration of dexmedetomidine leads to transient elevation of blood pressure, whilst dexmedetomidine infusions cause brady- cardia or hypot ension. Summary \200 Sedation may facilitate invasive treatments for critically ill patients. Long-acting sedati ve drugs contribute to confusion and prolonged length of stay. Sedation monitoring should b e routine in critical care. Sedation protocols incorporating monitoring and daily hold redu ce length of stay. Short-acting drugs and non-benzodiazepine hypnotics look promising and n eed further evaluation Volatile anesthetic agents Inhaled anesthetic agents such as the halogenated hydrocar- bon iso \202 uorane can be administered via the breathing circuit, and these may be used when intolerance of other sedatives occurs or to help treat refractory bronchospasm. A concen- t ration of 0.3 \200\2230.6% iso \202 uorane should provide satisfactory sedation. A common problem on the ICU has been the requirement for an anesthetic machine and scavenging of exh aled gasses. The development of anesthetic-conserving devices can allow the use of an ICU v entilator which does not need a gas-scavenging system. \200 Further reading Bailie GR, Cockshott ID, Douglas EJ, et al. Pharmacokinetics of pro- pofol during and after long-term continuous infusion for mainte- nance of sedation in ICU patient s. Br J Anaesth 1992; 68: 486 \200\22391. Kam PC, Cardone D. Propofol infusion syndrome. An esthesia Opioids Whilst primarily used as analgesic agents, the sedative and antitussive properties of opioids enhance the effects of other sedatives. Whilst opioids have sedative effects, th ey do not diminish awareness or produce any sort of amnesia for stressful events. 2007; 62: 690 \200\223701. Kelly DF, Goodale DB, Williams J, et al. Propofol in the treatment of moderate and severe h ead injury: A randomized, prospective double-blinded pilot trial. J Neurosurg 1999; 90: 104 2 \200\22352. Sedation monitoring Ideally sedation should attain the goal of a calm ICU patient, easily a roused, with maintenance of the normal sleep \200\223wake cycle. Some patients may require deeper levels of sedation to facilitate mechanical ventilation. Daily inter- ruption of sed ative infusions leads to reduction of duration of ventilation and length of stay. Subjectiv e sedation scales as part of a protocol improve outcome and are recom- mended by internatio nal guidelines. Sedation and delirium scales such as the Richmond Agitation and Sedation Sc ale (RASS) and the Confusion Assessment Method (CAM- ICU) should provide accurate, reliable data that are simple Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. seda- tion is associated w ith prolongation of mechanical ventilation. Chest 1998; 114: 541 \200\2238. Sackey PV, Martling CR, Granath F, et al. Prolonged iso \202 urane seda- tion of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med 2004; 32: 2241 \200\2236. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30: 119 \200 \22341. Kress JP, Pohlman AS, O \200\231Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471 \200\2237. Half-life (h) Active metabolites Elimination Agent Receptor Dose (bolus) Dose (infusion/ maintenance) Plasma protein binding Desmethylation and hydroxylation produces active metabolites Conjugation of active metaboli tes to inactive glucuronides Conjugation to inactive glucuronides Diazepam BZ 0.03 \200\2230.1mg/kg q 0.5 \200\2236h 98% 20 \200\223120 Active metabolites desmethyldiazepam; 3-hydroxydiazepam; oxazepam Lorazepam BZ 0.02 \200\2230.06mg/kg q 2 \200\2236 h 0.02 \200\2230.08 mg/kg q 0.5 \200\2232h 0.01 \200\2230.1mg/kg/h 90% 8 \200\22315 None A-Hydroxymidazolam Hydroxylated by Midazolam BZ 0.04 \200\2230.2mg/kg/h 96% 3 \200\22311 hepatic cytochrome P-450 to -hydroxymidazolam and excreted by the kidney Conjugates of 2, 6-di-idopropyl-1, 4-quinol Propofol GABA 2 \200\22312mg/kg/h 98% 26 \200\22332 Haloperidol 0.03 \200\2230.15mg/kg q 0.5 \200\2236h 0.04 \200\2230.15mg/kg/h 18 \200\22354 BZ = benzodiazepine; GABA = -aminobutyric acid. 210 S WADDY Muscle relaxants Neuromuscular blockade is used in as an aid to intubation and as an adjunctive treatment fo r particular situations in the already ventilated and adequately sedated patient. with a family history of myotonia and those with muscular dystrophy. Suxamethonium is less effective in conditions reducing the number of