Patient monitoring during therapy Routine respiratory monitoring is all that is required (a ir- way patency, respiratory rate, clinical evaluation of the adequacy of ventilation, SpO2 and blood gas analysis). Continuous oxygen saturation monitoring should be used in all hyp oxic patients. Always assess and optimize face mask position as any air entrainment will re duce the effec- tiveness of this intervention. Safety Standard safety precautions for compressed gasses are all that is required. Helium i s inert and insoluble in human tis- sues at atmospheric pressure. Helium does have a high t hermal conductivity but does not cause signi \201 cant airway or whole patient cooling, ev en in neonates. Stopping helium \200\223oxygen therapy Helium \200\223oxygen therapy can be withdrawn as soon as de \201 nitive therapy has taken suf \201 cient effect to reduce res- piratory distress. It may be useful as an intermitte nt ther- apy in such conditions as acute severe asthma where periodic reductions in the wor k of breathing can prevent decompensation and thereby prevent the need for intuba- tion and mechanical ventilation. Expected effects Administering helium \200\223oxygen should improve the ef \201 - ciency o f ventilation and thereby reduce respiratory dis- tress. However, it is only a temporizing intervention, i.e. it extends the period of time available for de \201 nite treatment for the underlying condition to be delivered; it is not in itself therapeutic. Indications for helium \200\223oxygen mask ventilation (CPAP, BiPAP, PSV) Heliox may reduce the work of breathing to a similar extent to positive pressure mask ventilation. The effec t of these two interventions is additive such that a patient fail- ing one, may benefit fro m the addition of the other. Delivering heliox mixtures through positive pressure mask vent ilation devices is problematic, as none is currently designed for this. Some clinicians hav e tried entraining heliox21 at 15l/min into the mask, or as near to it in the circuit as pr actical. However, the ef \201 cacy of this technique, in particular the actual gas mixture delivered to the patient, is uncertain. Presentation Helium should only be available as heliox21 (79% helium \200\223 21% oxygen). This is because you will never want to deliver a gas mixture with <21% oxygen. Face mask administration Helium \200\223oxygen gas mixtures can be delivered through any ti ght- \201 tting mask. The mask should preferably have a reser- voir bag into which the hel iox is delivered, and one or more one-way expiratory valves. Every effort should be made to minimize air entrainment. Specialist masks and mixing/neb- ulizing circuits are available commercially. Supplemental oxy- gen can be provided either through a Y-piece mixing circuit or via nasal specs worn underneath the tight- \201 tting mask. Indications for helium \200\223oxygen IPPV via endotracheal or tracheostomy tube Severe ins piratory and/or expiratory \202 ow limitation neces- sitates the use of dangerously high airway pressures Nebulization Generating a respirable aerosol using heliox21 through a standard, gas-driven, updraft nebulization chamber requires 163 CHAPTER 10.5 Helium \200\223oxygen gas mixtures Further reading Ball JA, Grounds RM. Calibration of three capnographs for use with helium a nd oxygen gas mixtures. Anesthesia 2003; 58: 156 \200\22360. ( \211 35cm H2O) and/or high levels of intrinsic PEEP. The effectiveness of instituting hel ium \200\223oxygen will be limited by the degree to which oxygen supplementation is require d. A reversible pathology should have been identi- \201 ed and a treatment plan institute d. Patients may respond to relatively small reductions in gas density such that even an FiO 2 of 0.7 should not necessarily preclude a therapeu- tic trial. It is sometimes possible to decrease the FiO2 gradually as ventilation improves, thus decreasing the gas density furth er. Chatmongkolchart S, Kacmarek RM, Hess DR Heliox delivery with noninvasive positive pressure ventilation: a laboratory study. Respir Care 2001; 46: 248 \200\22354. Colebourn CL, Barber V, Young YD. Use of helium \200\223oxygen mixture in adult patients pr esenting with exacerbations of asthma and chronic obstructive pulmonary disease: a systemat ic review. Anesthesia 2007; 62: 34 \200\22342. Fink JB. Opportunities and risks of using heliox in your clinical prac- Patient monitoring during IPPV therapy Routine respiratory/ventilator monitoring is all tha t is required. There are currently only two commercially avail- able ventilators designed f or use with heliox. Of note, both of these can be used to deliver mask ventilation. Some ot her ventilators can be connected to heliox in place of air. Heliox may interfere with both internal performance and patient monitoring. Extreme care needs to employed to avoid the de livery of excessive or inadequate tidal volumes. Always use a pressure