 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Notes \200 The epidural catheter should typically be placed in the mid-dermatome range of the site of the pain. Fentanyl is more lipid-soluble than non-synthetic opioids so gains faster access to opioid receptors. Low bupivacaine concentrations are less likely to block larger diamete r motor \201 bres allowing the patient to mobilize. It is usual to infuse combinations of drugs in lower doses to maximize the analgesic effect while minimizing side effects. Highe r volume infusions block a greater range of nerve routes. A bolus of 1 \200\2232mL of local anesthetic will typically block one dermatome. Age reduces the volume required. Inadequate block may respond to a bolus dose or increasing the infusion rate. Clonidine may enhance a nalgesia provided by epidural opioids and local anesthetics. Coagulation should be checked before removing an epidural catheter to avoid haematoma. At least 12 hours should be left a fter the last dose of low molecular weight heparin. EPIDURAL ANALGESIA 307 Drug dosages Concentration 2 \200\2234mcg/mL 50mcg/mL 20mcg/mL 0.1 \200\2230.125% 2mcg/mL Dose 0 \200\22340mcg/h 0 \200\2230.5mg/h 0 \200\2230.2mg/h 12.5mg/h 15 \200\22320mcg/h Fentanyl Morphine Diamorphine Bupivacaine Clonidine See also: Non-opioid analgesics, p302; Opioid analgesics, p304; Respiratory failure, p350; Hypotension, p380; Bradyarrhythmias, p386. 308 CHAPTER 18 Neurological drugs Sedatives and tranquilisers Types \200 \200 \200 \200 Benzodiazepines, e.g. diazepam, midazolam, lorazepam. Major tranquilizers, e.g. chlorpromaz ine, haloperidol. Anesthetic agents, e.g. propofol, iso \202 urane. A2 agonists, e.g. clon idine, dexmedetomidine. Uses \200 Sedation and anxiolysis. Routes \200 \200 \200 \200 IV (benzodiazepines, haloperidol, propofol, clonidine, dexmedetomidine). IM (benzodiazepine s, chlorpromazine, haloperidol). PO (diazepam, lorazepam, chlorpromazine, haloperidol, clon idine). Inhaled (iso \202 urane). Side effects \200 Hypotension (benzodiazepines, chlorpromazine, haloperidol, propofol, clonidine, dexmedetomi dine). Respiratory depression (benzodiazepines, chlorpromazine, haloperidol, propofol). Arr hythmias (chlorpromazine, haloperidol). Dry mouth (clonidine, dexmedetomidine). Extrapyrami dal disorder (chlorpromazine, haloperidol). Fluoride toxicity (iso \202 urane). Rebound ag itation on drug withdrawal (benzodiazepines). \200 \200 \200 \200 Notes \200 Sedative drugs have cardiovascular and respiratory side effects. Objective assessment of th e depth of sedation is necessary to ensure comfort does not give way to excessive sedation. All sedatives are cumulative so doses must be kept to a minimum. Stopping sedation daily h as been shown to reduce critical care stay. Benzodiazepines have an advantage of being amne sic. Midazolam is slowly metabolized in 10% of patients. All benzodiazepines accumulate in renal failure; care must be taken to avoid excessive dosage by regular reassessment of need . Propofol in sub-anesthetic doses is short-acting, but effects are cumulative with prolong ed infusion or with coexisting hepatic/renal failure. Large dose propofol may contribute si gni \201 cantly to calorie intake via the fat emulsion. As chlorpromazine and haloperidol antagonize catecholamines, they may cause vasodilatation and hypotension. Dystonic reaction s and arrhythmias (e.g. torsade de pointes) are also occasionally seen. A2 antagonists offe r both analgesia and sedation, and are synergistic with opiates. Dexmedetomidine causes min imal respiratory depression and the patient is easily rousable. Bradycardia and hypotension may occur, especially with the loading dose. Iso \202 urane is short-acting although cumu lative effects have been recorded with prolonged use that also carries the theoretical risk of \202 uoride toxicity. Exhaled iso \202 urane should be adequately scavenged. \200 \200 SEDATIVES AND TRANQUILISERS 309 Drug dosages Bolus 0.05 \200\2230.15mg/kg IV/IM 50mcg/kg IV/IM 1mg IV 0.5 \200\2232mg/kg IV 25 \200\2235 0mg IM 2 \200\22310mg IV/IM Infusion Too long-acting 10 \200\22350mcg/kg/h Too long-acting 1 \200\2233mg/kg/h Too long- acting Too long-acting 100 \200\223150mcg/h Diazepam Midazolam Lorazepam Propofol Chlorpromazine Haloperidol Clonidine Dexmedetomidine Loading infusion of 6.0mcg/kg/h over 10min, followed by maintenance infusion of 0.2 \200 \2230.7mcg/kg/h. Note that the above doses are a guide only and may need to be altered widely according to i ndividual circumstances. Key papers Kress JP, Pohlman AS, O Connor MF, et al. (2000) Daily interruption of sedative infusions in criti- cally ill patients undergoing mechanical ventilation. N Engl J Med 342: 1471 \200\2237. Pandharipande PP, Pun BT, Herr DL, et