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. Cerebroprotective agents inhibit one or more points along the path of cell death. Ideal age nts would also enhance repair. Clinical models requiring cerebroprotection generally involv e either focal or global cerebral ischaemia. These include stroke, traumatic brain injury ( TBI), vasospasm following aneurysmal subarachnoid hemorrhage (aSAH), cardiac arrest and car diopulmonary bypass. Despite extensive preclinical evidence, most clinical trials have so f ar failed to demonstrate clear cerebroprotective ef \201 cacy. Much of this is a re \202 ection of the limitations of preclinical and clinical trials. The timing of therapy appears critical, i.e. early institution or even initiation prior to the insult. It is likely that multitherapy is the most effective strategy. The following list is by no means exhaustive. Focus is on those agents which currently show promise. HMG CoA reductase inhibitors (statins) Proposed mechanisms of action: anti-in \202 ammator y (reduced thrombogenesis and platelet activation), improved vaso- motor reactivity (upregu lation of endothelial NOS), reduced generation of reactive oxygen species. Two large clinic al trials have demonstrated the role of statins in the prevention of stroke. There is some evidence that statins may reduce the ischaemic de \201 cit following vasospasm in aSAH pat ients . A phase III clinical trial is currently underway. Progesterone Proposed mechanism of action: reduced excitotoxicity through GABA-mediated inh ibition, alteration of blood \200\223 brain barrier to reduce oedema formation, inhibition of apoptosis, anti-in \202 ammatory. A phase II clinical trial has demonstrated safety in TBI patients . Pharmacological cerebroprotection N-methyl-D-aspartate (NMDA) antagonists Proposed mechanis m of action: blockade of excitotoxic activity. Many have dose-limiting side effects in huma ns. Multiple clinical trials in stroke and TBI have failed to prove ef \201 cacy. An RCT o f 171 patients undergoing coronary artery bypass graft (CABG) demonstrated a reduction in n europsychological de \201 cit at 2 months in patients receiving remacemide pre- and post-o peratively . Hypothermia A wealth of preclinical trials point to hypothermia as a cer- ebroprotectant. T his is likely to be due to more than reduc- tion of the CMR, as even mild hypothermia (T = 34 C) appears bene \201 cial. Proposed mechanisms of action include reduction in excitoxi city, lipid peroxidation and free radical damage. Promising phase II trials in TBI did not translate into a positive phase III study. Clifton et al. investigated the effect of hypoth ermia (target T 33 C within 8h of injury) on outcome at 6 months following TBI. The study was halted after enrolment of 392 of planned 500 patients because the treatment was not eff ective. Patients >45yrs had poorer outcomes. The current NABIS:H IIR trial by the same inve s- tigators examines the effect of hypothermia (target T 33 C within 4h of injury) in pati ents <45yrs. Two trials published simultaneously demonstrated that mild to moderate therape utic hypothermia improves neuro- logical outcome after cardiac arrest. Although the studies were relatively small (77 patients and 273 patients, respec- tively), their conclusion has been incorporated into ILCOR recommendations for advanced life support of unconscious pati ents with spontaneous circulation after out-of-hospital Anesthetic agents Proposed mechanisms of action: reduction in CMR and reduction in ICP, bot h of which may limit secondary dam- age, sodium channel blockade, inhibition of lipid perox ida- tion, free radical scavenging and potentiation of GABA-mediated inhibition. Clinical t rials are small and inconclusive. The Brain Trauma Foundation guidelines for the management of severe traumatic brain injury include thiopentone as 2nd tier therapy for severe refrac tory intracranial hypertension. Although cerebroprotection has not been conclusively demons trated, thiopentone, propofol and volatile agents may extend the window of ischaemic tolera nce. Magnesium Proposed mechanism of action: inhibition of glutamate release, NMDA receptor bloc kade, calcium channel blockade, vasodilation. Large clinical trials in stroke and TBI 215 CHAPTER 13.5 Cerebroprotective agents cardiac arrest . Importantly, the need for avoidance of hyperthermia is stressed. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acu te brain injury. N Engl J Med 2001; 344: 556 \200\22363. Other strategies Decompressive craniectomy Wide decompressive craniectomy to reduce raised ICP makes good sense in terms of prevention of secondary brain injury. It has been well des cribed in the setting of TBI and stroke. Two large multi-center trials involving TBI patien ts are currently underway. http://www.clinicaltrials.gov/ct/show/ NCT00178711 http://www.braintrauma.org/guidelines http://www.fastmag.info http://www.rescueicp.com http://www.stashtrial.com Maintenance of cerebral blood \202 ow and oxygenation Whilst the search for de \201 niti ve cerebroprotective agents continues, preventative and supportive strategies must not be f orgotten. Careful attention to maintenance of CBF is paramount. Targets should be set to ac hieve adequate CPP, appropriate arterial carbon dioxide tension, promotion of cerebral veno us drainage and early control of raised ICP. Cerebral oxygen delivery needs to meet cerebra l oxygen requirements. Early airway protection, controlled ventila- tion, appropriate sedat ion, control of seizures and preven- tion of hyperthermia will all promote cerebral oxygen demand vs supply balance. These fundamental strategies remain the mainstay of cerebral prot ection. http://www.surgery.cuhk.edu.hk/imash-trial Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reduces vasospasm after aneurysmal subarach noid hemorrhage: results of a pilot ran- domized clinical trial. Stroke 2005; 36: 2024 \200 \2236. Muir KW, Lees KR, Ford I, et al. Magnesium for acute stroke (Intravenous Magnesium Ef \201 cacy in Stroke trial): randomized controlled trial. Lancet 2004; 363: 439 \200\22345. Temkin NR, Anderson GD, Winn HR, et al. Magnesium sulfate for neuroprotection after traumat ic brain injury: a randomized con- trolled trial. Lancet Neurol 2007; 6: 29 \200\22338. The Hypothermia after Cardiac Arrest Group. Mild therapeutic hypothermia to improve the neu rologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549 \200\22356. Tseng MY, Czosnyka M, Richards H, et al. Effects of acute treatment with pravastatin on cer ebral autoregulation, and delayed ischemic de \201 cits after aneurysmal subarachnoid hemo rrhage: a phase II randomized placebo-controlled trial. Stroke 2005; 36: 1627 \200\22332. W right DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a ran- domised clinical trial of pro gesterone for acute traumatic brain injury. Ann Emerg Med 2007; 49: 391 \200\223402. Further reading Amarenco P, Bogousslavsky J, Callahan A 3rd, et al, Stroke Prevention by Ag gressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose artorvostatin af ter stroke or transient ischemic attack. N Engl J Med 2006; 355: 549 \200\22359. Arrowsmith JE, Harrison MJ, Newman SP, et al. Neuroprotection of the brain during cardiopul monary bypass: a randomized trial of remacemide during coronary artery bypass in 171 patien ts. Stroke 1998; 29: 2357 \200\22362. 216 A EYNON Mannitol and hypertonic saline Introduction The capillary endothelial cells within the brain are con- nected via tight jun ctions forming a blood \200\223brain barrier (BBB). The BBB is a semi-permeable membrane th at limits bulk movement of \202 uid from the brain capillaries into the parenchyma. The B BB is moderately permeable to water but relatively impermeable to small solutes and protein s. Glucose and certain amino acids are actively transported across the BBB. The BBB is not present in the choroid plexus or in certain areas of the hypothalamus. The BBB may be disru pted by pathology, especially in head injuries and anoxic insults. When this occurs, there is \202 ow of proteins and electrolytes into the brain parenchyma creating a hydrostatic pressure that results in \202 uid move- ment into the tissue. This is known as vasogenic oedema. Cytotoxic oedema is due to swelling of the neuronal and/ or glial cells, frequently results from hypoxic injury and is the predominant process in the very acute stages follow ing brain injury. and increase the risk of renal impairment. There is no evi- dence that administration of ma nnitol results in reduction of cerebral water content from normal brain alone, causing a wo rsening of midline shift in the presence of a mass lesion. Practical administration The priorities in the management of a patient with acute intracran ial hypertension, from whatever cause, are the same as for all critically ill patients, nam ely ABC (control of airway, breathing and circulation). The airway must be protected, 100% oxygen applied and the pCO2 controlled between 4 and 5kPa. These may require intubation and ventilation. ICP should be presumed to be at least 20mm Hg in a patient who is