control mode and mea sure the FiO2. Switching gas mixtures between heliox and nitrox usually requires recalibrat ion of the pneumotachograph, which in most ventilators cannot be performed whilst deliverin g ventilation to a patient. Capnography is also affected by substituting helium for nitroge n. The ef \201 cacy of heliox over nitrox should be evident almost immediately, with a max i- mal effect seen within 15min. tice. Respir Care 2006; 51: 651 \200\22360. Hess DR. Heliox and noninvasive positive-pressure ventilation: a role for heliox in exacerb ations of chronic obstructive pulmo- nary disease? Respir Care 2006; 51: 640 \200\22350. Hess DR, Fink JB, Venkatamaran ST, et al. The history and physics of heliox. Respir Care 2006; 51: 608 \200\22312. Hurford WE, Cheifetz IM. Should heliox be used for mechanically ventilated patients? Respir Care 2007; 52: 582 \200\22394. Kim IK, Saville AL, Sikes KL. et al. Heliox-driven albuterol nebuliza- tion for asthma exac erbations: an overview. Respir Care 2006; 51: 613 \200\2238. Myers TR. Use of heliox in children. Respir Care 2006; 51: 619 \200\22331. Oppenheim-Eden A , Cohen Y, Weissman C, et al. The effect of helium on ventilator performance: study of \201 ve ventilators and a bedside pitot tube spirometer. Chest 2001; 120: 582 \200\2238. Smith SW, Biros M. Relief of imminent respiratory failure from upper airway obstruction by use of helium \200\223oxygen: a case series and brief review. Acad Emerg Med 1999; 6: 953 \200\223-6. Stopping helium \200\223oxygen therapy Assuming that helium \200\223oxygen has proven to be ef \201 cacious and that a suf \201 cient time interval has elapsed to allow de \201 ni tive therapy to have taken effect, then institute a trial of switching the inspiratory gas mixture back to nitrogen oxygen. If this results in a signi \201 cant deterioration in res pi- ratory mechanics, then re-institute helium \200\223oxygen and set a time interval at wh ich a re-trial of nitrogen \200\223oxygen will be undertaken. Intermittent use of a helium \200\223oxygen mix- ture may be considered as part of a weaning strategy. Tassaux D, Jolliet P, Thouret JM, et al. Calibration of seven ICU ven- tilators for mechani cal ventilation with helium \200\223oxygen mixtures. Am J Respir Crit Care Med 1999; 160: 2 2 \200\22332. Wigmore T, Stachowski E. A review of the use of heliox in the criti- cally ill. Crit Care Resusc 2006; 8: 64 \200\22372. Published trials There are a signi \201 cant number of published trials of heliox in a var iety of settings. These have been extensively reviewed However, there is currently insuf \201 cient evidence to justify its routine use. This page intentionally left blank 165 Chapter 11 Cardiovascular drugs Chapter contents B-Adrenergic agonists 166 Phosphodiesterase inhibitors 168 Vasodilators 17 0 Vasopressors 174 Antiarrhythmic agents 176 Chronotropes 178 Antianginal agents 182 Antipl atelet agents 184 Diuretics and the critically ill 186 Levosimendan 190 166 J CORDINGLEY b-Adrenergic agonists B-Adrenergic agents are used commonly for cardiovascu- lar support in critical care to increase cardiac output via B1 receptor-mediated inotropic and chronotrop ic effects (see Chapter 11.6) in order to maintain adequate organ per- fusion. Non-cardiova scular indications for B2 agonists include bronchodilatation (Chapter 10.1) and uterine rel axation. Research is ongoing into the potential bene \201 ts of B2 ago- nists in reducing EVLW in patients with ARDS. Effects of b-adrenergic agonists Most B-adrenergic agonists in clinical use are active at more than one type of adrenergic receptor (B1, B2, B3, A1 and A2 ). \200 Epinephrine infusion has been associated with increased arterial blood lactate concentratio n, metabolic acidosis and worsening markers of splanchnic perfusion. As with all B agonists , epinephrine increases the incidence of arrhyth- mias. In general, it is used to manage pa tients with low car- diac output unresponsive to other inotropic agents. Epinephrine is giv en as a IV bolus during cardiac arrest (as part of resuscitation algorithms) because of its vasocon- strictor action. Epinephrine is the drug of choice for the management of anaphyla ctic shock both because of A1-mediated vasocon- striction and B2-mediated inhibition of mas t cell release of in \202 ammatory mediators including histamine. \200 Dose \200\224IV bolus (during cardiac arrest): 1mg. IM (ana- phylaxis): 0.5mg. IV infusion: 0.01 \200\2231mcg/kg/min; usually started at dose in the range 0.02 \200\2230.05mcg/kg/min . Adverse effects \200\224tachycardia, arrhythmias, vasoconstric- tion with potential organ dysfunction and necrosis, met- abolic acidosis, hyokalaemia, increased blood glucose and l actate concentrations, increased metabolic rate. Cardiac \200\224B1 (and to a much lesser degree B2) effects include increased heart rate, i ncreased conduction velocity throughout the heart