al. (2007) Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS random ized controlled trial. JAMA 298: 2644 \200\22353. Girard TD, Kress JP, Fuchs BD, et al. (2008) Ef \201 cacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awa kening and Breathing Controlled trial): a randomized controlled trial. Lancet 371: 126 \200 \22334. Monitoring sedation Frequent, objective reassessment of sedation depth and degree of agita- tion with corresponding adjustment of infusion doses is necessary to avoid severe cardiova scular and respiratory depression. Simple sedation scores are available to aid assessment, e.g. Riker Score, CAM-ICU. UCL Hospitals Sedation Score Agitated and restless Awake and uncomfortable Aware but calm R oused by voice, remains calm Roused by movement Roused by painful or noxious stimuli Unrous able Natural sleep Sedation doses are adjusted to achieve a score as close as possible to. Positive scores require increased sedation doses and negative scores require reduced sedati on doses. +3 +2 +1 0 \200\2231 \200\2232 \200\2233 A See also: IPPV \200\224failure to tolerate ventilation, p52; IPPV \200\224assessment of wea ning, p60; EEG/CFM moni- toring, p204; Respiratory stimulants, p256; Delirium, p442. 310 CHAPTER 18 Neurological drugs Muscle relaxants Types \200 \200 Depolarising, e.g. suxamethonium. Non-depolarising, e.g. pancuronium, atracurium, cisatracu rium, vecuronium, rocuronium. Mode of action \200 Suxamethonium is structurally related to acetylcholine and causes initial stimulation of mu scular contraction seen clinically as fasciculation. During this process, continued stimula tion leads to desensitization of the post- synaptic membrane of the neuromuscular junction with ef \202 ux of K+ ions. Subsequent \202 accid paralysis is short-acting (2 \200\2233 min) and cannot be reversed (is actually potentiated) by anticholinesterase drugs. Prolonge d effects occur with congenital or acquired pseudo-cholinesterase de \201 ciency. Non-depo larising muscle relaxants prevent acetylcholine from depolarising the post-synaptic membran e of the neuromuscular junction by competitive blockade. Reversal of paralysis is achieved by anticholinesterase drugs such as neostigmine. They have a slower onset and longer durati on of action than the depolarising agents. Uses \200 \200 To facilitate endotracheal intubation. To facilitate mechanical ventilation where optimal s edation does not prevent patient interference with the function of the ventilator. Routes \200 IV. Side effects \200 \200 \200 \200 Hypertension (suxamethonium, pancuronium). Bradycardia (suxamethonium). Tachycardia (pancur onium). Hyperkalaemia (suxamethonium). Notes \200 Modern practice and developments in ventilator technology have rendered use of muscle relax ants less common. It is now rarely necessary to fully paralyze muscles to facilitate mechan ical ventilation. Frequently reassess requirements for muscle relaxants. Ideally, relaxants should be stopped intermittently to allow depth of sedation to be assessed. If mechanical ventilation proceeds smoothly when relaxants have been stopped, they probably should not be restarted. Suxamethonium is contraindicated in spinal neurological disease, hepatic diseas e, and for 5 \200\22350 days after burns. Atracurium and cisatracurium are non-cumulative a nd popular choices for infusion. Non-enzymatic (Hoffman) degradation allows clearance indep endent of renal or hepatic function, although effects are prolonged in hypothermia. Rocuron ium has the most rapid onset of the non-depolarising muscle relaxants. MUSCLE RELAXANTS 311 Drug dosages Bolus 50 \200\223100mg 4mg 25 \200\22350mg 10mg 5 \200\2237mg 40 \200\22350mg Infusion 2 \200\2235mg/min 1 \200\2234mg/h 25 \200\22350mg/h 2 \200\2234mg/h Excessive half life 20 \200\22340mg/h Suxamethonium Pancuronium Atracurium Cisatracurium Vecuronium Rocuronium See also: Endotracheal intubation, p42; IPPV \200\224failure to tolerate ventilation, p52; IPPV \200\224failure to deliver ventilation, p54; Sedatives and tranquilisers, p308; Critic al care neuromuscular disorders, p460; Post-operative critical care, p620. 