comatose, a nd the cerebral per- fusion pressure (CPP = MAP \200\223 ICP) should be maintained above 6 0mm Hg, with the use of inotropes as necessary. If the patient shows signs of coning at any stage (pupillary dilatation and/or contralateral hemiparesis), 2ml/kg of 20% mannitol shou ld be administered. This dose can be repeated if there is no response or if signs of coning recur. As detailed above, this is not a treatment but rather a hold- ing measure until oth er therapies can be employed. Hypotension, secondary to the diuretic effects of mannitol, s hould be avoided, as this may cause secondary brain injury. The use of high doses of mannit ol as a rescue therapy for patients with a GCS of 3 and pupillary abnormalities has been di scredited. Mannitol Mannitol is a low molecular weight solute (182Da) that can be added to crystalloid solution to make it hyperosmolar. It is commonly used as a 20% solution (1098mosm/kg). The European Brain Injury Consortium and the Brain Trauma Foundation recommended mannitol as t he osmotic drug of choice in brain-injured patients. The Brain Trauma Foundation recommends 2ml/kg of 20% mannitol, infused over 20min, for patients with clinical signs of raised ICP or deteriorating neurological function, before ICP monitoring is instituted. These guideli nes are based on studies that show better ICP control and slightly better outcomes in patie nts given mannitol compared with barbiturate coma. As such, there remains considerable conf usion over the optimal treatment regime, the effectiveness of mannitol, especially compared with hypertonic saline solutions, and the timing of its usage. Hypertonic saline Hypertonic saline (HTS) is an attractive alternative to mannitol as an os motic agent. The BBB permeability to sodium is low, thus producing an osmotic gradient wher e the BBB is intact. Administration of HTS produces an increase in circulating blood volume and consequent rise in CPP. HTS may also modulate the in \202 ammatory response by reduci ng leucocyte adhesion to the endothelium. HTS does not have the diuretic properties of mann itol, thus reducing the risk of hypotension and volume depletion following its usage. A var iety of concentrations of HTS are available ranging from 3% (1026mosm/kg) to 23.4% (8008mos m/kg). Animal studies have suggested that HTS may be more effective than mannitol in reduci ng raised ICP, and with a longer duration of action. In adult patients with raised ICP, HTS has been shown to produce a signi \201 cant decrease in ICP that correlates with increasi ng serum osmolarity. Interestingly, the effects of HTS seem to extend long after the osmoti c effects have disappeared and to be poorly correlated with serum sodium concentration. HTS may produce decreases in ICP in patients who are refractory to the action of mannitol, sug gesting that the two agents have differing mechanisms of action. Outcome studies in the adu lt population are limited. A number of trials have reported the bene \201 cial effects of HTS in pediatric popula- tions where it has been used largely as an infusion rather than as bolus, rescue therapy. Osmolalities have been allowed to rise as high as 371mOsm/kg. HTS m ay cause a number of systemic side effects. These include coagulopathies, fluid overload an d electrolyte disturbances. In particular, HTS may cause a non-anion gap metabolic acidosis , hypokalaemia and hypocalcaemia. Concerns regarding renal impairment, central pontine Actions of mannitol Mannitol reduces ICP within a few minutes. Distribution is rapid, with a half-life of 10min. Its diuretic action occurs within 1 \200\2234h, such that its bene \201 cial effects cannot result from it being an osmotic diuretic. Serum osmolarity is incr eased following mannitol administration. This draws water into the vascular compartment fro m all tissues (including the brain), resulting in a temporary increase in blood pressure. I f autoregulation is intact, the increase in CPP will cause cerebral vasoconstriction and co nse- quent reduction in ICP. The haematocrit is reduced follow- ing mannitol administration . This may also increase CBF and oxygen delivery. Mannitol also decreases CSF produc- tion, which leads to a reduction in cerebral volume and consequently a reduction in ICP. It is a lso a free radical scavenger. Mannitol does accumulate in the interstitium following repeat ed doses. If this rises signi \201 cantly, there is a theoreti- cal risk that the normal g radient between brain and blood is reversed and cerebral oedema is worsened. If repeated do ses are