acetylcholine receptors, such as myasthenia gravis. Due to the tonic contraction, its use is often avoided in patients with penetrating ocular injury and raised ICP, although this is an area of debate. Physiology Depolarization of the motor neuron results in the fusion of vesicles containing acetylcholine with the neuronal mem- brane, each releasing 10 000 molecules of acetylcholi ne into the synaptic cleft. The acetylcholine receptors are grouped together on the postsyn aptic membrane at the motor end plate by a complex series of steps during synapse formation that depend upon the action of agrin released from the nerve and rapsyn within the muscle \201 bre. The synaptic cleft is only 20nm, enabling rapid association of acetylcholine wi th the receptor, opening non-selective ion channels and resulting in membrane depolarizatio n and calcium in \202 ux into the muscle \201 bre. The available pharma- ceutical agents act on the nicotinic acetylcholine receptor (nAChR) on the postsynaptic membrane. Non-depolarizing blockers There are two classes of acetylcholine receptor competi- tive ant agonists, aminosteroids and benzylisoquinolinium compounds; however, the differences in the functional properties of each agent are more important clinically. Aminosteroids Pancuronium is long acting with a half-life of 100 \200\223130min, a time of onset of 1 \200\2233min and is 60 \200\22380% eliminated by the kidneys, the remainder bein g hepatic. Its duration is there- fore increased in renal and hepatic failure. It is vagoly tic, and use can result in tachycardia which may be undesirable in the critically unwell. V ecuronium is shorter acting (half-life 80 \200\22390min) with a time of onset of 1.5 \200 \2233min and is only 10 \200\22320% eliminated by the kidneys, the remainder being hepatic metabolism; however, one of its highly active metabolites is eliminated by the kidney and i t has been associated with prolonged blockade following infusion. It is not vagolytic. Rocu ronium has a very rapid onset of 1.0 \200\2231.5min, and this has led to its use in modi \201 ed rapid sequence induction in those patients in whom suxamethonium is contraindicated . If propofol is used as an induction agent, the incidence of \200\230acceptable \200\231 intubating conditions is the same as for suxam- ethonium; however, if the more stringent \200\230excellent \200\231 intu- bating conditions are applied, suxamethonium is better (RR 0.87) Rocuronium has a half-life of 60 \200\223100min and is <10% elimi- nated by the kidn ey, the remainder being hepatically metabolized; its duration of action increases in hepati c failure and in the elderly. Depolarizing blockers Suxamethonium is the only available depolarizing blocker, it acts by binding the nAChR, resulting in ion channel opening and muscle depolarization; it then occu pies the receptor for far longer than acetylcholine, preventing further depo- larization un til it has dissociated from the receptor and dif- fused away to be metabolized by plasma ch olinesterase. Use Suxamethonium is used in rapid sequence induction and intubation at a dose of 1.0 \200 \2231.5mg/kg. Its onset of action is <1min and duration is usually 7 \200\2238min. Cautions Potassium is released from muscles during depolarization and serum levels rise by 0.5 \200\2231.0mmol/l following suxame- thonium. Avoid in hyperkalaemia. Any cause of sever e immobility or dennervation results in a decrease in acetycholine release, and this in tur n causes upregulation of acetylcholine receptors. The receptors produced are also of a \200\230fetal \200\231 type, resulting in an increased sensitivity to suxamethonium, failur e to aggregate at the muscle end plate and increased ion \202 ux when activated. Under th ese conditions, suxamethonium can cause a dra- matic rise in potassium, leading to cardiac arrest, and must be avoided. Benzylisoquinolinium compounds Atracurium has an intermediate duration of action, with a ha lf-life of 21min and an onset of 2.0 \200\2232.5min. It has the great advantage of being me tabolized by Hofmann degra- dation and ester hydrolysis, making it ideal for patients with renal or hepatic dysfunction (although degradation is slowed in acidosis and hypothermia). It can cause histamine release and hypotension. An inactive metabolite, laudanos- ine, caus es seizures in dogs, but even in very prolonged