312 CHAPTER 18 Neurological drugs Anticonvulsants Types \200 \200 \200 \200 \200 \200 Benzodiazepines, e.g. lorazepam, diazepam, clonazepam. Phenytoin. Carbamazepine. Sodium val proate. Magnesium sulfate. Thiopental. Uses \200 \200 \200 Control of status epilepticus. Intermittent seizure control. Myoclonic seizures (clonazepam , sodium valproate). Routes \200 IV (lorazepam, diazepam, clonazepam, phenytoin, sodium valproate, magnesium sulfate, thiope ntal). PO (diazepam, clonazepam, phenytoin, carbamazepine, sodium valproate). PR (diazepam) . \200 Side effects \200 \200 \200 \200 \200 \200 \200 \200 \200 Sedation (benzodiazepines, thiopental). Respiratory depression (benzodiazepines, thiopental ). Nausea and vomiting (phenytoin, sodium valproate). Ataxia (phenytoin, carbamazepine). Vi sual disturbance (phenytoin, carbamazepine). Hypotension (diazepam, thiopental)). Arrhythmi as (phenytoin, carbamazepine). Pancreatitis (thiopental). Hepatic failure (sodium valproate ). Notes \200 Common insults causing seizures include cerebral ischaemic damage, space-occupying lesions, drugs or drug/alcohol withdrawal, metabolic encephalopathy (including hypoglycaemia), and neurosurgery. Anticonvulsants provide control of seizures but do not replace removal of the cause where this is possible. Onset of seizure control may be delayed by up to 24h with ph enytoin, but a loading dose is usually given during the acute phase of seizures. Magnesium sulfate is especially useful in eclamptic seizures (and in their prevention). Phenytoin has a narrow therapeutic range and a non-linear relationship between dose and plasma levels. T herefore, it is essential to monitor plasma levels. Enteral feeding should be stopped tempo rarily while oral phenytoin is administered. Carbamazepine has a wider therapeutic range th an phenytoin and there is a linear relationship between dose and plasma levels. Therefore, it is not critical to monitor plasma levels. Plasma concentrations of sodium valproate are not related to effects so monitoring of plasma levels is not useful. ANTICONVULSANTS 313 Intravenous drug dosages Bolus 4mg 2.5mg repeated to 20mg 18mg/kg at <50mg/min 20mmol over 10 \200\22320min 400 \200 \223800mg 1mg 1 \200\2233mg/kg Infusion Lorazepam Diazepam Phenytoin Magnesium sulfate Sodium valproate Clonazepam Thiopental 100mg 8-hourly 5 \200\22310mmol/h 1 \200\2232mg/h Lowest possible dose Key papers Treiman VA for the Veterans Affairs Status Epilepticus Cooperative Study Group. (1998) A com- parison of four treatments for generalized convulsive status epilepticus. N E ngl J Med 339: 792 \200\2238. Magpie Trial Collaboration Group. (2002) Do women with pre-eclampsia, and their babies, ben e \201 t from magnesium sulfate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 359: 1877 \200\22390. The Collaborative Eclampsia Trial. (1995) Which anticonvulsant for women with eclampsia? Ev idence from the Collaborative Eclampsia Trial. Lancet 345: 1455 \200\22363. See also: EEG/CFM monitoring, p204; Generalized seizures, p444. 314 CHAPTER 18 Neurological drugs Neuroprotective agents Types \200 \200 \200 \200 Diuretics, e.g. mannitol, furosemide. Corticosteroids, e.g. dexamethasone. Calcium antagoni sts, e.g. nimodipine. Barbiturates, e.g. thiopental. Uses \200 \200 \200 Reduction of cerebral oedema (mannitol, furosemide, dexamethasone). Prevention of cerebral vasospasm (nimodipine). Reduction of cerebral metabolic rate (thiopental). Routes \200 IV. Notes \200 Cerebral protection requires generalized sedation and abolition of seizures to reduce cereb ral metabolic rate, cerebral oedema, and neuronal damage during ischaemia and reperfusion. Mannitol reduces cerebral interstitial water as a result of its osmotic load. The effect is transient and best where the blood brain barrier is intact. Interstitial water is mainly r educed in normal areas of brain and this may accentuate cerebral shift. Repeated doses accu mulate in the interstitium and may eventually increase oedema formation; mannitol should on ly be given 4 \200\2235 times in 48h. In addition to its osmotic effect, there is some evid ence of cerebral vasoconstriction due to a reduction in blood viscosity and free radical sc avenging. The loop diuretic effect of furosemide encourages salt and water loss. There may also be a reduction of CSF chloride transportation, reducing the formation of CSF. Dexameth asone reduces oedema around space-occupying lesions such as tumors. Corticosteroids are not currently considered useful in head injury or after a cerebrovascular accident, but bene \201 t has been shown if given early after spinal injury. Corticosteroids encourage salt an d water retention and must be withdrawn slowly to avoid rebound oedema. Nimodipine is used to prevent cerebral vasospasm during recovery from cerebrovascular insults. As a calcium ch annel blocker, it also prevents calcium ingress during neuronal injury. This calcium ingres s is associated with cell death. It is commonly used in the management of subarachnoid hemo rrhage for 5 \200\22314 days. Thiopental reduces cerebral metabolism, thus prolonging the t ime that the brain may sustain an ischaemic insult. However, it also reduces cerebral blood \202 ow although blood \202 ow is redistributed preferentially to ischaemic areas. Thi opental acutely reduces intracranial pressure and this is probably the main cerebroprotecti ve effect. Seizure control is a further bene \201 t. Despite these effects, barbiturate co ma has not been shown to improve outcome in cerebral insults of various causes. NEUROPROTECTIVE AGENTS 315 Drug dosages Bolus 20 \200\22340g 6-hourly Infusion Mannitol Furosemide Dexamethasone Nimodipine Thiopental 1 \200\2235mg/h 4mg 6-hourly or 8 \200\22316mg od 0.5 \200\2232.0mg/h Lowest possible dose 1 \200\2233mg/kg Key papers Edwards P, Arango M, Balica L, et al and the CRASH trial collaborators. (2005) F inal results of MRC CRASH, a randomized placebo-controlled trial of intravenous corticoster oid in adults with head injury-outcomes at 6 months. Lancet 365: 1957 \200\2239. Allen GS, Ahn HS, Preziosi TJ, et al. (1983) Cerebral arterial spasm \200\224a controlled t rial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308: 619 \200\223 24. Bracken MB, Shepard MJ, Holford TR, et al. (1997) Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord inj ury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. Na tional Acute Spinal Cord Injury Study. JAMA 277: 1597 \200\223604. See also: Intracranial pressure monitoring, p200; Jugular venous bulb saturation, p202; EEG /CFM monitoring, p204; Other neurological monitoring, p206; Anticonvulsants, p312; Coma, p4 38; Generalized seizures, p444; Intracranial hemorrhage, p448; Subarachnoid hemorrhage, p45 0; Stroke, p452; Raised intracranial pressure, p454; Head injury (1), p594; Head injury (2) , p596. This page intentionally left blank 317 Chapter 19 Hematological drugs Anticoagulants 318 Thrombolytics 320 Coagulants and anti \201 brinolytics 322 318 CHAPTER 19 Hematological drugs Anticoagulants Types \200 \200 Heparin. Low molecular weight (LMW) heparin, e.g. dalteparin, enoxaparin, tinzaparin, fonda parinux. Heparinoids, e.g. danaparoid. Direct thrombin inhibitors, e.g. lepirudin, dabigatr an, rivaroxaban. Anticoagulant prostanoids, e.g. epoprostenol, alprostadil. Sodium citrate. Warfarin. \200 \200 \200 \200 Modes of action \200 Heparin potentiates naturally occurring antithrombin, reduces platelet adhesion to injured vessels, and promotes in vitro aggregation. LMW heparin appears to in \202 uence factor Xa activity speci \201 cally; simpler pharmacokinetics allow a smaller dose to be effective. Heparanoids are similar to heparin, with 10 \200\22320% risk of cross-reactivity. Use is m ainly restricted to treating heparin-induced thrombocytopaenia syndrome (HITS) and DVT prop hylaxis. No antidote is available. Lepirudin is a recombinant form of hirudin that forms an irreversible complex with thrombin. It is unrelated to heparin so can be used to treat HIT S. Antibody formation occurs in 40% of patients treated with lepirudin >6 days. Half-life i s long and there is no antidote. Dabigatran and rivaroxaban are being developed for oral th romboprophylaxis or treatment of thromboembolism without monitoring. There are no antidotes , but half-lives are short. Prostanoids affect the balance between native TXA2 and PGI2. So dium citrate chelates ionized calcium. Warfarin produces a controlled de \201 ciency of vi tamin K-dependent coagulation factors (II, VII, IX, and X). Effects develop in 48 \200\2237 2h. \200 \200 Uses \200 \200 Maintenance of an extracorporeal circulation. Prevention or treatment of thromboembolism. Routes \200 \200 \200 IV (heparins, heparinoids, prostanoids, sodium citrate). SC (heparins). PO (warfarin). Side effects \200 Bleeding. \200 Hypotension (anticoagulant prostanoids). \200 Hepari n-induced thrombocytopaenia. \200 Hypocalcaemia and hypernatraemia (sodium citrate). Notes \200 Alprostadil is less potent than epoprostenol. As it is metabolized in the lungs, systemic v asodilatation effects are usually minimal. For extracorporeal use, citrate has advantages o ver heparin as it has no antiplatelet activity and is readily haemo \201 ltered. ANTICOAGULANTS 319 Drug Dosages Unfractionated heparin Dose is titrated to produce an APTT of 1.5 \200\2233 times control. This usually requires 500 \200\2232000IU/h with an initial loading dose of 3000 \200\223500 0IU. Low molecular weight heparin For DVT prophylaxis, give 2500 \200\2235000IU dalteparin or 20 \200\22340mg enoxa- parin SC daily. For anticoagulation of an extracorporeal circuit, an I V bolus of 35IU/kg dalteparin or 0.25mg/kg enoxaparin is followed by an infusion of 13IU/kg dalteparin or 0.1mg/kg enoxaparin. Adjust dose to maintain anti-factor Xa activity at 0.5 \200\2231IU/mL (or 0.2 \200\2230.4IU/mL if high risk of hemorrhage). For DVT or pulmonary e mbolism, give 200IU/kg dalteparin or 1.5mg/kg enoxaparin SC daily (or 100IU/kg dalteparin b d if at risk of bleeding). Heparinoids Caution in patients with renal insuf \201 ciency. For DVT, prophylaxis give 75 0 anti-Xa units danaparoid SC bd. For DVT or pulmonary embolism with history of HITS, give a loading dose of 2500 anti-Xa units danaparoid IV, then infusion of 400U/h for 2h, 300U/h for 2h, then maintenance of 200U/h for \201 ve days. Target a thera- peutic anti-Xa level during the infusion of 0.5 \200\2230.7 anti-Xa units/mL. For anticoagulation of an extraco rporeal circuit, a loading dose of 3,500 anti-Xa units danaparoid IV is followed by continu ous infusion of 100 anti-Xa units/h. Direct thrombin Inhibitors Lepirudin: 0.1 \200\2230.4mg/kg bolus followed by 0.1 \200\2230. 