given, it is prudent to measure serum osmolality. The concern that toxicity is indu ced if the serum osmolality exceeds 320mosm/kg is largely theoretical. It is important to e nsure that patients do not become dehydrated through repeated mannitol usage as that may wo rsen cerebral injury 217 CHAPTER 13.6 Mannitol and hypertonic saline leading to an increase in brain water content. It is there- fore, important to wean hyperos molar solutions slowly. myelinolysis and rebound increases in ICP have not been con \201 rmed. HTS of >2% concentr ation should be given via a central venous catheter due to the risk of throm- bophlebitis, thus limiting its usage in the pre-hospital setting. Rebound oedema may occur if hyperosmol ar therapy has been prolonged, leading to equilization of the osmolar gra- dient across the BBB. Within a few hours of hyperosmolar therapy, levels of intracellular electrolytes and organic osmoles increase. These restore cell size to normal despite the hyperosmolar state. When hyperosmolar therapy is discontinued, a reverse gradient may be established, Further reading Ogden AT, Mayer SA, Connolly ES Jr. Hyperosmolar agents in neurosurgical pr actice: the evolving role of hypertonic saline. Neurosurgery 2005; 57: 207 \200\22315. Task Force of the American Association of Neurological Surgeons and Joint Section in Neurot rauma and Critical Care. Guidelines for the management of severe head injury. Brain Trauma Foundation, 1995. Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Datab ase Syst Rev 2007; (1): CD001049. This page intentionally left blank 219 Chapter 14 Hematological drugs Chapter contents Anticoagulants and heparin-induced thrombocytopenia 220 Thrombolysis 224 Anti \201 brinoly tics 226 220 B HUNT Anticoagulants and heparin-induced thrombocytopenia Introduction For >50 years, the options for therapeutic anticoagulation were limited to unf ractionated heparin (UFH) and oral vitamin K antagonists. While highly effective, both drug s have major safety problems. Both have narrow therapeutic ranges, substantial interindivid ual dose variability, major side effects and require regular therapeutic drug monitor- ing, with a narrow therapeutic window and high incidence of bleeding complications. Low molecul ar weight heparins (LMWHs; 1980s) repre- sented a substantial advance in therapeutic antico agulation. Predictable pharmacokinetics with thus no requirement for monitoring, as well as a longer half-life and thus less frequent dosing, and a lower frequency of heparin-induced thrombocytopenia (HIT). In the 1990s several new parenteral anticoagulants appeared, inclu ding the synthetic heparin derivatives fondaparinux and the direct thrombin inhibitors arga troban, hirudin and bivalirudin. The present decade sees the emergence of an exciting new g eneration of oral anticoagulants, which do not require routine thera- peutic monitoring. Th ese are mainly oral direct thrombin inhibitors such as Dabagatran and oral antiXa agents su ch as Rivaroxaban. adult). The aPTT ratio (aPTT-R) is measured 4 \200\2236h after commencing the infusion, and the rate of infusion adjusted accordingly. Thereafter, the APTT-R should be monitored at l east once every 24h, as heparin requirements can change rapidly over time. The platelet cou nt should be checked before starting UFH and repeated at least every other day between days 4 and 14 of UFH treatment. If the patient has received heparin within the last 100 days, p late- let count monitoring should begin within 24h of starting heparin to monitor for HIT. Prophylactic doses of SC UFH range from 5000 to 7500IU bd. aPTT monitoring is not required when prophylactic doses are used, but the platelet count should be monitored as HIT can occ ur. The aPTT is sensitive to both thrombin and factor Xa inhi- bition. The aPTT can be expr essed in seconds or as a ratio to a control aPTT time (aPTT-R). An aPTT-R of 1.5 \200\2232. 