 \200 \200 BLOOD TRANSFUSION 249 Key paper Hebert P, Wells G, Blajchman M, et al. for the Tranfusion Requirements in Critica l Care Investigators. (1999) A multicentre, randomized, controlled clinical trial of transf usion require- ments in critical care. N Engl J Med 340: 409 \200\22317. See also: Basic resuscitation, p338; Upper gastrointestinal hemorrhage, p412; Bleeding vari ces, p414; Lower intestinal bleeding and colitis, p420; Jaundice, p428; Anemia, p472; Sickl e cell disease, p474; Haemolysis, p476; Hyperkalaemia, p488; Anaphylactoid reactions, p578. 250 CHAPTER 13 Fluids Blood products Types \200 \200 \200 Plasma, e.g. fresh frozen plasma. Platelets. Concentrates of coagulation factors, e.g. cryo precipitate, factor VIII concentrate, factor IX complex, Octaplex. Recombinant technologies , e.g. factor VIIa, factor VIII. Uses \200 Vitamin K de \201 ciency (fresh frozen plasma, factor IX complex, Octaplex). Hemophilia (c ryoprecipitate, factor VIII, recombinant factor VIIa). von Willebrand \200\231s disease (cr yoprecipitate). Fibrinogen de \201 ciency (cryoprecipitate). Christmas disease (factor IX complex). \200 \200 \200 Routes \200 IV. Notes \200 A unit (150mL) of fresh frozen plasma is usually collected from one donor and contains all coagulation factors, including 200U factor VIII, 200U factor IX, and 400mg \201 brinogen. It is stored at \200\22330*C and should be infused within 2h once defrosted. Platelet con centrates are viable for three days when stored at room temperature. Viability decreases if they are refrigerated. They must be infused quickly via a short giving set with no \201 lter. Indications for platelet concentrates include platelet count <10x109 or <50x109 with spontaneous bleeding or to cover invasive procedures and spontaneous bleeding with platelet dysfunction. They are less useful in conditions associated with immune platelet destructio n (e.g. ITP). A 15mL vial of cryoprecipitate contains 100U factor VIII, 250mg \201 brinog en, factor XIII, and von Willebrand factor and is stored at \200\22330*C. In hemophilia, c ryoprecipitate is given to achieve a factor VIII level >30% of normal. Factor VIII concentr ate contains 300U factor VIII per vial. In severe hemorrhage due to hemophilia, 10 \200\223 15U/kg are given 12-hourly. Recombinant factor VIIa is indicated for control of bleeding in patients with hemophilia with inhibitors to factors VIII or IX, or congenital factor VII d e \201 ciency. It forms complexes with exposed tissue factor and is not dependent on the p resence of factors VIII or IX. It has been shown to reduce blood transfusion requirements i n major blunt trauma. Success has been reported in cases of uncontrollable intra- operative bleeding (90mcg/kg repeated every 2 \200\2233h until bleeding stops). Octaplex is a prothr ombin complex concentrate for the substitution of factors II, VII, IX, and X in treatment o r prophylaxis of hereditary and acquired coagulation factor disorders, e.g. warfarin overdo se. BLOOD PRODUCTS 251 Key paper Boffard KD, for the NovoSeven Trauma Study Group. (2005) Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two paralle l randomized, placebo- controlled, double-blind clinical trials. J Trauma 59: 8 \200\22315. See also: Plasma exchange, p114; Full blood count, p220; Coagulation monitoring, p222; Coll oids, p246; Blood transfusion, p248; Anticoagulants, p318; Bleeding disorders, p468; Clotti ng disorders, p470; Platelet disorders, p478. This page intentionally left blank 253 Chapter 14 Respiratory drugs Bronchodilators 254 Respiratory stimulants 256 Nitric oxide 258 Surfactant 260 254 CHAPTER 14 Respiratory drugs Bronchodilators Types \200 \200 \200 \200 B2 agonists, e.g. salbutamol, epinephrine, terbutaline. Anticholinergics, e.g. ipratropium. Theophyllines, e.g. aminophylline. Others, e.g. magnesium, ketamine, iso \202 urane. Uses \200 Relief of bronchospasm. Routes \200 \200 \200 Inhaled (salbutamol, epinephrine, terbutaline, ipratropium, iso \202 urane). Nebulised (sa lbutamol, epinephrine, terbutaline, ipratropium). IV (salbutamol, epinephrine, terbutaline, ipratropium, aminophylline, magnesium, ketamine). PO (aminophylline). Side effects \200 \200 CNS stimulation (salbutamol, epinephrine, terbutaline, aminophylline). Tachycardia (salbuta mol, epinephrine, terbutaline, aminophylline, ketamine). Hypotension (salbutamol, terbutali ne, aminophylline, iso \202 urane). Hyperglycaemia (hydrocortisone, prednisolone, epinephr ine). Hypokalaemia (salbutamol, epinephrine, terbutaline). Lactic acidosis (salbutamol) \200\224rare. \200 \200 \200 Notes \200 Selective B2 agonists are usually given by inhalation via a pressurized aerosol or a nebuli ser. Inhalation often gives rapid relief of bronchospasm. The aerosol is of less bene \201 t in severe asthma unless used with a spacer device. They can be given by IV infusion. Neb ulised drugs