15mg/kg/h infusion. Caution in patients with renal insuf \201 ciency. Anticoagulant prostaglandins Usual dose range is 2.5 \200\22310ng/kg/min. If used for an ex tracorporeal circu- lation, infusion should be started 30min prior to commencement. Sodium citrate Infused at 5mmol/L of extracorporeal blood \202 ow. Monitor Ca2+ (ideally ionized levels and treat as needed). Warfarin Start at 10mg/day orally for two days, then 1 \200\2236mg/day according to INR. Fo r DVT prophylaxis, pulmonary embolus, mitral stenosis, atrial \201 bril- lation, and tiss ue valve replacements, maintain INR between 2 \200\2233. For recurrent DVT or pulmonary emb olus, and mechanical valve replace- ments, the INR should be kept between 3 \200\2234.5 See also: Extracorporeal respiratory support, p78; Electrical cardioversion, p94; Intra-aor tic balloon counter- pulsation, p102; Coronary revascularisation techniques, p104; Haemo(di a) \201 ltration (2), p110; Plasma exchange, p114; Coagulation monitoring, p222; Blood pro ducts, p250; Coagulants and anti \201 brinolytics, p322; Pulmonary embolus, p376; Acute co ronary syndrome (1), p388; Clotting disorders, p470. 320 CHAPTER 19 Hematological drugs Thrombolytics Types \200 \200 More \201 brin-speci \201 c, e.g. alteplase (rtPA), tenecteplase, reteplase. Older agent s, e.g. streptokinase, urokinase. Modes of action Activate plasminogen to form plasmin which degrades \201 brin. Uses \200 \200 \200 \200 Life-threatening thrombosis or embolus. Acute myocardial infarction. Acute ischaemic stroke (alteplase). To unblock indwelling vascular access catheters. Routes \200 IV. Side effects \200 \200 \200 \200 Bleeding \200\224treat with tranexamic acid 1g IV tds. Hypotension and arrhythmias. Embolis ation from pre-existing clot as it is broken down. Anaphylactoid reactions (anistreplase, s treptokinase, urokinase). Contraindications (absolute) \200\224ESC guidelines \200 \200 \200 \200 \200 \200 \200 Previous intracranial hemorrhage or stroke of unknown origin. Structural cerebrovascular le sion or malignant intracranial neoplasm. Ischaemic stroke within six months (not acute stro ke within 3h). Recent major trauma/surgery/head injury (<3wk). Gastrointestinal bleeding wi thin last month. Aortic dissection. Active bleeding or bleeding diathesis. Contraindications (relative) \200\224ESC guidelines \200 Transient ischaemic attack in pr eceding six months. \200 Oral anticoagulant therapy. \200 Pregnancy within one week pos t-partum. \200 Non-compressible vascular puncture. \200 Traumatic CPR. \200 Poorly co ntrolled hypertension (systolic blood pressure >180mmHg). \200 Advanced liver disease. \200 Infective endocarditis. \200 Active peptic ulcer. Notes \200 In acute myocardial infarction, they are of most value when used within 12h of onset. They may require adjuvant therapy (e.g. aspirin with streptokinase or heparin with rtPA) to maxi mize the effect. In acute ischaemic stroke, alteplase may be bene \201 cial within three h ours of onset. Exclude hemorrhage and diffuse swelling by CT scan. Anaphylactoid reactions to streptokinase are not uncommon, particularly in those who have had streptococcal infecti ons. Do not expose patients twice between \201 ve days and one year of the last dose. THROMBOLYTICS 321 Drug dosages Alteplase (rtPA) Dose schedule for acute myocardial infarction is 15mg IV bolus, then 0.75mg/kg over 30min, then 0.5mg/kg over 1h to a maximal dose of 100mg. This is then followed by heparin for 24 \200\22348h. For pulmonary embolism: 10mg over 1 \200\2232min, then 90mg over 2h, followed by heparin. For acute ischaemic stroke: 0.1mg/kg over 1 \200\2232min, then 0.8mg/kg over 60 min. Avoid heparin for 24h. For acute MI: IV bolus of 0.5mg/kg over 10s followed by heparin for 24 \200\22348h. For acute MI: two IV boluses of 10 units given 30min apart followed by heparin for 24 \200\22348h. For acute MI: 1.5 million units over 60min. Heparin for 24 \200\22348h optional. For severe venous thrombosis: 250,000 units over 30min followed by 10 0,000 units/h for 24 \200\22372h). For pulmonary embolism: 1.5 million units over 2h. For u nblocking indwelling vascular catheters: 5000 IU are instilled. For thromboembolic disease: 4400IU/kg is given over 10min followed by 4400IU/kg/h for 12 \200\22324h. Tenecteplase Reteplase Streptokinase Urokinase Key papers Task Force on management of acute myocardial infarction of the European Society of Cardiology. (2003) Management of acute myocardial infarction in patients with ST-segment elevation. Eur Heart J 24: 28 \200\22366. Task Force Report of the European Society of Cardiology. (2000) Guidelines on diagnosis and management of acute pulmonary embolism. Eur Heart J 21: 1301 \200\22366. British Thoracic Society guidelines for the management of suspected acute pulmonary embolis m. (2003) Thorax 58: 470 \200\22384. See also: Coagulation monitoring, p222; Coagulants and anti \201 brinolytics, p322; Pulmon ary embolus, p376; Acute coronary syndrome (1), p388. 322 CHAPTER 19 Hematological drugs Coagulants and anti \201 brinolytics Types \200 \200 \200 \200 \200 \200 Vitamin K. Prothrombin complex concentrate, e.g. Octaplex , Beriplex . Protamine. Tranexa mic acid. Activated factor VII (FVIIa). Fresh frozen plasma. Uses \200 To reverse a prolonged prothrombin time, e.g. malabsorption, oral anticoagulant therapy, B- lactam antibiotics or critical illness (vitamin K, Octaplex , Beriplex ). To reverse the effects of heparin (protamine). Bleeding from raw surfaces, e.g. prostatectomy, dental extr action (tranexamic acid). Bleeding from thrombolytics (tranexamic acid). Bleeding from majo r trauma or hemophilia (FVIIa). \200 \200 Routes \200 \200 IV (vitamin K, protamine, tranexamic acid, FVIIa). PO (vitamin K, tranexamic acid). Notes \200 The effects of vitamin K are prolonged so avoid where patients are dependent on oral antico agulant therapy. A dose of 10mg is given PO or by slow IV injection daily. In life-threaten ing hemorrhage due to warfarin excess, 5 \200\22310mg is given by slow IV injection with ot her coagulation factor concentrates (Octaplex , Beriplex ). If INR >7 or in less severe h emorrhage, 0.5 \200\2232mg may be given by slow IV injection with minimum lasting effect on oral anticoagulant therapy. Protamine has an anticoagulant effect of its own in high doses . Protamine 1mg neutralizes 100IU unfractionated heparin if given within 15min. Less is req uired if given later since heparin is excreted rapidly. Protamine should be given by slow I V injection according to the APTT. Total dose should not exceed 50mg. Protamine injection m ay cause severe hypotension. Tranexamic acid has an anti \201 brinolytic effect by antagon izing plasminogen. Recombinant factor VIIa is licensed for use in hemophilia, but a number of case series in major trauma, orthopedic and cardiac surgery report bene \201 t in sever e, intractable bleeding that had not responded to standard measures. COAGULANTS AND ANTIFIBRINOLYTICS 323 Drug dosages Vitamin K Octaplex Beriplex Protamine Tranexamic acid Factor VIIa 5 \200\22310mg IV 30 \200\22350IU/kg IV 30IU/kg IV 25 \200\22350mg slow IV 1 \200\2231.5g IV 6 \200\22312 hourly 90mcg/kg slow IV, repeated as necessary 1.5 \200\2232 hourly See also: Coagulation monitoring, p222; Blood products, p250; Anticoagulants, p318; Thrombo lytics, p320; Bleeding disorders, p468; Clotting disorders, p470. This page intentionally left blank 325 Chapter 20 Miscellaneous drugs Antimicrobials 326 Corticosteroids 328 Prostaglandins 330 Immunomodulatory therapies in sep sis 332 Rituximab 334 326 CHAPTER 20 Miscellaneous drugs Antimicrobials Types \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Penicillins, e.g. benzylpenicillin, \202 ucloxacillin, piperacillin, ampicillin. Cephalos porins, e.g. cefotaxime, ceftazidime, cefuroxime. Carbapenems, e.g. imipenem, meropenem. Am inoglycosides, e.g. gentamicin, amikacin, tobramycin. Quinolones, e.g. cipro \202 oxacin. Glycopeptides, e.g. teicoplanin, vancomycin. Macrolides, e.g. erythromycin, clarithromycin. Tetracyclines, e.g. tigecycline. Other, e.g. clindamycin, metronidazole, linezolid, co-tri moxazole, rifampicin. Antifungals, e.g. amphotericin, \202 uconazole, caspofungin, vorico nazole, itraconazole. Antivirals, e.g. aciclovir, ganciclovir. Uses \200 \200 \200 Treatment of infection. Prophylaxis against infection, e.g. peri-operatively. Local choice of antimicrobial varies. As a guide, the following choices are common: \200 Pneumonia (hospital-acquired Gram-negative) \200\224ceftazidime, cipro \202 oxacin, merope nem or piperacillin/tazobactam (piptazobactam). Pneumonia (community acquired) \200\224cefu roxime + clarithromycin. Systemic sepsis \200\224cefuroxime 9 gentamicin (+ metronidazole if anaerobes likely). Routes \200 Generally given IV in critically ill patients. Side effects \200 \200 \200 Hypersensitivity reactions (all). Seizures (high dose penicillins, high dose metronidazole, cipro \202 oxacin). Gastrointestinal disturbance (cephalosporins, erythromycin, clindamyc