5 is usually associated with therapeutic anticoagulation, but because aPTT reagents have di ffering heparin sensitivity, local reference ranges should be used. Clinical use of the act ivated clotting time is now restricted to monitoring the very high heparin doses used for a nticoagulation in extra- corporeal circuits. Reversal As IV UHF has a short half-life, cessation of the infusion is usually suf \201 ci ent for the management of mild bleeding symptoms. For more severe bleeding, rapid reversal of the anticoagulant activity of UFH can be with 1mg protamine for every 100IU of heparin g iven within the previous hour up to a maximum of 40 \200\22350mg protamine. The dose can be repeated if necessary. Protamine is a protein derived from \201 sh milt, and can lead to allergic reactions. Unfractionated heparin Composition UFH is a naturally occurring glycosaminoglycan produced by mast cells and basophils derived from tissues rich in mast cells, such as porcine intest ine or bovine lung. The heparin molecule is a polymer of repeating disaccharide units, prim arily comprising sulfated glucosamine and uronic acid. Heparin is a heterogeneous mixture o f differing chain lengths, but most preparations have a mean molecular weight of 13 000 \200\22315000Da. Indications and contraindications The main indication in UK hospitals is perioperative brid g- ing of warfarin in patients with mechanical heart valves, during vascular surgery and ex tracorporeal circuits, and in renal failure. Otherwise for the treatment of venous thromboe mbolism and thromboprophylaxis, UFH has been largely superseded by LMWH except in renal fai lure. The only absolute contraindications to all types of heparin are current major bleedin g or con \201 rmed history of HIT, especially if in the last 100 days. Mechanism of action and pharmacology The anticoagulant activity of heparin is mediated by e ndog- enous antithrombin, a physiological inhibitor of coagula- tion. A speci \201 c penta saccharide sequence of the heparin molecule binds to antithrombin inducing a conformational change and a 1000-fold increase in antithrombin activity. In turn, antithrombin inhibits t hrombin and factor Xa, both essential factors for normal coagulation. Only the pen- tasacch aride sequence is required for the inhibition of fac- tor Xa (anti-Xa activity), whereas a longer sequence of 18 saccharides, including the pentasaccharide, is necessary for thrombin inhibition. Anticoagulant activity in different heparins depends on the distribution of he parin chain molecular weights. The activ- ity of heparins is standardized in either Interna tional Units (IU) as determined by the World Health Organization international standard, or United States Pharmacopoeial (USP) units. Heparins are only active when administered paren terally; IM administration should be avoided as it can result in large haematomas. The half -life of IV UFH is 45 \200\223 60min, demanding continuous IV infusion for effective anti- coagulation. UFH given SC has a lower bioavailability than IV heparin. By the SC route, UFH activity starts at 2h and lasts 10h, necessitating twice daily administration. Adverse effects A slight fall in platelet count (of <30% compared with base- line) occurs i n up to 1/3 of patients within the \201 rst 4 days of starting heparin. This is a reversi ble dose-dependent phenomenon, not associated with bleeding or thrombosis, and does not req uire cessation of heparin. Falls in platelet count of >50% compared with baseline should ra ise the possibility of HIT. HIT is a life-threatening complication of heparin treatment and occurs in 0.3 \200\2236.5% of those receiving UFH. The onset is typically between 5 and 10 days after starting UFH, unless heparin has previ- ously been administered, in which case it may begin earlier. The cause is development of an IgG antibody to heparin and platelet f actor 4, which forms a complex capable of activating and depleting platelets. Because the t hrombocy- topenia is due to platelet activation, patients with HIT are paradoxically at hig h risk of both venous and arterial thrombosis; bleeding is rare. Other features may include necrotizing skin changes at heparin injection sites Dosing Treatment with IV UFH is usually initiated with an IV bolus over 5min (5000IU for a 70kg adult) followed by continu- ous IV infusion (15 \200\22325IU/kg/h, or 1400IU/h for a 7 0kg 221 CHAPTER 14.1 Anticoagulants and heparin-induced thrombocytopenia or a history of anaphylactic reactions to heparin injection. A clinical scoring system for suspected HIT has been devel- oped, and can be useful in determining the need for further i nvestigation. The diagnosis of HIT may be con \201 rmed by speci \201 c enzyme- linked im munosorbent assay (ELISA) or by functional platelet studies. The treatment is immediate ces sation of all heparins (including line \202 ushes and including LMWH), and initiation of an alternative anticoagulant such as danapar- oid, hirudin or fondaparinux at therapeutic d oses. Platelet transfusion is contraindicated, and warfarin should not be started until the platelet count has recovered, as it may cause microvascular necrosis. Adverse effects HIT is rare when compared with