require a minimum volume of 4mL and a driving gas \202 ow of 6 \200\2238L/mi n (higher or lower \202 ow creates the wrong particle size for drug delivery). In extremi s, epinephrine may be used IV, SC, or injected down the endotracheal tube. As epinephrine i s not selective, arrhythmias are more likely. However, the A agonist effect may reduce muco sal swelling by vasoconstriction, further improving air \202 ow. Ipratropium bromide does not depress mucociliary clearance, but may thicken sputum due to its anticholinergic effect . It is synergistic with B2 agonists, but has a slower onset of action. Its use in critical care is poorly studied. Aminophylline is synergistic with B2 agonists. Dosages must be adj usted according to plasma levels (range 10 \200\22320mg/L) since toxic effects may be sever e. Dose requirements are lower with heart failure, liver disease, chronic air \202 ow limi tation, fever, erythromycin, and higher in children, smokers, and those with a moderate to high alcohol intake. Magnesium is a useful adjunctive therapy for severe asthma. Ketamine o r iso \202 urane may be useful for sedation and bronchodilatation in the ventilated asthma tic. \200 BRONCHODILATORS 255 Drug dosages Aerosol* 100 \200\223200mcg 250 \200\223500mcg Nebuliser* 2.5 \200\2235mg 5 \200\22310mg 0.5mg 250mcg IV bolus IV infusion 3 \200\22320mcg/min Salbutamol Terbutaline Epinephrine Ipratropium Aminophylline 1.5 \200\2235mcg/min 5mg/kg over 20min 1.2 \200\2232g over 20min 1 \200\2232mg/kg 0.5mg/kg/h Magnesium Ketamine * Aerosols and nebulisers are usually given four to six times daily, but may be gi ven more frequently if necessary. <0.75mg/kg/h In extremis, epinephrine may be given as 0.1 \200\2230.5mg subcutaneously, injected down th e endotracheal tube or by IV infusion. See also: Chest physiotherapy, p90; Pulmonary function tests, p148; Corticosteroids, p328; Chronic air \202 ow limitation, p354; Acute chest infection (1), p356; Asthma \200\224gene ral management, p364. 256 CHAPTER 14 Respiratory drugs Respiratory stimulants Types \200 \200 Drug antagonists, e.g. naloxone, \202 umazenil. CNS stimulants, e.g. doxapram. Uses \200 \200 Acute respiratory failure due to failure of ventilatory drive. Drug-induced ventilatory fai lure, e.g. as a result of excessive sedation or post-operatively. Routes \200 IV. Modes of action \200 \200 \200 Naloxone \200\224short-acting opiate antagonist. Flumazenil \200\224short-acting benzodiaze pine antagonist. Doxapram \200\224generalized central nervous system stimulant with predomi nant respiratory stimulation at lower doses. Stimulation of carotid chemoreceptors at very low doses with increased tidal volumes. Side effects \200 \200 \200 Seizures ( \202 umazenil, doxapram). Tachyarrhythmias (naloxone, \202 umazenil). Halluci nations (doxapram). Notes \200 Respiratory stimulants are mainly used in patients with chronic air \202 ow limitation who develop acute hypercapnic respiratory failure. Effects of doxapram are short-lived so infu sion is necessary. After about 12h infusion, the effects on ventilatory drive are reduced. Naloxone may be used in respiratory depression due to opiate drugs. Since it reverses all o piate effects, it may be better to reverse respiratory depression with non-speci \201 c re spiratory stimulants, e.g. doxapram leaving pain relief intact. It may need to be repeated where long-acting opiates are involved. Most benzodiazepines are long-acting compared to \202 umazenil so repeated doses may be necessary. Flumazenil should not be used in mixed ov erdose. RESPIRATORY STIMULANTS 257 Drug dosages IV bolus 0.1 \200\2230.4mg 0.2mg over 15min (0.1mg/min to max 2mg) 1 \200\2231.5mg/kg over 30s IV infusion Naloxone Flumazenil Doxapram 2 \200\2233mg/min Key paper Greenstone M, Lasserson TJ. (2003) Doxapram for ventilatory failure due to exacer bations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev CD000223. Revi ew. See also: Respiratory failure, p350; Chronic air \202 ow limitation, p354; Sedative poison ing, p526; Post-operative critical care, p620. 258 CHAPTER 14 Respiratory drugs Nitric oxide Nitric oxide (NO) is a fundamental mediator in many physiological processes. O ne of the most important effects is smooth muscle relaxation; NO is a major local controlle r of vascular tone via effects on cyclic GMP. Inhaled NO NO is provided for inhalation from cylinders and is added to the inspira- tory l imb of the ventilator circuit by a servo control device to achieve a concentration of 1 \200\22340ppm. Most patients require less than 20ppm. Inhalation produces vasodilatation at the site of gas exchange, and may improve ventilation-perfusion matching and reduce pulmon ary artery pressures. However, randomized multicentre studies in patients with acute lung i njury revealed no long-term bene \201 t nor outcome improvement. Side effects NO is immediately bound to