administration in humans this does not appe ar to reach toxic concentrations or cause problems. Cisatracurium is a potent isomer of atr acurium with very similar properties, except dosing is 70% lower and there- fore there is l ess histamine release, hypotension and lauda- nosine production. Mivacurium is metabolized by plasma cholinesterases, has an onset of 1.5 \200\2232.5min and a duration of action of o nly 2 \200\223 5min. Its use in the critically ill has not been extensively investigated. C linical use of prolonged muscular blockade X There is a distinct lack of good evidence from trials for the use of prolonged neuromuscular blockade in intensive care. The following ar e areas where neuromuscular blockade is Avoid suxamethonium in: \200 \200 \200 \200 \200 \200 \200 Hyperkalaemia Burns (if >24h after injury) Crush injuries (if >2 days after injury) Guillai n \200\223Barr syndrome Spinal cord injury Stroke Prolonged immobilization or neuromuscul ar blockade (i.e. do not use or use with great caution for the re-intubation of intensive c are patients). One in 3200 patients are homozygous for plasma cholineste- rase de \201 ciency and will re main paralyzed for 3 \200\2238h. Suxamethonium can cause malignant hyperthermia (see Chapte r 22.13) and should also be avoided in those 211 CHAPTER 13.3 Muscle relaxants used when conventional therapies are failing and/or adequate sedation and analgesia alone f ail to produce the desired effect. Is the blockade adequate? This will depend on the indication; to achieve ventilator synchro ny a very small degree of block may be enough, whereas to abolish a cough re \202 ex in a patient with critically raised ICP a much higher degree of block is required. Facilitating mechanical ventilation Whilst it is becoming more unusual with modern ventilat ors, there are occasions when patient \200\223ventilator asynchrony impacts negatively on g as exchange despite prolonged attempts to adjust ventilator settings and increasing seda- t ion. Evidence for bene \201 t in the literature is lacking, and the use of muscular blocka de must be approached on a case by case basis. Beware that some patients suffer clinically signi \201 - cant worsening of ventilation \200\223perfusion mismatching on paralysis; if this happens don \200\231t do it again to that patient! Whilst there is no particular reaso n why it is necessary if sedation is adequate, some ICUs paralyze patients who are being tu rned prone to improve their ventilation. Is the blockade too much? The best clinical assessment is to have frequent \200\230block b reaks \200\231. If bolus blockade is being used, wait until move- ment starts to cause prob lems again before giving more; if an infusion is used a daily hold is an absolute minimum, and 12 hourly may be more appropriate. This answers two questions: \201 rst, do they stil l need muscular blockade as well as sedation; and, secondly, are they receiving an appro- p riately titrated dose. Electrical stimulation \200\230twitch testing \200\231 Should always be used as an objecti ve adjunct to clinical assessment. There are various guidelines used; however, in general, the presence of clinically adequate block but with at least two out of four contractions on a \200\230train of four \200\231 test still present can be regarded as an appropriately t itrated dose. Reduction of oxygen consumption This is often cited as a reason for paralyzing dif \201 cu lt to oxygenate patients. However, the literature does not support the ef \201 cacy of thi s. Again, in the most dif \201 cult patients, it is often attempted and should be done so on a case by case basis. Essential care Patients who are paralyzed must have special attention paid to: \200 Shivering when actively cooling When actively cooling patients for therapeutic reasons shiv ering can limit the cooling process and potentially result in a harmful increase in metabol ic demand. In this context, the use of muscular blockade to allow further cooling may be ne cessary. Pressure areas (including peripheral nerve compres- sion) Physiotherapy and joint mobility Deep vein thrombosis prophylaxis Eye care and closure \200 \200 Muscle spasm and hyperpyrexia Rarely, conditions such as tetanus can lead to dangerous and intractable muscle spasms, and muscular blockade may be necessary to allow adequate ventila tion. In the speci \201 c case of malignant hyperpyrexia, dantrolene is used as it acts di rectly on the muscle to prevent release of calcium from the sarcoplasmic reticulum and ther efore uncouples myocyte contraction. The dose of dantrolene is 1mg/kg repeated as necessary to a maximum of 10mg/kg. It has also been used in severe neuroleptic malignant syndrome. 