and increased rate of idi- oventricular p acemakers. All B-adrenergic agonists increase myocardial oxygen consumption and may pre- ci pitate myocardial ischaemia in susceptible patients (dobutamine is used to carry out myocar dial stress test- ing). Beta agonists increase the incidence of cardiac arrh- thymias. Bloo d vessels \200\224 B2 agonists induce vasodilatation in coronary muscle, skeletal muscle, a nd pulmonary, splanchnic and renal arterioles and arteries. A2 agonists cause vasoconstrict ion in splanchnic, renal and skin ves- sels, and to a lesser degree in coronary and pulmona ry arterioles and arteries. Metabolic effects \200\224 B2 agonists cause increased glycog- enolysis, gluconeogenesis in liver and skeletal muscle, increased potassium uptake in skele tal muscle, and increased lipolysis. Norepinephrine (noradrenaline) Norepinephrine is the neurotransmitter found in sympa- theti c post-ganglionic nerve \201 bres and is a mixed B1 and A1 agonist. Infusion results in i ncreased blood pressure and usually no change or an increase in cardiac output. Care must b e taken to ensure that patients are not or do not become hypovolaemic, as in these circumst ances cardiac output may decrease and peripheral perfusion become severely impaired. Norepi nephrine is generally used to maintain adequate MAP following volume resuscitation and afte r adequate cardiac output has been restored. Norepinephrine is there- fore commonly used in combination with another B ago- nist or PDE3 inhibitors in patients with cardiogenic shock . In patients with volume-resuscitated septic shock, nore- pinephrine infusion has been rep orted to improve urine output and glomerular \201 ltration rate (GFR). \200 The clinical effects of a speci \201 c agent result from the sum of actions at different r eceptors and may alter as dose increases. In addition, effects may vary with alterations in intravascular volume. As with vasoconstrictor drugs, it is important to optimize circulati ng volume for a particular patient before initiating B agonist therapy. This may include th e use of cardiac out- put monitoring. The half-lives of all the B agonists listed in this c hapter are very short (a few minutes) with the exception of ephe- drine. Caution should be used in patients already receiving monoamine oxidase inhibitors (MAOIs). In some patients, particularly with sepsis, increasing doses of B agonists may be required to achieve the sam e clinical effects. Dose \200\224IV infusion: 0.01 \200\2231mcg/kg/min. Normal starting dose: 0.02 \200\2230.05 mcg/kg/min. Adverse effects \200\224vasoconstriction with potential organ dysfunction and n ecrosis, metabolic acidosis, arrhythmias. Isoprenaline Isoprenaline is a synthetic agonist at B receptors and has no A-adrenergic eff ects. Infusion results in increased heart rate and cardiac output, but decreased MAP becaus e of B2-mediated vasodilatation. Its main use is as a chrono- trope for the temporary manag ement of bradycardias. It is also occasionally used as an inotrope in patients with pul- mo nary hypertension because of its pulmonary vasodilator effects. \200 \200 Drugs Epinephrine (adrenaline) Epinephrine is a naturally occurring catecholamine in the ad renal medulla. It is a mixed A-, and B1and B2-adrenergic agonist. At low doses, B2-mediated vasodilatation predom- inates, but at higher non-physiological doses increasing vasoconstr iction (skin, mucosa, GI tract, kidneys and sys- temic veins) occurs as a result of A1-adre nergic receptor agonism. Epinephrine is used most commonly as an inotrope in patients with low cardiac output despite optimal \202 uid resuscitation and unresponsiveness to other i notropes. Dose \200\224IV infusion: 0.5 \200\22310mcg/min. Adverse effects \200\224tachycardia, arrhy thmias. Dopamine Dopamine is the natural metabolic precursor of epine- phrine and norepinehrine, an d is an agonist at dopamine, A and B receptors. Effects vary according to infusion rate. At doses of 0 \200\2235mcg/ kg/min, dopamine receptor effects predominate, resulting CHAPTER 11.1 b-Adrenergic agonists 167 in renal and splanchnic vasodilatation. Urine output may increase as a result of a proximal tubular diuretic effect. At doses of 5 \200\22310mcg/kg/min, B1 effects result in increase d heart rate and contractility. At doses of 10 \200\22320mcg/kg/min, A1 receptor-mediated e ffects are more marked, leading to vasoconstriction. Dopamine has been used to maintain blo od pressure in patients with septic shock, but norepinephrine is more likely to be effectiv e. Addition of low-dose dopamine infusion to other cardio- vascular support in critically i ll patients does not decrease the requirement for acute RRT. In patients post-cardiac surge ry, use of dopamine is associ- ated with an increased incidence of atrial \201 brillation . \200 Salbutamol Salbutamol is a selective B2 agonist primarily used for its bronchodilator effec