hemoglobin ensuring local effects only. There is no tolerance, but patients can become dependent on continued inhalation with rebound pulmonar y hypertension and hypoxaemia on withdrawal. For this reason, withdrawal must be gradual. E xcessive humidi- \201 cation of inspired gasses may form nitric acid with NO; the use of heat- moisture exchangers rather than water baths is recommended. Monitoring NO and nitrogen dioxide concentrations can be monitored in the inspira- tory lim b of the ventilator circuit with fuel cell analysers or by chemilumi- nescence. It is extre mely rare to see toxic nitrogen dioxide concentrations (>5ppm). Methaemoglobin is formed wh en NO binds to hemoglobin. Prolonged inhalation at higher doses may rarely produce signi \201 cant methaemoglobinaemia (>5%) so this should be monitored daily. Achieving the correct dose Approximately 50% of patients with severe respiratory failure sh ow short- term improvement in PaO2 with NO. However, the most effective dose varies. It is usual to start at 1ppm for 10min and monitor the change in PaO2/FIO2 ratio. An increase sho uld be followed by an increase in nitric oxide concentration to 5ppm for a further 10min. T hereafter, the dose is adjusted according to response at 10min intervals until the most eff ective dose is found. It is important to assess the dose response at daily intervals, aimin g to keep the dose at the lowest effective level. Scavenging Since the concentrations used are so small, dilution of exhaled gasses into the atmosphere is unlikely to produce important environmental concen- trations. In the air-cond itioned intensive care environment, air changes are so frequent as to make scavenging unnec essary. NITRIC OXIDE 259 Key papers Dellinger RP, Zimmerman JL, Taylor RW, et al, for the Inhaled Nitric Oxide in AR DS Study Group. (1998) Effects of inhaled nitric oxide in patients with acute respiratory d istress syndrome: results of a randomized phase II trial. Crit Care Med 26: 15 \200\22323. Lundin S, Mang H, Smithies M, et al, for the The European Study Group of Inhaled Nitric Oxi de. (1999) Inhalation of nitric oxide in acute lung injury: results of a European multicent re study. Intensive Care Med 25: 911 \200\2239. See also: Acute respiratory distress syndrome (2), p362. 260 CHAPTER 14 Respiratory drugs Surfactant In ARDS, there is decreased surfactant production, biochemical abnor- mality of the surfactant produced, and inhibition of surfactant function. The net result is alveolar and small airway collapse. Surfactant also con- tributes to host defense against microorgan isms. Surfactant replacement would be expected to exert therapeutic effects on lung mechani cs, gas exchange, and host defense. Instillation of surfactant (either as a liquid or nebulised) via the ET tube into the lungs is associated with improved outcome in neonatal respira- tory distress syndrome. Potential indications in adults include ARDS, pneu- monia, chronic air \202 ow limitation, and asth ma. Multiple studies in ARDS have yet to demonstrate mortality bene \201 t though this may be related to the type of surfactant, the volume, or the delivery system used. Studies have demonstrated improved oxygenation with recombinant surfactant protein C but no improvement in survival in patients with ARDS. Complications of surfactant treatment have included increased cough, sputum production, bro nchospasm, increased peak airway pressure, and adverse effects on pulmonary function. These can be minimized by adequate sedation and neuromuscular blockade before instilling surfact ant. SURFACTANT 261 Key paper Spragg RG, Lewis JF, Walmrath HD. et al. (2004) Effect of Recombinant Surfactant Protein C \200\223Based Surfactant on the Acute Respiratory Distress Syndrome. N Engl J Med 351: 884 \200\22392. See also: Acute respiratory distress syndrome (2), p362. This page intentionally left blank 263 Chapter 15 Cardiovascular drugs Inotropes 264 Vasodilators 266 Vasopressors 268 Hypotensive agents 270 Anti-arrhythmics 272 Chronotropes 274 Anti-anginal agents 276 264 CHAPTER 15 Cardiovascular drugs Inotropes Types \200 Catecholamines, e.g. epinephrine, norepinephrine, dobutamine, dopamine. Phosphodiesterase ( PDE) inhibitors, e.g. milrinone, enoximone. Dopexamine. Calcium sensitisers, e.g. levosimen dan. Cardiac glycosides, e.g. digoxin (weak). \200 \200 \200 Modes of action \200 Increase force of myocardial contraction, either by stimulating cardiac B1 adrenoreceptors (catecholamines), decreasing cAMP breakdown (PDE inhibitors), increasing calcium sensitivit y (Ca sensitizers), directly increasing contractility (digoxin), or inhibiting neuronal reu ptake of noradrenaline (dopexamine). All agents, except digoxin, have, to greater or lesser degrees, associated dilator or constrictor properties via A1 and B1 adrenoreceptors, dopam inergic receptors, or KATP channels. Digoxin may