1 Problems and complications Prolonged paralysis and neuropathy This is the most signi \201 cant complication of using neu- romuscular blockers. Prolonged recovery from neuromus- cular blockade may be a simple pharmacodynamic phenomenon in the critically ill patient fa iling to metabolize the drugs as predicted. Many drugs can potentiate the duration of neuro muscular blockade; rather than learning lists, just stick to regular suspension of the infu sion and be aware of your individual patient \200\231s clinical response and recovery. More severely, neuromuscular blockade is a major risk factor for critical care myopathy, or acu te quadriplegic myopathy syndrome (AQMS). It is not possible to screen for AQMS, and only 5 0% of patients have a measured rise in serum creatine phosphokinase concentration. Concomit ant steroids are especially high risk for severe myopathy. There may also be an increased r isk with aminoglycoside antibiotics or cyclosporin. Management of raised ICP Once again the evidence for doing this is rather limited; however, there are situations when everything else has been done and the pressure is still high. Mo st ICUs will have a protocol for managing raised ICP, and neuromuscular blockade will featu re somewhere, usually before barbitu- rate coma or craniectomy. There is no particular reas on to use paralysis for transfer of patients with raised ICP if adequate sedation can be ac hieved; however, we all know that despite very high doses of sedation and analgesia some pa tients still gain additional relaxation and a fall in ICP following neuromuscular blockade, particularly during transfers and procedures. Use it in conjunction with ICP monitoring on a case by case basis. Further reading Murray MJ, Cowen J, DeBlock H, et al. Clinical practice guidelines for sust ained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2002; 30: 1 42 \200\22356. Perry J, Lee J, Wells G. Rocuronium versus succinylcholine for rapid sequence induction int ubation. Cochrane Database of Syst Rev 2003; (1): CD002788. Monitoring Is essential when using prolonged neuromuscular block- ade. The \201 rst monit or is clinical assessment: 212 J ADCOCK Anticonvulsant drugs other benzodiazepines, it causes sedation, hypotension, respiratory depression and occasion al respiratory arrest. Midazolam bolus can be used in early status at a dose of 5 \200\2231 0mg IV, which can be repeated once after 15min. If used as an infusion in intensive care, a loading dose of 0.15mg/kg should be administered, followed by an infusion of 0.05 \200\223 0.4mg/kg/h. It is available in 5ml ampoules containing 2mg/ ml, or a 2ml ampoule containin g 5mg. Anticonvulsant drugs are commonly used in intensive care patients, most often in patients w ith established epilepsy or in patients being treated speci \201 cally for status epilepti cus (SE). This chapter discusses in detail the anticonvulsant drugs commonly used to treat SE. First-line drugs: benzodiazepines Diazepam Diazepam is very effective in SE, and has been e xtensively studied. As with all benzodiazepines, its mechanism of action is via potentiatio n of the inhibitory neurotransmitter GABA. It can be administered by IV bolus injections or rectally, and has a rapid onset of action. Good brain levels are attained within 1min of a standard IV dose. Rectal administration produces a peak level after 20min. It is highly li pid soluble, is rapidly redistributed and therefore has a short duration of action. Sedatio n and hypotension may occur, and after repeat dosing, diazepam accumulates, resulting in pe rsisting high peak levels. This may result in sudden and unexpected CNS depression and card iorespiratory collapse. Diazepam is metabolized by hepatic enzymes. Bolus IV diazepam shoul d be given undiluted at a rate not exceeding 2 \200\2235mg/min, with standard adult bolus d ose being 10 \200\22320mg, with additional 10mg doses being given at 15min intervals to a m aximum of 40mg. It should not be mixed with other drugs. Second-line drugs Phenytoin This is