t. It is rarely used for cardiovascular support for patients with pulmonary hypertension. \200 \200 Dose \200\224IV infusion: initially 3 \200\22320mcg/min. Adverse effects \200\224tachycardi a, arrhythmias, hypoka- laemia. Role of b agonist drugs High-risk surgical patient A number of studies have reported improv ed survival of high-risk surgical patients when cardiac index or oxygen delivery are optimi zed to above normal levels during the perioperative period using \202 uids and B agonists . This does not appear to be agent speci \201 c and has been reported in various studies u sing dobutamine, epinephrine and dopex- amine. Dose \200\224IV infusion: 1 \200\22310mcg/kg/min. Normal starting dose is 2 \200\2235mcg/kg /min. Adverse effects \200\224tachycardia, arrhythmias, vasoconstric- tion, nausea and vomi ting. Post-cardiac surgery Low cardiac output post-cardiac surgery is relatively com- mon. Patien ts requiring a low degree of inotropic support are often managed with dopamine as this can usually be managed in level 2 critical care areas. For patients requiring more support, epi nephrine, dobutamine or a PDE3 inhibi- tor are commonly used. Dobutamine Dobutamine is a synthetic agonist at mainly B1 but also B2 and A1 receptors. IV infusion causes increased heart rate and stroke volume, and vasodilatation. The effect on b lood pressure is variable, and often concurrent norepinephrine infusion is required to prev ent hypotension. It is used pri- marily for the management of low cardiac output, despite a dequate \202 uid resuscitation, in patients with cardiogenic shock, usually post-MI or fo llowing cardiac surgery. Dobutamine has been recommended as the \201 rst-choice agent to increase cardiac output, when required, in patients with septic shock. \200 Cardiogenic shock Agents with both inotropic and vasodilator properties such as dobutamine or PDE3 inhibitors are common choices. Low dose epinephrine may be added if required. Tachy cardia may limit doses of B agonists. Septic shock In patients with septic shock and low ca rdiac output unre- sponsive to optimization of intravascular volume, dob- utamine has been recommended as the inotrope of choice. Cardiovascular optimization needs to be carried out as early as possible in order to decrease the incidence of multi-organ failure. Norepinephr ine is the \201 rst-line drug to increase MAP. Dose \200\224IV infusion: 0 \200\22320mcg/kg/min. Usual starting dose is 2 \200\2235mcg/kg/ min, and it is rarely required to use >10mcg/kg/min. Adverse effects \200\224tachycardia, a rrhythmias, hypotension. Dopexamine Dopexamine is a synthetic dopamine receptor and B2 receptor agonist. Dopexamine infusion causes increased heart rate, stroke volume and systemic vasodilatation (including renal and splanchnic), resulting in increased car- diac output. Its inotropic effects are m ild. \200 Dose \200\224IV infusion: 0.5 \200\2236mcg/kg/min. \200 Adverse effects \200 \224tachycardia, hypotension. Multi-organ failure Several meta-analyzes have consistently reported that attempting to tar get supranormal values of cardiac index or oxygen delivery in patients with established mul ti-organ failure does not improve survival. Further reading Brunton L, ed. Goodman and Gilman \200\231s pharmacological basis of Ephedrine Ephedrine is a direct A and B agonist, but also increases norepinephrine release from sympathetic nerves. Administration results in increased heart rate, cardiac out- put a nd blood pressure. Although it is active if given orally, it is usually administered as an IV bolus. Tachyphylaxis occurs, making it unsuitable for IV infusion. Its main use is as tr eatment of temporary hypotension associated with epidural or spinal anesthesia. \200 \200 therapeutics, 11th en. New York: McGraw Hill. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign; international guideline s for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296 \200 \223327. Rhodes A, Bennett ED. Early goal-directed therapy: an evidence- based review. Crit Care Med 2004; 32: S448 \200\22350. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of sever e sepsis and septic shock. N Engl J Med 2001; 345: 1368 \200\2231377. Dose \200\224IV bolus: 3 \200\2236mg every 3min, maximum 30mg. Adverse effects \200\224tach ycardia, arrhythmias, CNS stimula- tion. 168 G STRANDVIK & J CORDINGLEY Phosphodiesterase inhibitors Phosphodiesterases (PDEs) are a family of enzymes that inactivate cAMP. PDE inhibitors incr ease cAMP levels, leading to increased contractility in myocardial cells and relaxation in smooth muscle. To date, 11 PDE subtypes have been identi \201 ed in mammals, although only 5 subtypes have been found to have clinical relevance in humans. PDE inhibitors relevant t o critical care will be discussed in this section and are classi \201 ed into non-selectiv e and selective inhibitors. of calcium by the sarcoplasmic reticulum of the