cause splanchnic vasoconstriction and, for an inotropic effect, usually requires higher plasma levels. The increase in cardiac work i s partially offset in those drugs possessing associated dilator effects. Other than epineph rine (when used for its vasoconstrictor effect in cardiopulmonary resuscitation) or digoxin (for long-term use in chronic heart failure), inotropes are usually given by continuous IV infusion titrated for effect. Uses \200 \200 \200 Myocardial failure, e.g. post-myocardial infarction, cardiomyopathy. Myocardial depression, e.g. sepsis. Augmentation of oxygen delivery in high-risk surgical patients. Side effects \200 \200 \200 Arrhythmias (usually associated with concurrent hypovolaemia). Tachycardia (usually associa ted with concurrent hypovolaemia). Hypotension (related to dilator properties 9 concurrent hypovolaemia). Hypertension (related to constrictor properties). Anginal chest pain, or ST segment and T wave changes on ECG. Catecholamines decrease metabolic ef \201 ciency, enhan ce B-oxidation of fat, and are prothrombotic. They are used to create models of myocardial ischaemia/necrosis. In vitro, they cause immune suppression and enhance bacterial growth. \200 \200 Notes \200 Epinephrine, norepinephrine, dobutamine, and dopamine should be given via a central vein as tissue necrosis may occur secondary to peripheral extravasation. INOTROPES 265 Drug dosages Epinephrine Norepinephrine Dobutamine Dopamine Dopexamine Milrinone Infusion starting from 0.05mcg/kg/min Infusion starting from 0.05mcg/kg/min Infusion from 2 .5 \200\22325mcg/kg/min Infusion from 2.5 \200\22330mcg/kg/min Infusion from 0.5 \200\2236m cg/kg/min Loading dose of 50mcg/kg over 10min, followed by infusion from 0.375 \200\2230.75 mcg/kg/min Loading dose of 0.5 \200\2231mg/kg over 10min, followed by infusion from 5 \200 \22320mcg/kg/min 0.5mg given PO or IV over 10 \200\22320min. Repeat at 4 \200\2238h interva ls until loading achieved (assessed by clinical response). Maintenance dose thereafter is 0 .0625 \200\2230.25mg/d, depending on plasma levels and clinical response. 12 \200\22324mcg/ kg over 10min (avoid if hypotensive), followed by 0.1mcg/kg/min for 24h Enoximone Digoxin Levosimendan Haemodynamic effects Cardiac output +/++ Epinephrine \200\223 Norepinephrine ++ Dobutamine + Dopamine ++ Dopexa mine ++ Milrinone ++ Enoximone + Digoxin ++ Levosimendan BP blood pressure; HR heart rate, SVR systemic vascular resistance. BP HR SVR + ++ 0/ \200\223 +/++ 0/ \200\223 \200\223 \200\223 0/ \200\223 0/ \200\223 + \200\223 + \200\223 + + + \200\223 + + ++ \200\223 +/++ \200\223 \200\223 \200\223 + \200\223 See also: Intra-aortic balloon counterpulsation, p102; Cardiac output \200\224central therm odilution, p178; Cardiac output \200\224peripheral thermodilution, p180; Cardiac output \200\224indicator dilution, p182; Cardiac output \200\224Doppler ultrasound, p184; Cardiac output \200\224pulse contour analysis, p186; Cardiac output \200\224other techniques, p188; Basic resuscitation, p358; Cardiac arrest, p340; Hypotension, p380; Tachyarrhythmias, p384 ; Acute coronary syndrome (1), p388; Acute coronary syndrome (2), p390; Heart failure \200 \224management, p394; Multiresistant infection, p562; Care of the potential organ/tissue do nor, p656. 266 CHAPTER 15 Cardiovascular drugs Vasodilators Types \200 \200 \200 \200 \200 \200 \200 \200 \200 Nitrates, e.g. glyceryl trinitrate, isosorbide dinitrate. Angiotensin-converting enzyme (AC E) inhibitors, e.g. captopril. Smooth muscle relaxants, e.g. sodium nitroprusside, hydralaz ine. A-adrenergic antagonists, e.g. phentolamine. B2-adrenergic agonists, e.g. salbutamol. Calcium antagonists, e.g. nifedipine, diltiazem. Dopaminergic agonists, e.g. dopexamine. Ph osphodiesterase inhibitors, e.g. enoximone, milrinone. Prostaglandins, e.g. epoprostenol (p rostacyclin, PGI2), alprostadil (PGE1). Brain natriuretic peptide analogs, e.g. nesiritide. Modes of action \200 Increase cGMP concentration (by nitric oxide donation or by inhibiting cGMP breakdown) or a cts directly on dopaminergic receptors leading to vasodilatation. Reduce (to varying degree s) ventricular preload and/or afterload. Reduce cardiac work. \200 Uses \200 \200 \200 \200 \200 \200 Myocardial failure, e.g. post-myocardial infarction, cardiomyopathy. Angina/ischaemic heart disease. Systemic hypertension (speci \201 c causes, e.g. phaeochromocytoma). Peripheral vascular disease/hypoperfusion. Splanchnic perfusion (dopexamine, dopamine). Pulmonary hype rtension (inhaled NO or prostaglandins). Side effects/complications \200 \200 \200 \200 Hypotension (often associated with concurrent hypovolaemia). Tachycardia (often associated with concurrent hypovolaemia). Symptoms include headache, \202 ushing, postural hypotensi on. Renal failure (ACE inhibitors) \200\224especially with renal artery stenosis, hypovolae mia, non-steroidals. Notes \200 Glyceryl trinitrate and isosorbide dinitrate reduce both preload and afterload. At higher d oses, the afterload effect is more prominent. Tolerance to nitrates usually commences withi n 24 \200\22336h. unless intermittent oral dosing is used. Progressive increases in dose ar e required to achieve the same effect. Prolonged (>24 \200\22336h) dose-related administrat ion of sodium nitroprusside can rarely produce a metabolic acidosis related to cyanide accu mulation. ACE inhibitor tablets can be crushed and given either sub-lingually or by naso-ga stric tube. Dopaminergic drugs improve splanchnic blood \202 ow though clinical bene \201 ts are unproved. Hydralazine has an unpredictable effect on blood pressure and, if giv en IV, should be used with caution. VASODILATORS 267 Drug dosages Nitrates Glyceryl trinitrate 2 \200\22340mg/h Isosorbide dinitrate 2 \200\22340mg/h 20 \200\223400mc g/min 5 \200\22310mg by slow IV bolus, repeat after 20 \200\22330min. Alternatively, give b y infusion starting at 200 \200\223300mcg/min and reducing to 50 \200\223150mcg/ min. Capto pril: 6.25mg test dose increasing slowly to 50 \200\223100mg tds Enalapril: 2.5mg test dose increasing to 40mg od or 20mg bd Lisinopril: 2.5mg test dose increasing to 40mg od 5 \200 \22320mg PO. Capsule \202 uid can be injected down nasogastric tube or given sublingually 2 \200\2235mg IV slow bolus. Repeat as necessary. Infusion from 0.5 \200\2236mcg/kg/min Lo ading dose of 50mcg/kg over 10min, followed by infusion from 0.375 \200\2230.75mcg/kg/min L oading dose of 0.5 \200\2231 mg/kg over 10 min followed by infusion from 5 \200\22320mcg/kg /min Infusion from 2 \200\22330ng/kg/min Inhalation: 2 \200\22340ppm 2mcg/kg bolus, followe d by infusion of 0.01 \200\2230.03mcg/kg/min Sodium nitroprusside Hydralazine ACE inhibitors Nifedipine Phentolamine Dopexamine Milrinone Enoximone Epoprostenol, alprostadil Nitric oxide Nesiritide See also: Blood pressure monitoring, p164; Cardiac output \200\224central thermodilution, p 178; Cardiac output \200\224peripheral thermodilution, p180; Cardiac output \200\224indicat or dilution, p182; Cardiac output \200\224Doppler ultrasound, p184; Cardiac output \200\224 pulse contour analysis, p186; Cardiac output \200\224other techniques, p188; Anti-anginal a gents, p276; Hypertension, p382; Acute coronary syndrome (1), p388; Acute coronary syndrome (2), p390; Heart failure \200\224management, p394. 268 CHAPTER 15 Cardiovascular drugs Vasopressors Types \200 A-adrenergic, e.g. norepinephrine, epinephrine, dopamine, ephedrine, phenylephrine, methoxa mine. Drugs reducing production of cyclic GMP (in septic shock), e.g. methylthioninium chlo ride (methylene blue). Vasopressin or synthetic analogs, e.g. terlipressin. Modes of action \200 \200 Acting on peripheral A-adrenergic or vasopressin V1 receptors. Blocking cGMP and NO product ion (methylene blue). Arteriolar vasoconstriction and venoconstriction increases SVR and CVP. Uses \200 To increase organ perfusion pressures, particularly in high output, low peripheral resistan ce states, e.g. sepsis, anaphylaxis, to maintain adequate cerebral perfusion pressure or fo llowing neurological injury. To raise coronary perfusion pressures in cardiopulmonary resus citation (epinephrine, vasopressin). Side effects/complications \200 \200 \200 \200 Increased cardiac work. Decreased cardiac output. Myocardial and splanchnic ischaemia. Incr eased myocardial irritability, arrhythmias, and tachycardia, especially with concurrent hyp ovolaemia. Decreased peripheral perfusion and distal ischaemia/necrosis. Notes \200 Pressor agents should be avoided, if possible, in low cardiac output states as they may fur ther compromise the circulation. Methoxamine and phenylephrine are the \200\230purest \200 \231 pressor agents; other A-adrenergic agents have some inotropic properties. Ephedrine is similar to epinephrine, but its effects are more prolonged. Effects of pressor agents on s planchnic, renal, and cerebral circulations are variable and unpredictable. Pulmonary vascu lar resistance is also raised by these agents. Methylthioninium chloride (methylene blue) i nhibits the NO-cGMP pathway. Its use has only been reported in a few small case series. A m ulticentre study of a NO synthase inhibitor (L-NMMA) was prematurely discontinued due to ad verse outcomes. Vasopressin (short half-life, infusion needed) and terlipressin (longer hal f-life, can be given by bolus) may be effective in treating catecholamine-resistant vasodil atory shock. Paradoxically, such patients respond to small doses that have no pressor effec t in healthy people. Large RCTs in septic shock show no outcome difference between types of catecholamine, but improved outcomes from low-dose vasopressin (over norepinephrine) in th e less severe shock subgroup. Excessive dosing of any pressor agent may lead to regional is