a drug of \201 rst choice in established SE. It is hi ghly effective and has a long duration of action. It can also be continued as long-term tre atment. It causes minimal respi- ratory or cerebral depression, although hypotension is mor e common. Initial infusion takes 20 \200\22330min in adults, and the onset is slow. It ther efore needs to be given in conjunc- tion with a short-acting rapid onset benzodiazepine. It is well known that phenytoin has easily saturable pharmacoki- netics, but this is less of a problem in the acute setting. However, careful monitoring of level is required. It must b e given in normal saline to prevent precipitation, and must not be mixed with other drugs f or the same reason. It should not be given IM because of erratic absorption, and can cause thrombophlebitis. Other CNS effects can occur in the acute setting, particularly at high do ses, such as nys- tagmus and ataxia. Other adverse effects include nausea and vomiting, ras h and hepatic blood dyscrasias. If the drug is then continued in the longer term via the or al route once the status has been abolished, then its interac- tion with other drugs may be come problematic. This is because it is highly protein bound and because it is metabo- lize d via the P450 enzyme system and is therefore a power- ful inducer of hepatic enzymes. Phen obarbitone and carbemazepine have variable and unpredictable effects (either increase or de crease) on phenytoin levels since they both induce and compete for hepatic enzymes. Sodium valproate may elevate phenytoin levels by displacing it from its protein-binding site and a lso by inhibiting its metabolism. It decreases levels of many other drugs, including phenob ar- bitone. It inhibits carbemazepine, warfarin, oestrogens, benzodiazepines and corticoste roids. Other drugs whose levels are reduced by phenytoin and require monitoring and adjustm ent include frusemide and cyclosporin. Drugs that signi \201 cantly increase phenytoin lev els include isoniazid, omeprazole, cimetidine and sulfonamides. Drugs that lower phenytoin levels include amiodarone. Adult loading does is 15 \200\22318mg/kg, and the rate of admini s- tration should not exceed 50mg/min, with a lower infusion rate (<20mg/min) in the elderl y. Phenytoin is usually avail- able as 5ml ampoules containing 250mg of phenytoin sodium. Lorazepam Lorazepam has a smaller volume of distribution and is less lipid soluble than dia zepam. It has a slower onset but a longer duration of action. It has signi \201 cant advan tages over diazepam. It does not accumulate in lipid stores, and has strong cerebral bindin g and a long duration of action due to its distribution half-life. Lorazepam is extremely e ffective in status, and it is effective for up to 12h after a single dose (longer than diaz epam). Its main disadvantage is the rapid development of tolerance, with repeated doses bei ng much less effective. It shares the sedating side effects of all benzodiazpeines, but sud den cardiorespiratory collapse is much less likely because of its relative lipid insolubili ty and the lack of accumulation after a single dose. It is administered by IV bolus, and, a s distribution is slow, the rate of injection is not critical. In adults, a bolus dose of 0 .07mg/kg to a maximum of 4mg is given, which can be repeated once after 20min if required. It is usually available as a 1ml ampoule of 4mg/ml. Midazolam Unlike other benzodiazepines, midazolam is water soluble but becomes lipophilic a t physiological pH, allowing rapid transfer across the blood \200\223brain barrier. It may therefore be used buccally, intranasally and IM, as well as via the IV route. Buccal midazo lam (10mg in 2ml) has been shown to be as effective as rectal diazepam (10mg) in the manage ment of acute seizures in children. Because it is water soluble, midazolam takes 3 times lo nger than diazepam to peak EEG effects, and therefore repeat dosing should be delayed by se veral minutes to assess sedative effects fully. Its action is short lived because of a shor t half-life, and therefore the relapse rate is high after a single bolus injection. It is m ore suited as the benzodiazepine of choice for use as an infu- sion, as it is less likely t o accumulate because of its smaller volume of distribution and kinetic characteristics. As with Fosphenytoin This is an inactive water-soluble phenytoin