in, teicoplanin, vancomycin, co-trimoxazole, rifampicin, metronidazole, cipro \202 oxacin, amphotericin, \202 ucytosine). Vestibular damage (aminoglycosides). Renal failure (amino glycosides, teicoplanin, vancomycin, cipro \202 oxacin, rifampicin, amphotericin, aciclovi r). Erythema multiforme (co-trimoxazole). Leucopaenia (co-trimoxazole, metronidazole, teico planin, cipro \202 oxacin, \202 ucytosine, aciclovir). Thrombocytopaenia (linezolid). Pe ripheral neuropathy (metronidazole). \200 \200 \200 Notes \200 Antimicrobials should be chosen according to microbial sensitivities, usually based on advi ce from the microbiology laboratory. Appropriate empiric therapy for serious infections sho uld be determined by likely organisms, taking into account known community and hospital inf ection, and resistance patterns. Up to 10% of penicillin-allergic patients are also cephalo sporin-allergic. Optimal duration of therapy is unknown. \200 ANTIMICROBIALS 327 Drug dosages (intravenous) Benzylpenicillin Flucloxacillin Ampicillin Piptazobactam Ceftazidime Ceftriaxone Cefuroxime Gentamicin Amikacin Tobramycin Erythromycin Metronidazole Clindamycin Cipro \202 oxacin C o-trimoxazole Tigecycline Imipenem Meropenem Rifampicin Teicoplanin Vancomycin Linezolid Ch loramphenicol Amphotericin Flucytosine Fluconazole Caspofungin Voriconazole Itraconazole Ac iclovir Ganciclovir Most antimicrobials need dose adjustment for renal or hepatic failure. 1.2g 6-hourly (2-hourly for pneumococcal pneumonia) 500mg \200\2232g 6-hourly 500mg \200 \2231g 6-hourly 4.5g 6 \200\2238 hourly 2g 8-hourly 1 \200\2234g daily 750mg \200\2231.5g 8 -hourly 1.5mg/kg stat, then by levels (usually 80mg 8-hourly) 7.5mg/kg stat, then by levels (usually 500mg 12-hourly) 5mg/kg stat, then by levels (usually 100mg 8-hourly) 500mg \200 \2231g 6 \200\22312hourly 500mg 8-hourly or 1g 12-hourly PR 300 \200\223600mg 6-hourly 200 \200\223400mg 12-hourly 960mg 12-hourly in Pneumocystis carinii pneumonia 100mg initially, then 50mg 12-hourly 1 \200\2232g 6 \200\2238 hourly 500mg \200\2231g 8-hourly 600mg daily 4 00mg 12-hourly for 3 doses, then 400mg daily 500mg 6-hourly (monitor levels) 600mg 12-hourl y 1 \200\2232g 6-hourly 250mcg \200\2231mg/kg daily 25 \200\22350mg/kg 6-hourly 200 \200 \223400mg daily 70mg stat, then 50 \200\22370mg daily 400mg 12-hourly on \201 rst day, th en 200 \200\223300mg 12-hourly 200mg 12-hourly for 2 days, then 200mg daily 10mg/kg 8-hourl y 5mg/kg 12-hourly Common choices for speci \201 c organisms S. aureus MRSA S. pneumoniae Cefuroxime, benzylpenicillin N. meningitidis Ceftriaxone, cefo taxime, benzylpenicillin Cefuroxime, cefotaxime H. in \202 uenzae Ampicillin, ceftazidime, cipro \202 oxacin, gentamicin, imipenem, E. coli meropenem Flucloxacillin Teicoplanin, vancomycin, linezolid Klebsiella spp. Ceftazidime, cipro \202 oxacin, gentamicin, imipenem, meropenem Ceftazidim e, cipro \202 oxacin, gentamicin, imipenem, meropenem, P. aeruginosa piptazobactam See also: Virology, serology and assays, p226; Infection \200\224treatment, p554; Multi-res istant infection, p562. 328 CHAPTER 20 Miscellaneous drugs Corticosteroids Uses \200 Anti-in \202 ammatory \200\224corticosteroids are often given in high dose for their anti- in \202 ammatory effect, e.g. asthma, allergic and anaphylactoid reactions, vasculitic dis orders, rheumatoid arthritis, in \202 ammatory bowel disease, neoplasm-related cerebral oe dema, ARDS, laryngeal oedema (e.g. after intubation), and after spinal cord injury. Bene \201 t is unproven in cerebral oedema following head injury or cardiac arrest. Infection \200\224though their immunosuppressive actions may increase susceptibility to infection, co rticosteroids are often used with antibiotics as \201 rst-line therapy to reduce the in \202 ammatory response of microbial killing, e.g. miliary TB, bacterial meningitis, pneumoc ystis pneumonia. Only in cerebral malaria has speci \201 c detriment been shown. In septic shock, high dose, short-course corticosteroids were ineffective/detrimental. However, more recent trials found improved survival with \200\230low dose \200\231 hydrocortisone (50mg qds) 9 \202 udrocortisone (50mcg), although only in the severe \200\230vasopressor-unre sponsive \200\231 subset. Pressor requirements fell faster with corticosteroid therapy. The short corticotropin (ACTH) test is not reliable in determining adrenal responders from non -responders. Free cortisol levels should ideally be assayed, but this is not routinely offe red by hospitals. Replacement therapy \200\224for patients with Addison \200\231s disease a nd post-adrenalectomy or pituitary surgery. Fludrocortisone is also usually required long-t erm for its mineralocorticoid Na+ retaining effect. Higher replacement doses are needed in chronic