chaemia, e.g. cardiac, splanchnic. Digital ischaemia may respond to prompt administration o f intravenous prostanoids (e.g. PGE1, PGI2). \200 VASOPRESSORS 269 Drug dosages Norepinephine Epinephrine Dopamine Methoxamine Ephedrine Methylthioninium chloride (methyle ne blue) Vasopressin Terlipressin Infusion starting from 0.05mcg/kg/min Infusion starting from 0.05mcg/kg/min Infusion from 5 \200\22350mcg/kg/min 3 \200\22310 mg by slow IV bolus (rate of 1mg/min) 3 \200\22330mg by slow IV bolus 1 \200\2232mg/kg over 15 \200\22330min 0.01 \200\2230.04U/min for sepsis 0.25 \200\2230.5mg bolus, repeated at 30min intervals as necessary to maximum 2mg Key papers L pez A, Lorente JA, Steingrub J, et al. (2004) Multiple-center, randomized, pl acebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32: 21 \200\22330. Annane D, Vignon P, Renault A, et al. for the CATS Study Group. (2007) Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial. Lan cet 370: 676 \200\22384. Russell JA, Walley KR, Singer J, et al. for the VASST Investigators. (2008) Vasopressin ver sus nore- pinephrine infusion in patients with septic shock. N Engl J Med 358: 877 \200\223 87. See also: Blood pressure monitoring, p164; Cardiac output \200\224central thermodilution, p 178; Cardiac output \200\224peripheral thermodilution, p180; Cardiac output \200\224indicat or dilution, p182; Cardiac output \200\224Doppler ultrasound, p184; Cardiac output \200\224 pulse contour analysis, p186; Cardiac output \200\224other techniques, p188; Tissue perfusi on monitoring, p194; Intracranial pressure monitoring, p200; Jugular venous bulb saturation , p202; Other neurological monitoring, p206; Basic resuscitation, p338; Cardiac arrest, p34 0; Hypotension, p380; Sepsis and septic shock \200\224 treatment, p560; Anaphylactoid react ions, p578; Head injury (2), p588; Spinal cord injury, p590; Care of the potential organ/ti ssue donor, p656. 270 CHAPTER 15 Cardiovascular drugs Hypotensive agents Types \200 \200 B-blockers are being used more often in critical car e practice for their bene \201 cial effects in heart failure, and for arrhythmia and blood pressure control. Care needs to be taken with regard to their negative inotropic and chron otropic effects so, if in doubt, use small doses to begin with or shorter-acting agents suc h as esmolol or labetalol given by infusion. Despite their promise in reducing post-operati ve cardiovascular mor- tality and morbidity, a recent large trial assessing peri-operative meto- prolol showed reduction in cardiovascular complications, but an increased incidence o f stroke. Vasodilators. B-blockers. Modes of action \200 Vasodilators reduce preload and afterload to variable degrees, depending on type and dose. In addition, nitrates, sodium nitroprusside (acts more on arterial vessels), and ACE inhibi tors will often increase cardiac output in heart failure states. B-blockers reduce the forc e of myocardial contractility. A-blockers reduce vascular tone and can increase cardiac out put. \200 Uses \200 \200 \200 Hypertension \200\224systemic and pulmonary. Heart failure \200\224to reduce afterload 9 pr eload (caution with B-blockers). Control of blood pressure, e.g. dissecting aortic aneurysm . Side effects/complications \200 \200 \200 \200 \200 \200 \200 \200 Excessive hypotension. Heart failure (with B-blockers). Peripheral hypoperfusion (with B-bl ockers). Bronchospasm (with B-blockers). Decreased sympathetic response to hypoglycaemia (w ith B-blockers). Tachyphylaxis (with nitrates). Cyanide toxicity (with sodium nitroprusside ). Unpredictable blood pressure lowering with nifedipine. Exercise caution when treating a hypertensive emergency. Exercise caution when using B-blockers and calcium channel blockers together. HYPOTENSIVE AGENTS 271 Drug dosages Nitrates Glyceryl trinitrate 2 \200\22340mg/h Isosorbide dinitrate 2 \200\22340mg/h 20 \200\223400mc g/min Ramipril: 1.25mg test dose rising to 10mg od Captopril: 6.25mg test dose rising to 25 mg tds Enalapril: 2.5mg test dose rising to 40mg od Lisinopril: 2.5mg test dose rising to 4 0mg od 5 \200\22310mg PO. Capsule \202 uid can be injected down nasogastric tube or given sublingually. 2 \200\2235mg IV slow bolus. Repeat as necessary. A titrated loading dose re gimen is commenced followed by infusion (50 \200\223200mcg/kg/min). Initially given as slow IV 1mg boluses, repeated at 2min intervals until effect is seen (to maximum 5mg). 0.25 \200\2232mg/min Sodium nitroprusside ACE inhibitors Nifedipine Phentolamine Esmolol Propranolol Labetalol Key paper POISE Study Group. (2008) Effects of extended-release metoprolol succinate in pat ients under- going non-cardiac surgery (POISE trial): a randomized controlled trial. Lancet 371: 1839 \200\22347. See also: Blood pressure monitoring, p164; Vasodilators, p266; Hypertension, p382. 