prodrug, which is metabolized to p henytoin. The equimolar equivalent of 1mg of phenytoin is 1.5mg of fosphenytoin, and is sup plied in a ready mixed solution of 50mg phenytoin equivalents (PE) per ml (i.e. 75mg/ml). T his is to standardize the solu- tion to that of parenteral phenytoin. Fosphenytoin can be g iven at three times the rate of phenytoin, and should be given at 150mg/min. Fosphenytoin i s completely bioavailable following IM administration, although it is not routinely 213 CHAPTER 13.4 Anticonvulsant drugs bance, and rarely acute hypersensitivity. It should be used with caution in the elderly, an d in those with hepatic, renal or cardiac dysfunction. Thiopentone should be made up in nor mal saline and should not be administered with other drugs. The following regime is recomme nded in SE: a 100 \200\223250mg bolus over 20s, with further 50mg boluses every 2 \200\2233 min until seizures are abolished, with intubation and ventilation. An infusion of 3 \200 \2235mg/kg/h should continue to attain a blood level of 40mg/l. After 24h, metabolism may be at saturation, and blood levels should be measured once or twice daily to ensure they ar e not excessive. Thiopentone should continue until seizure activity has ceased as moni- tor ed by burst suppression on EEG for 12 \200\22324h. The usual preparation is a vial containi ng 2.5g with 100ml of dilutant to produce a 2.5% solution. recommended in the treatment of SE as this route has not been well studied in this particul ar circumstance. Peak con- centration occurs at 30min after administration. The half-life i s 15min. Although more expensive, it causes less throm- bophlebitis, less hypotension and i s better tolerated and easier to administer. Hepatic or haemopoietic adverse reactions, lik e those seen with phenytoin, also may occur. Phenobarbitone This is also a drug of choice in the treatment of established status. It is highly effective, has a rapid onset of action, has prolonged anticonvulsant effect and may also have a cerebral protective effect. Tolerance is unusual, and once seizures are control led they usually do not recur. There is also some evidence that if given with barbiturate a nesthesia it can reduce the risk of relapse following anesthetic withdrawal. The disadvanta ges are excessive sedation, hypotension and respiratory depression. Skin reactions are rare . With more prolonged therapy after the initial treatment of status, there is a risk of acc umulation, and therefore blood level monitor- ing is essential. Although it is a very stabl e drug, it should not be given via the IV infusion with other agents (e.g. phenytoin) as pr ecipitation may occur. Similarly to phenytoin, it is a powerful hepatic enzyme inducer, and therefore also may increases the metabolism of estrogen, steroids, warfarin, benzodiazepin es and carbemazepine. Its effect on phenytoin is unpredictable. Loading adult dose in adult s is 10mg/kg (doses up to 20mg/kg have been used), at a rate of 100mg/min, followed by main te- nance of 1 \200\2234mg/kg/day (either IV or orally). Phenobarbitone is usually availabl e in 1ml ampoules containing 200mg. Propofol This non-barbiturate anesthetic agent is also used in the treatment of resistant S E. Although it has signi \201 cantly less inherent antiepileptic properties compared with thiopen- tone, there is growing evidence of its usefulness in the management of status, and its ease of use offers some advantages. It also has neuroexcitatory effects, which can cau se muscle rigidity or abnormal movements including myoclonus, which can be mistaken for sei zures. Seizures have, however, been reported to occur occasionally with propofol withdrawal . It is extremely lipid soluble and has a high volume of distribution, and thus acts rapidl y in SE. It remains effective during continuous infusion, and a major advantage is that rec overy of consciousness following dis- continuation is very quick. It causes profound respir atory and cerebral depression, but hypotension is uncommon and cardiac side effects are few . Long-term use (e.g. in patients with prolonged intractable status) causes lipaemia, acido sis and rhabdomyolysis. The dose may need to be reduced when administered with ongoing use of benzodiazepines, opiates and phenothiazines. It may potentiate neuromuscular blockade of vecuronium. Higher doses may be required with