cardiac myocyte is increased with the use o f PDE3 inhibitors. This diastolic relaxation is of particular bene \201 t in neonates, chi l- dren, and adults with poorly compliant ventricles. The inhibition of PDE 3 in vascular s mooth muscle results in the potentiation of cGMP, causing vasodilatation. As a consequence, these agents result in reductions in systemic vascular resistance, pulmonary vascular resi stance and venous pressures. There is some evidence for synergistic action between PDE3 inh ibitors and B agonists such as dobutamine in the setting of low cardiac output states. This effect has been well described in neonatal cardiac surgery. PDE3 inhibitors may also be us eful as \201 rst-line inotropic agents in patients who have either been on long-term B- b lockers, or who have a clinical indication for B-blockade in the setting of a low cardiac o utput state. As with all potent vasodilators, caution should be exer- cised in their use in the presence of left or right cardiac out \202 ow tract obstruction of any cause. PDE3 in hibitors are usually given by IV infusion and it is important to consider that their half-l ives are considerably longer than those of cathecholamines. Dose reduction may be necessary in the presence of renal impairment and par- ticularly in elderly patients. Acute toleranc e does not appear to be a feature of these agents. There is concern about a potential incre ase in mortality with the long-term use of PDE3 inhibitors in patients with chronic heart f ailure. The reasons for this are unclear, but may be related to hypotension and an increase in both ven- tricular and atrial arrhythmias. There is no evidence of increased mortality with PDE3 inhibitors used short-term in the intensive care setting. The main role for PDE3 inhibitors is in cardiac surgical intensive care patients. There appears to be little diffe r- ence between agents in terms of effect. Due to the marked reduction in systemic vascular resistance, there is currently no role for these agents in patients with septic shock. Non-selective PDE inhibitors Methylxanthines Theophylline and aminophylline (water-soluble complex of theophylline and ethylenediamine) act through non-spe- ci \201 c PDE3 and 4 inh ibition, resulting in increased intracel- lular cAMP levels. In addition, theophyllines are competitive antagonists of adenosine receptors. The main effects are increased heart rate, bronchodilatation, diuresis and anti- in \202 ammatory effects. Adverse effects include t achyarryth- mias, tremor, electrolyte and glucose abnormalities, and nausea, vomiting and d iarrhea. The clinical utility of theophylline in the critical care setting is controversial . Meta-analyzes have not found bene \201 t for the use of IV theophylline for acute severe asthma. However, international consensus guidelines recommend its use as rescue therapy fo r patient \200\231s refractory to stand- ard asthma treatment. No RCTs have demonstrated a bene \201 t for theophylline in COPD patients suffering acute exacerbations. However, it m ay have a role in patient \200\231s refractory to standard therapy. Small studies have show n increased diaphragmatic strength and mucociliary clearance in patients in ICUs. Due to ri sk \200\223 bene \201 t considerations, theophylline is not routinely used for these indic ations in critically ill patients. IV theophylline is administered as aminophylline slowly over 20min; it is extremely irritant. The initial loading dose is 250 \200\223500mg (5mg/kg ), followed by an infusion at 500mcg/ kg/h. Extreme caution should be used in patients alre ady on chronic theophylline therapy because of the risk of adverse effects. Theophylline un dergoes hepatic metabolism, and this is impaired in hepatic and cardiac failure. Plasma the ophylline levels should be measured 4 \200\2236 hourly, aiming for a target concentration o f 10 \200\22320mg/l. Adverse effects may be seen in the therapeutic range and are more like ly with theophylline levels >20mg/l. Arrhythmias and convulsions may pre-date other signs o f toxicity. An important side effect of theophylline is hypokalaemia, the incidence of whic h is increased when it is used in combination with B agonists. Milrinone \200 Milrinone is administered IV as a loading dose of 20 \200\223 50mcg/kg over 10min (diluted) , followed by infusion at a rate of 0.1 \200\2230.75mcg/kg/min. The loading dose is often o mitted if hypotension is anticipated. It is usually contin- ued for at least 12h post-cardi ac surgery or for 48 \200\22372h in congestive cardiac failure. It has a half-life of 30 \200\22360min, but this may be signi \201 cantly prolonged in patients with renal dysfunct ion. In this scenario, dose reduction is nec- essary to prevent severe vasodilatation. Milr inone has been studied extensively in cardiac surgical and heart failure patients. There is evidence that it facilitates weaning from cardiopulmonary