272 CHAPTER 15 Cardiovascular drugs Anti-arrhythmics Only anti-arrhythmics commonly used in the ICU setting are described. For supraventricular tachyarrhythmias: \200 Adenosine, verapamil, amiodarone, digoxin, B-blockers, magnesium. For ventricular tachyarrhythmias: \200 Amiodarone, lidocaine, \202 ecainide, bretylium, B-blockers, magnesium. Uses \200 Correction of supraventricular and ventricular tachyarrhythmias which either compromise the circulation or could potentially do so. Differentiation between supraventricular and ventr icular arrhythmias using adenosine. Side effects/complications \200 All anti-arrhythmic agents have side effects; they are negatively inotropic to greater or l esser degrees and may induce profound hypotension (e.g. verapamil, B-blockers) or bradycard ia (e.g. B-blockers, amiodarone, digoxin, lidocaine). B-blockers, in particular, should be used with caution because of these effects. All A \200\223V blockers are contraindicated in re-entry tachycardia (e.g. Wolff \200\223Parkinson \200\223White syndrome). Notes \200 Adenosine: very short-acting; may revert paroxysmal SVT (other than atrial \202 utter and \201 brillation) to sinus rhythm. Ineffective for VT. Contraindicated in 2* and 3* heart block, sick sinus syndrome, asthma. May cause \202 ushing, bronchospasm, and occasional severe bradycardia, especially in patients taking dipyridamole. Amiodarone: effective again st all types of tachyarrhythmia. Usually given by IV infusion but requires initial loading dose. When converting from IV to oral dosing, initial high oral dosing (200mg tds) is still required. Contraindicated in patients with thyroid dysfunction. Has low acute toxicity tho ugh may cause severe bradycardia and both chronic and acute pulmonary \201 brosis. Avoid with other class III agents (e.g. sotalol). Must be given via central vein as causes periph eral phlebitis. Can also cause pulmonary \201 brosis and abnormal thyroid function. B-blo ckers: for SVT. Caution when using B-blockers with verapamil. Bretylium: may take 15 \200 \22320min to take effect; now used predominantly for resistant VF/VT. CPR should be continu ed for at least 20min. Digoxin: slow-acting, requires loading (1 \200\2231.5mg) to achieve therapeutic plasma levels over 12 \200\22324h (can be done over 4 \200\2236h). Contraindica ted in 2* and 3* heart block. May cause severe bradycardia. Low K+ and Mg2+, and markedly r aised Ca2+ increase myocardial sensitivity to digoxin. Amiodarone raises digoxin levels. Li docaine: 10mL of 1% solution contains 100mg. No effect on SVT. Contraindicated in 2* and 3* heart block. May cause bradycardia and CNS side effects, e.g. drowsiness, seizures. Verapa mil: should generally not be given with B-blockers as profound hypotension and bradyarrhyth mias may result. Pre-treatment with 3 \200\2235mL 10% calcium gluconate by slow IV bolus pr events the hypotensive effects of verapamil without affecting its anti-arrhythmic propertie s. \200 ANTI-ARRHYTHMICS 273 Modes of action (Vaughan \200\223Williams classi \201 cation) Class I Action Reduces rate of rise of action potential: Ia: Increases action potential duration Ib : Shortens duration Ic: Little effect Reduces rate of pacemaker discharge Prolongs duration of action potential and hence length of refractory period Examples Ia: disopyramide Ib: lidocaine Ic: \202 ecainide B-blockers Amiodarone Sotalol Verapamil Diltiazem II III IV Antagonizes transportation of calcium across cell membrane Drug dosages Adenosine 6mg rapid IV bolus. If no response after 1min, give 12mg. If no response after 1min, repeat 12mg. 5mg/kg over 20min (or 150 \200\223300mg over 3min in emergency), then IV infusion of 15mg/kg/24h in 5% glucose via central vein. Reduce thereafter to 10mg/kg/24h (approx. 600m g/d) for 3 \200\2237d, then maintain at 5mg/kg/24h (300 \200\223400mg/d). Esmolol: A titrat ed loading dose regimen is commenced followed by an infusion rate of 50 \200\223200mcg/kg/m in. Propranolol: Initially given as slow IV boluses of 1mg, repeated at 2min intervals to a maximum of 5mg. Labetalol: 0.25 \200\2232mg/min Sotalol: Dosage range is 20 \200\223120mg IV (0.5 \200\2231.5mg/kg) administered over 10min. Repeat 6-hourly, if necessary. Metoprolo l: 2.5 \200\2235 mg injected IV at rate of 1 \200\2232mg/min, repeated at 5min intervals un til satisfactory response is seen or total dose of 10 \200\22315mg given. Atenolol: 2.5mg I V over 2.5min, repeated at 5min intervals until response is seen or maximum of 10mg In emer gency, 5mg/kg by rapid IV bolus. If no response after 5min, repeat or increase to 10mg/kg. 0.5mg given IV over 10 \200\22320min. Repeat at 4 \200\2238h intervals until loading achiev ed (assessed by clinical response). Maintenance dose thereafter is 0.0625 \200\2230.25mg/d, depending on plasma levels and clinical response. 1mg/kg slow IV bolus for loading, then 2 \200\2234mg/min infusion. Should be weaned slowly over 24h. 10 \200\22320mmol over 1 \200 \2232h (over 5min in emergency). 