corticosteroid takers undergoing stress, e.g. surgery, infection. Immunosuppressive \200\224after organ transplantation. Side effects/complications \200 \200 \200 \200 \200 \200 \200 \200 Sodium and water retention (especially with mineralocorticoids). Hypoadrenal crisis if stop ped abruptly after prolonged treatment. Immunosuppressive: increased infection risk. Neutro philia. Impaired glucose tolerance/diabetes mellitus. Hypokalaemic alkalosis. Osteoporosis, proximal myopathy (long-term use). Increased susceptibility to peptic ulcer disease and GI bleeding. Notes \200 Oral fungal infection is relatively common with inhaled corticosteroids, but systemic and p ulmonary fungal infection is predominantly seen in the severely immunocompromised (e.g. AID S, post-chemotherapy) and not those taking high-dose corticosteroids alone. Choice of corti costeroid for short-term anti-in \202 ammatory effect is probably irrelevant, provided the dose is suf \201 cient. Chronic hydrocortisone should be avoided for anti-in \202 ammato ry use because of its mineralocorticoid effect, but is appropriate for adrenal replacement. Prednisone and cortisone are inactive until metabolized by the liver to prednisolone and h ydrocortisone, respectively. Glucocorticoids antagonize the effects of anticholinesterase d rugs. Corticosteroids probably do not cause critical illness myopathy. CORTICOSTEROIDS 329 Relative potency and activity Equivalent anti- in \202 ammatory dose (mg) 25 0.75 20 4 5 5 \200\223 Glucocorticoid activity ++ ++++ ++ +++ +++ +++ + Mineralocorticoid activity ++ \200\223 ++ + + + ++++ Drug Cortisone Dexamethasone Hydrocortisone Methylprednisolone Prednisolone Prednisone Flud rocortisone Drug dosages Anti-in \202 ammatory dose 4 \200\22320mg tds IV 100 \200\223200mg qds IV 500mg \200\2231g IV daily 40 \200\22360mg od PO \200\223 Drug Dexamethasone Hydrocortisone Methylprednisolone Prednisolone Fludrocortisone Replacement dose \200\223 20 \200\22330mg daily \200\223 2.5 \200\22315mg mane 0.05 \200 \2230.3mg daily Weaning Acute use (<3 \200\2234 days): Short-term use ( \211 3 \200\2234 days): Medium-term use (weeks): Long-term use (months/years): can stop immediately. wean over 2 \200\2235 days. wean over 1 \200\2232 weeks. wean slowly (months to years). Key papers Bracken MB, Shepard MJ, Holford RT, et al. (1997) Administration of methylpredni solone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spin al cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlle d Trial. National Acute Spinal Cord Injury Study. JAMA 277: 1597 \200\223604. Prasad K, Garner P. (2000) Steroids for treating cerebral malaria. Cochrane Database Syst R ev. (2): CD000972. Review. de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study In vestigators. (2002) Dexamethasone in adults with bacterial meningitis. N Engl J Med 347: 15 49 \200\22356. Annane D, S bille V, Charpentier C, et al. (2002) Effect of treatment with low doses of hy drocortisone and \202 udrocortisone on mortality in patients with septic shock. JAMA 288: 862 \200\22371. Sprung C, Annane D, Keh D, et al for the CORTICUS study group. (2008) Hydrocortisone therap y for patients with septic shock. N Engl J Med 358: 111 \200\22324. See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 sepsis, p332; Airway obstruction, p348; Acute respiratory distress syndrome (2), p364; Asthma \200\224 general management, p364; Me ningitis, p446; Raised intracranial pressure, p454; Myasthenia gravis, p458; Platelet disor ders, p478; Hypercalcaemia, p494; Hypoadrenal crisis, p524; Sepsis and septic shock \200 \224treatment, p560; HIV related disease, p566; Rheumatic disorders, p572; Vasculitis, p574 ; Anaphylactoid reactions, p578; Spinal cord injury, p590. \200\223), p212; Full blood count, p220; Immunomodulatory therapies in 330 CHAPTER 20 Miscellaneous drugs Prostaglandins Types \200 \200 Epoprostenol (prostacyclin, PGI2). Alprostadil (PGE1). Modes of action \200 Stimulate adenyl cyclase, thus increasing platelet cAMP concentration; this inhibits phosph olipase and cycloxygenase, and thus reduces platelet aggregation (epoprostenol is the most potent inhibitor known). Reduces platelet procoagulant activity and release of heparin neut ralizing factor. May have a \201 brinolytic effect. Pulmonary and systemic vasodilator by relaxation of vascular smooth muscle. \200 Uses \200 Anticoagulation, particularly for extracorporeal circuits, either as a substitute or in add ition to heparin. Pulmonary hypertension. Microvascular hypoperfusion (including digital va sculitis). Haemolytic uraemic syndrome. Acute respiratory failure (by inhalation). \200 \200 \200 Side effect and complications \200 \200 \200 Hypotension. Bleeding (particularly at cannula sites). Flushing, headache. Notes \200 