the rate with UFH. Patients with cutaneous r eactions to LMWHs may tolerate other LMWH formulations or danaparoid, but cross-reac- tivit y rates are high. Fondaparinux is a useful alternative in this scenario. Danaparoid Danaparoid sodium is a low molecular weight heparinoid derived from animal intes tinal mucosa. It is a mixture of heparan, dermatan and chondroitin sulfates, and, like LMWH s, inhibits factor Xa via antithrombin, with little anti- IIa activity. Danaparoid is admin istered parenterally, either IV or SC, and has an elimination half-life of 24h. It is used primarily for the treatment of HIT. Clearance of danapar- oid is partially renal, so dose r eduction and therapeutic monitoring is required in patients with renal failure. There is no speci \201 c reversal agent for danaparoid \200\224it is not neu- tralized by protamine s ulfate. Low molecular weight heparins LMWHs are produced by the depolymerization of UFH. Mechanism of action and pharmacology The anticoagulant activity of LMWHs is mediated by ant i- thrombin. An antithrombin-binding pentasaccharide sequence alone is required for the inh ibition of factor Xa (anti-Xa activity), whereas a longer sequence of 18 saccha- rides, inc luding the pentasaccharide, is required for the bridging function necessary to inhibit thro mbin. This explains the higher ratio of anti-Xa to anti-IIa activity of smaller LMWH molecu les. In contrast to UFH, which is rapidly cleared by the reticu- loendothelial system, LMWH s are cleared slowly by a renal mechanism. In those with normal renal function, the bioa- v ailability and clearance of SC LMWHs are suf \201 ciently pre- dictable to allow dosing wi thout monitoring. Coumarins The coagulation factors II, VII, IX and X, as well as the natu- rally occurring a nticoagulants protein C and S, are depend- ent upon vitamin K. In each case, synthesis of t he functional protein requires the post-translational -carboxylation of N-terminal glutam ine residues, and warfarin antagonizes the effect of vitamin K. Peak serum concentrations a re reached at 3h of oral administration, and the half-life is 36 \200\22342h. Warfarin is highly protein bound, mainly to albumin. Despite rapid absorp- tion of warfarin and other c oumarins, the onset of the anti- coagulant effect is delayed as it requires the gradual dep letion of functional coagulation factors. Metabolism is hepatic, requiring the cytochrome P 450-2C9 hepatic microsomal enzyme. A number of genetic and environmental factors affect the absorption, pharmacokinetics and pharmacodynamics of coumarins. Genetic polymorphisms of t he CYP2C9 enzyme are primarily responsible for differences in warfarin metab- olism. The mo st common polymorphisms, CYP2C9*2 and CYP2C9*3, are each seen in 10% of Caucasians, and ar e associated with a reduced warfarin requirement. A small proportion of individuals (<1%) h ave a hereditary resist- ance to coumarins mediated by reduced af \201 nity of the cou- ma rin receptor and require very large doses of coumarins (e.g. \211 30mg warfarin daily) to achieve an anticoagulant effect. Dosage and monitoring LMWHs should be dosed according to the manufacturer \200\231s instruc tions. Given the renal clearance of LMWHs, bleeding complica- tions are more common; with r enal failure, dose adjust- ment is necessary and should be guided by monitoring of the anti -Xa level or UFH should be used. One of the advantages of LMWHs is that routine monitor- in g is not necessary unless there is renal failure or in mor- bidly obese patients. If monito ring is required, the aPTT is not suf \201 ciently sensi- tive to anti-Xa activity so dire ct measurement of plasma anti-Xa activity is required. As anti-Xa activity declines rap- id ly in vitro, analytic samples must be rapidly transported to the laboratory on ice, centrif uged at 4 C, separated and either assayed immediately or frozen at \200\22370 C for subs e- quent analysis. Target anti-Xa ranges vary by LMWH prod- uct and indication; manufacture rs \200\231 data should be consulted. Because of the risk of HIT, patients receiving LMWHs should have a baseline platelet count on the day of starting treatment, and platelet counts every 2 \200\2234 days between days 4 and 14 of treatment. Interactions Foods rich in vitamin K1 (phytonadione) reduce the ef \201 - cacy of coumarin s by overcoming its inhibition of vitamin K recycling. Numerous drugs and herbal remedies a re known to interact with coumarins and alter the anticoagulant effect. In addition, antipl atelet agents, including NSAIDs, can lead to an