concomitant theophyl- line administration. I n SE, a bolus of 1 \200\2232mg/kg is administered, followed by an infusion of 1 \200\2235mg /kg/h, as guided by the EEG burst suppres- sion pattern. After the patient has been seizure free for 12 \200\22324h, the dose can be gradually reduced over 24h to min- imize the risk of rebound seizures. It is available as 20ml ampoules containing 10mg/ml as an emulsion. Sodium valproate Sodium valproate is available in IV form and, although it is not recommend ed as \201 rst-line treatment for established SE, it may be a useful third-line agent, wh ich some units administer before using general anesthetic agents. It is certainly useful fo r administration to patients who for any reason cannot take their usual dose of valproate b y mouth, or whose serum level of valproate is low and must be increased quickly. In general , it is well tolerated, but patients with known liver dysfunction or mitochondrial disease may not be good candidates for this drug. Cases of pancreatitis have been reported after IV valproate. Valproic acid is given as an IV loading dose of 20mg/kg dissolved in normal sal ine and infused at a rate of 20 \200\223 50mg/min. Third-line drugs: anesthetic agents Thiopentone Thiopentone is used for barbiturate anesthe sia in SE. It is a very effective anticonvulsant drug, and may have cerebral- protective ef fects. The most signi \201 cant side effect is hypo- tension, and many patients require pr essor therapy. It also has saturable pharmacokinetics and a strong tendency to accumulate. If high doses are given, blood levels may remain high despite discontinuation, and days may pass before recovery of consciousness. Blood monitoring is essential, of both thiopentone and its metabolite pentonbarbitone. Other toxic effects include hepatic and pancreatic dist ur- Further reading Kumar A, Bleck TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992; 20: 483 \200\2238. Limdi NA, Shimpi AV, Faught E, et al. Ef \201 cacy of rapid IV administra- tion of valproi c acid for status epilepticus. Neurology 2005; 64: 353 \200\2235. Lowenstein DH, Alldredge BK. Status epilepticus, N Engl J Med 1998; 338: 970 \200\2236 Shorvon SD. Status epilepticus: its clinical features and treatment in children and adults. Cambridge: Cambridge University Press, 1994. Shorvon S, Dreifuss F, Fish D, et al. The tre atment of epilepsy. Oxford: Blackwell Science Ltd, 1996. 214 H MADDER Cerebroprotective agents have failed to demonstrate clear bene \201 t. The MAGPIE trial demonstrated a signi \201 cant reduction in the incidence of eclampsia in women with pre-eclampsia, which may be rel- evant to the discussion of cerebroprotection. The FAST- MAG trial is designed to evaluate the effect of early administration of magnesium on outcome in acute stroke patients. Magnes ium loading dose is delivered in the \201 eld by paramedics within 2h of symptom onset. A phase III trial in aSAH patients is currently underway The aSAH clinical model has the adv antage that the cerebroprotective inter- vention can be in place before the insult (vasospa sm) occurs. Cerebroprotection is the prevention or reduction of brain injury from an ischaemic or hypox ic insult before or during the time of insult. Neuroresuscitation refers to prevention or r eduction of injury after the injury has occurred. Understanding the pathophysiology of isch aemia is essen- tial as this points to which agents might work. The ischae- mic cascade inv olves release of excitatory neurotransmitters (such as glutamate), opening of cell membrane channels to allow calcium and sodium in \202 ux, generation of free radicals and ultimate ly membrane depolarization. Cell death occurs via two processes: \200 \200 Erythropoietin Erythropoietin (EPO) secretory sites and receptors have been identi \201 ed within the brain. Hypoxia and other stressors may result in increased production of EPO an d expression of EPO receptors (hypoxic cerebral pre-conditioning). Proposed mechanisms of a ction: blockade of apoptosis path- way at multiple steps (both neuronal and endothelial cel ls), enhancement of neurogenesis and angiogenesis. A phase II clinical trial has shown safe ty in stroke patients. A phase II trial in aSAH patients is currently underway. Necrosis: early, via process of in \202 ammation. Apoptosis: delayed, via mitochondrial an d DNA dam- age.