2.5mg slow IV. If no response, repeat to a maximum of 20mg . An IV infusion of 1 \200\22310mg/h may be tried. 10% calcium gluconate solution should be readily available. Amiodarone B-blockers Bretylium Digoxin Lidocaine MgSO4 Verapamil See also: Electrical cardioversion, p94; ECG monitoring, p162; Cardiac arrest, p340; Tachya rrhythmias, p384. 274 CHAPTER 15 Cardiovascular drugs Chronotropes Types \200 Anticholinergic, e.g. atropine, glycopyrronium bromide. Modes of action \200 The anticholinergic drugs act by competitive antagonism of acetylcholine at peripheral musc arinic receptors and decreases atrioventricular conduction time. Uses \200 \200 All types of bradycardia including 3* heart block. High dose atropine is used in cardiopulm onary resuscitation protocols for treatment of asystole. Side effects/complications \200 Anticholinergic drugs produce dry mouth, reduction and thickening of bronchial secretions, and inhibition of sweating. Urinary retention may occur, but parenteral administration does not lead to glaucoma. Notes \200 The anticholinergic agents are usually given by IV bolus, repeated as necessary. They are f requently used as a bridge to temporary pacing, but should not be considered a substitute. External or internal pacing should be readily accessible. Atropine nebulisers have been use d successfully in patients developing symptomatic bradycardia during endotracheal suction. Neurological effects may be seen with atropine but not glycopyrronium bromide. CHRONOTROPES 275 Drug dosages Atropine 0.3 \200\2230.6mg IV bolus. 3mg is needed for complete vagal blockade or cardiopulmonary re suscitation. 0.2 \200\2230.4mg IV bolus Glycopyrronium bromide See also: Temporary pacing (1), p96; Temporary pacing (2), p98; ECG monitoring, p162; Cardi ac arrest, p340; Bradyarrhythmias, p386. 276 CHAPTER 15 Cardiovascular drugs Anti-anginal agents Types \200 \200 \200 \200 Vasodilators, e.g. nitrates, calcium antagonists. B-blockers. Potassium channel openers, e. g. nicorandil. Antiplatelet/anticoagulant agents: aspirin, heparin, clopidogrel. Modes of action \200 Calcium channel blockers cause competitive blockade of cell membrane, slow calcium channels leading to decreased in \202 ux of calcium ions into cells. This leads to inhibition of c ontraction and relaxation of cardiac and smooth muscle \201 bres, resulting in coronary a nd systemic vasodilatation. Nitrates may cause ef \202 ux of calcium ions from smooth musc le and cardiac cells, and also increases cGMP synthesis resulting in coronary and systemic vasodilatation. B-blockers inhibit B-adrenoreceptor stimulation, reducing myocardial work a nd oxygen consumption. This effect is somewhat offset by compensatory peripheral vasoconstr iction. Potassium channel openers vasodilate by relaxation of vascular smooth muscle. The p otassium channel opening action works on the arterial circulation while a nitrate-type acti on provides some venodilatation. Though aspirin, heparin, and clopidogrel have no direct an ti-anginal effect, patients with unstable angina bene \201 t from the reduction in platele t aggregation and thrombus formation. Uses \200 Angina pectoris. Side effects/complications \200 \200 See Dilators, Hypotensive agents. Nicorandil is contraindicated in hypotension and cardioge nic shock. It should be avoided in hypovolaemia. Headache and \202 ushing are the major r eported side effects. Rapid and severe hyperkalaemia has been reported after cardiac surger y. Notes \200 Combination therapy involving nitrates, B-blockade, aspirin, clopidogrel 9 heparin 9 calciu m antagonists 9 glycoprotein IIb/IIIa antagonists are used in acute coronary syndromes; thr ombolytic therapy confers no added advantage. Local guidelines should be consulted. Potassi um channel openers belong to a new class of drug yet to be extensively evaluated in critica lly ill patients and should be thus used with caution, especially when hyperkalaemia is a c oncern. Angina may occasionally be worsened by a \200\230coronary steal \200\231 phenomeno n where blood \202 ow is diverted away from stenosed coronary vessels. This does not occu r with nicorandil. ANTI-ANGINAL AGENTS 277 Drug dosages Glyceryl trinitrate 0.3mg sublingually, 0.4 \200\2230.8mg by buccal spray, 2 \200\22340mg/h by IV infusion 10 \200\22320mg tds orally, 2 \200\22340mg/h by IV infusion 5 \200\22320mg PO. The capsule \202 uid can be aspirated then injected down nasogastric tube or given sublingually. Given either orally at doses of 10 \200\223100mg tds or IV as slow boluses of 1mg, repeated at 2m in intervals to a maximum of 5mg until effect is seen. This can be repeated 2 \200\2234 hou rly as necessary. 10 \200\22320mg PO bd 300mg PO loading dose, then 75mg PO od 75 \200\2231 50mg PO od Isosorbide dinitrate Nifedipine Propranolol Nicorandil Clopidogrel Aspirin