increase in bleeding risk. Reversal Most bleeding complications can be managed by dose reduction or cessation of LMWH. For severe bleeding, par- tial reversal of the anticoagulant activity of LMWH can be achie ved with 1mg protamine for every 100IU of LMWH given within the previous 8h (maximum 40 \200\22350mg pro- tamine); this can reverse up to 90% of anti-IIa and 60% of anti-Xa activi ty. A partial return of LMWH anticoagulant activity may be seen 3h after reversal due to co ntinued LMWH absorption from the SC injection site. Protamine can be re-administered if nec essary. Monitoring Because of the considerable interindividual variability in dose requirements, an d the myriad food and drug interac- tions, coumarins require routine therapeutic monitoring of the INR. Reversal Administration of vitamin K1 can reverse the anticoagulant effects of coumarins, b ut takes at least 6h, as it necessitates the de novo production of active -carboxylated c oagula- tion factors by the liver. 222 B HUNT sites of the thrombin molecule. Hirudin is given either as an IV infusion or by twice-daily SC injection. It is not active orally. As the clearance of hirudin is exclusively renal, t he half-life is highly dependent on renal function. With normal renal function, hirudin has a half-life of 60min after IV administra- tion, but in those with end-stage renal failure the half-life can be as long as 300h. Hirudin requires therapeutic monitoring. The aPTT is usu- ally used, with a typical target aPTT-R of 2.0 \200\2232.5. The ecarin clotting time m ay be a better alternative for hirudin moni- toring, but is less widely available. Hirudin is licensed for the treatment of thrombosis associ- ated with HIT. Its major adverse effect is bleeding. 40 \200\22370% of patients develop hirudin antibodies after a week of treatme nt. The antibodies are rarely inhibitory, but may bind to hirudin and reduce renal clearanc e, resulting in a prolongation of half-life. There is no speci \201 c reversal agent for h irudin. Options in bleeding patients include blood product support, activated prothrombin c omplex concentrates or recombinant acti- vated factor VII. Hirudin is not cleared by haemod ialysis. A dose of 10mg vitamin K will make anticoagulation with coumarins dif \201 cult during the following 2 weeks, so 1mg vitamin K may therefore be preferable in patients without life-t hreatening bleeding. FFP contains all the vitamin K-dependent coagulation fac- tors, and ca n reverse warfarin when given at a dose of 15 \200\223 20ml/kg. As the half-life of factor VII is short, vitamin K replacement should be given concomitantly. Prothrombin complex conc entrates (PCCs) are plasma- derived products containing the vitamin K-dependent coagulation factors in a concentrated form. The activity of PCCs is usually expressed in terms of unit s of factor IX, the typical dose required for warfarin reversal being 20IU/kg in a slow IV push over several minutes. Although more expen- sive than FFP, PCCs have the advantage of a small volume of administration, rapid preparation (no thawing required) and more complete reversal of warfarin activity. They are the treatment of choice when fast reversal is requi red. As with FFP, vitamin K replacement should be given in con- junction with PCCs. Adverse effects The principal adverse effect of coumarins is bleeding, with a risk of fatal hemorrhage of 0.25%/yr in unselected patients, the risk being much higer in critical care patients. In individuals with hereditary protein C de \201 ciency, cou- marin-induced skin necrosis due to microvascular throm- bosis can occur. This complication can be avoided by using an alternative anticoagulant (e.g. a LMWH) during cou- marin loading. Bivalirudin Bivalirudin is a recombinant 20 amino acid polypeptide analog of hirudin. It bi nds to the substrate-binding site of thrombin, but, unlike hirudin, can be cleaved by throm bin itself, making bivalirudin a reversible thrombin inhibitor. Bivalirudin has a half-life of 25min following IV injection. Because only a proportion of excretion is renal, clearanc e is less dependent upon renal function than for hirudin. Bivalirudin is monitored using th e aPTT or ecarin clotting time. Because of its short half-life, the clini- cal use of bival irudin is usually restricted to the manage- ment of acute coronary symptoms and to anticoag ulation during PCI. There is no speci \201 c reversal agent for bivalirudin. Because of th e short half-life, bleeding can be managed with blood product support alone until the antic oagulant activity declines.