bypass. In the cardiac intensive care setting, milrinone increases cardiac index without a marked increase in heart rate, b ut at the expense of reduced systemic vascular resistance. In a comparison study with dobut amine, both drugs increased cardiac index signi \201 cantly, but there was a greater achie vement in MAP in patients receiving dob- utamine. Milrinone had a slightly better safety pr o \201 le, Selective PDE inhibitors Phosphodiesterase type 3 Inhibitors PDE3 isoforms (A and B) are lo calized to numerous tis- sues, notably cardiac tissue, vascular smooth muscle and platelets . PDE3 inhibitors cause increased intracellular cal- cium accumulation (via inhibition of c AMP breakdown), resulting in improved contractility in cardiac myocytes. In addition, there is increased lusitropy (diastolic relaxa- tion), as the re-uptake of calcium is also a cAM P-depend- ent activity. There is evidence that the rate of re-uptake 169 CHAPTER 11.2 Phosphodiesterase inhibitors levels, resulting in vasorelaxation in the pulmonary vascular bed and, to a lesser extent, the systemic circulation. PDE5 receptors are also found in the lower oesophageal sphinc- te r, visceral smooth muscle and corpus cavernosum. with the dobutamine group suffering a higher incidence of hypotension and new AF. Milrinone has been found to be as effective as 20ppm NO in reducing pulmonary artery pressures in pa tients with pulmonary hypertension. Milrinone is generally preferred to other PDE3 inhibi- tors because of better PDE3 selectivity and its shorter half-life. Sildena \201 l \200 Sildena \201 l is licensed for use in erectile dysfunction and pulmonary hypertension. The dose is 12.5 \200\22350mg tds orally, and an IV formulation is available. In the context o f pulmonary hypertension, the long-term use of sildena \201 l has been associated in impro vements in RV mass and functional status. In intensive care patients, it is often used as a step-down therapy from iNO in patients with severe pulmonary hypertension. In this setting its use seems logical, but no outcome studies have been reported. Systemic hypoten- sion m ay occur. Recent evidence has suggested a role for sildena \201 l in the management of myo cardial ischaemia reperfusion injury. Thus it may \201 nd clinical application in the man agement of cardiac arrest and myocardial stunning post-cardiac surgery Enoximone \200 Enoximone causes an increase in cardiac index, and reduction in systemic vascular resistanc e when com- pared with both placebo and dobutamine. As with milri- none, enoximone has been found to facilitate weaning from cardiopulmonary bypass. Enoximone is administered as a bo lus of 0.5 \200\2231.5mg/kg, followed by an infusion at 5 \200\22310mcg/kg/min. It has a ha lf- life of 2h. Amrinone \200 \200 Amrinone has similar effects to the other PDE3 inhibitors. Impaired coagulation has been re ported in some patients recieving amrinone due to a reduction in platelet count and/or plat elet function. Amrinone is administered as a loading dose of 0.75 \200\223 1.5mg/kg, follow ed by an infusion of 10mcg/kg/min. It has an elimination half-life of 3.5h. Further reading Amsallem E, Kasparian C,; Haddour G, et al. Phosphodiesterase III inhibitor s for heart failure. Cochrane Database Syst Rev 2005; (1): CD002230. Feneck RO, Sherry KM, Withington PS, et al. European Milrinone Multicenter Trial Group: com parison of the haemodynamic effects of milrinone with dobutamine in patients after cardiac sur- gery. J Cardiothorac Vasc Anesth 2001; 15: 306 \200\22315. Dipyridamole This antiplatelet agent owes part of its mechanism of action to PDE3 inhibitio n. It also has a role in the management of pulmonary hypertension through PDE5 inhibition. Gillies M, Bellomo R, Doolan L, et al. Bench-to-bedside review: ino- tropic drug therapy af ter adult cardiac surgery \200\224a systematic lit- erature review. Crit Care 2005; 9: 266 \200\22379. Phosphodiesterase type 4 inhibitors Two experimental agents are currently being evaluated i n phase III trials in patients suffering from asthma and COPD. Selective PDE4 inhibition ha s anti-inflammatory and immune-modulating functions in the respiratory mucosa, resulting in clinical improvement in bronchoconstriction, mucous hypersecretion and airway remodeling. Kroegel C, Foerster. M. Phosphodiesterase-4 inhibitors as a novel approach for the treatmen t of respiratory disease: cilomilast. Expert Opin Invest Drugs 2007; 16: 109 \200\22324. Mitra A, Bassler D, Watts K, et al. Intravenous aminophylline for acute severe asthma in ch ildren over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev 2005, I ssue 2. Parameswaran K, Belda J, Rowe BH. Addition of intravenous amino- phylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000, Issue 4. Phosphodiesterase type 5 inhibitors PDE5 inhibitors prevent the breakdown of cGMP in pul- m onary vascular smooth muscle, increasing intracellular 170 A BRAME & J CORDINGLEY Vasodilators In critically ill patients, vasodilators may be indicated for treatment of systemic or pulm onary hypertension, reduc- tion of cardiac preload or treatment of vasospasm in spe- ci \201 c arterial systems. Caution is required if administering vasodilators to patients with low \201 xed cardiac output, e.g. severe aortic stenosis, because of the risk of inducin g severe hypotension. Hydralazine Hydralazine preferentially dilates arterioles via stimulation of cGMP. It is as sociated with re \202 ex sympathetic activity, resulting in tachycardia. Hydralazine cause s renin to be released by the juxtaglomerular apparatus, with subse- quent angiotensin prod uction, aldosterone release and sodium retention; thus B-blockers or diuretics are often ad ministered concurrently. Onset of action is within 5 \200\22310m IV, 20 \200\22330min orall y. The half-life is 2 \200\2234h, but in patients with renal disease the half- life may inc rease up to 16h. \200 \200 Nitrates Nitrates act directly on smooth muscle by release of NO from the parent molecule. Tolerance to nitrates can be reduced by the use of nitrate-free periods. Indications: hypertension, hypertensive crisis. Contraindications: SLE, severe tachycardia, high output heart failure, myocardial insuf \201 ciency due to mechanical obstruction, po rphyria. Dose and route: orally, 10 \200\22325mg bd \200\223qds for hyperten- sion. Increas e to 50 \200\22375mg qds in cardiac failure. By slow IV injection, 5 \200\22310 mg, may be repeated after 20 \200\22330min. By IV infusion, initially 200 \200\223300mcg/min, maintena nce usually 50 \200\223150mcg/min. Glyceryl trinitrate (GTN) GTN acts primarily on venous capacitance vessels, reduc- ing veno us return (preload). It has some arteriolar effect, decreasing afterload, and is a coronary vasodilator. Onset of action is 2 \200\2235min with a half-life of 3min. GTN undergoes hep atic and extrahepatic metabolism via red cells and vascular endothelium. Tachyphylaxis is c ommon, with tolerance occurring within 24 \200\22348h. \200 \200 Indications: congestive cardiac failure, cardiac ischaemia. Contraindications: aortic steno sis, hypertrophic obstructive cardiomyopathy (HOCM), hypoten- sion, tamponade, severe anemi a, hypertensive encepha- lopathy. Dose and route: available sublingually, orally, transder- mally and IV. Start IV infusion 10mcg/min and titrate by 10mcg/min to a maximum 200mcg/min . Diazoxide Diazoxide is an arteriolar vasodilator and antihypertensive. It inhibits insulin release, and hyperglycaemia may occur. Onset of action is 5 \200\22310min with duration of action of 4 \200\223 12h. Diazoxide is extensively protein bound, partly hepati- cally meta bolized and partly excreted unchanged. Dif \201 cult to use to control blood pressure over short time periods because of long half-life. \200 \200 \200 Isosorbide mononitrate (ISMN) ISMN is an orally administered nitrate used for angina prophy laxis and treatment of heart failure. Indications: hypertensive emergencies. Contraindications: ischaemic heart disease. Dose: by rapid IV injection, 1 \200\2233mg/kg with a maximum single dose of 150mg. Can be repeated after 5 \200\22315min as required. Isosorbide dinitrate (ISDN) ISDN has slower onset and is longer acting than GTN and can be administered sublingually, orally or by IV infusion. Calcium antagonists Calcium channel blockers have antianginal, antiarrythmic and vasodilato ry effects. In cardiac muscle, calcium antago- nism reduces myocardial contractility and ca rdiac output in a dose-dependent fashion. Impulse generation at the sinoatrial node and con duction via the atrioventricular node are calcium dependent, and blockade decreases sinus n ode pacemaker rate and atrioventricular node conduc- tion velocity. There are three classes of calcium channel antagonists: \200 Dihydropyridines (nifedipine, amlodipine, nimodipin e) \200 Diphenylalkylamines (verapamil) \200 Benzothiazepines (diltiazem) Directly acting vasodilators Sodium nitroprusside (SNP) The main action of SNP is relaxatio n of vascular smooth muscle in both arteries and veins that occurs via NO-stim- ulated incr ease in cGMP. At low doses, arterial vasodilata- tion predominates. The hypotensive effect of SNP is seen within 1 \200\2232 min and may cause re \202 ex tachycardia. Myocardial isc haemia can occur via a coronary steal syndrome. Circulatory half-life is 2min. Nitroprussi de metabolism can lead to methaemoglobin formation and metabolic aci- dosis. Speci \201 c therapy for overdose includes administra- tion of sodium nitrite followed by sodium thiocya nate. Tachyphylaxis may occur. \200 Nifedipine is an arteriolar vasodilator. It can be adminis- tered orally, sublingually or I V. Sublingual administration may cause rapid severe hypotension. Onset of action is 2 \200 \2235min. It is hepatically metabolized with a plasma half-life of 4h. \200 \200 Indications: immediate reduction of blood pressure in hypertensive crises, acute congestive cardiac failure, controlled hypotension intraoperatively. Contraindications: aortic coarct ation, congenital optic atrophy, high output cardiac failure, severe B12 de \201 - ciency. Dose: start 0.3 \200\2230.5/mcg/kg/min and titrate to maximum 8mcg/kg/min. Indications: angina, hypertension, Raynaud \200\231s syndrome. Contraindications: aortic st enosis, porphyria, cardiogenic shock. Dose: 5 \200\22320mg tds. Nimodipine has selective cerebral vasodilatory effects. It is indicated in the prevention a nd treatment of ischaemic neurological de \201 cit following subarachnoid hemorrhage. 171 CHAPTER 11.3 Vasodilators Peak plasma concentrations are reached within 1h, orally or IV. Half-life is 1 \200\2232h. Nimodipine undergoes hepatic metabolism; the dose should be halved in liver failure. \200 \200 Onset of action is 30 \200\22360min, peak action at 2 \200\2234h, and half- life is 8 \200 \22312h. 50% is excreted renally unchanged. \200 \200 \200 Indication: post-operative blood pressure control. Contraindication: (relative) depression. Dose: orally, 50 \200\223100mcg tds, increased to maximum 1.2mg/day; IV bolus, 10mcg repea ted until desired effect; IV infusion, 0.5 \200\2231.0mcg/kg/h. Contraindications: severely raised ICP. Dose: orally, 60mg 4 hourly; IV, 500mcg \200\2231mg /h initially, increased to 2mg/h as blood pressure tolerates. Verapamil and diltiazem are used as antiarrythmic and antianginal agents, and have limited vasodilatory actions. They should be used carefully in the presence of accessory conducting pathwaysm e.g. Wolf \200\223Parkinson \200\223White syn- drome, as VF may be precipitated. a-Adrenergic receptor antagonists Adrenergic receptors are subdivided into A1 and A2, and B1, B2 and B3 subtypes. \200 Methyldopa, an analog of L-dopa, causes decreased blood pressure by reduction in peripheral vascular resistance. It is hepatically metabolized and is renally excreted. Onset of actio n is 4 \200\2236h, half-life is 2h. Peak effect occurs at 3 \200\2236 h. Side effects inclu de sedation, lactation, extrapyramidal signs and neuropsychiatric sequelae. Coombs test may become positive; may cause problems with X-matching blood. \200 Dose: orally, 250 \200\223300mg bd/tds, increase to maximum 3g/day. A1 receptors are responsible for vasoconstriction, gut smooth muscle relaxation, increased salivation and glu- coneogenesis. A2 receptor agonists inhibit noradrenaline and acetyl- ch oline release and stimulate platelet aggregation. Angiotensin inhibitors Angiotensin-converting enzyme (ACE) inhibitors ACE inhibitors act by binding irreversibly to the angiotensin I binding site in the lung and preventing conversi on to angi- otensin II. Peripheral vascular resistance is decreased; car- diac output and h eart rate are unchanged. ACE inhibitors are used post-MI for their ventricular remodeling p roperties, and have been shown to improve long-term survival. Oral administration is usual, although enalaprilat is available as an IV agent for use in patients who are unable to tak e oral therapy. ACE inhibitors are renally excreted. Half-life is dependent on the preparat ion. \200 A-Blockade causes reduced systemic vascular resistance. There may be re \202 ex sympatheti c stimulation. Phentolamine is a non-selective reversible competitive antagonist at both A1 and A2 receptors Onset of activity is rapid, with duration of action of 10 \200\22315min. \200 \200 Phenoxybenzamine is a non-selective irreversible A1 and A2 receptor antagonis t. Noradrenaline re-uptake is blocked, potentiating the action of B agonists. Duration of a ction is 3 \200\2234 days. \200 \200 Indications: phaeochromocytoma. Dose: 2 \200\2235mg (IV), repeat as necessary Indications: phaeochromocytoma. Dose: orally, initially 10mg bd, increased to 1 \200\2232mg /kg in divided doses; IV, 1mg/kg daily, slow injection over 2h daily. Indications: hypertension, post-MI, cardiac failure, ischae- mic heart disease. Contraindic ations: hyperkalaemia, acute renal dysfunc- tion, renovascular disease, pregnancy, heredita ry angioedema. Dose: captopril 12.5 \200\22350mg 8 hourly. Onset of action 20 \200\22330min , duration of activity 4h. Peak effect 90min post-dose. May cause profound hypotension in c ritically ill; usual to start with test dose of 6.25mg. Prazosin is a competitive A1 receptor antagonist. \200 Indications: essential and renovascular hypertension, Raynaud \200\231s disease, benign pro static hypertrophy. Dose: initially 500mcg bd/tds at night, increased to 20mg/ day in divid ed doses. Pulmonary vasodilators In critically ill patients, pulmonary vasodilators are used to preve nt and treat acute RV failure. In addition, inhaled pul- monary vasodilators are often used to improve oxygena- tion in patients with ARDS, although RCTs have not demonstrated improv ed survival.