183 CHAPTER 11.7 Antianginal agents Nitrates These are used for their arterial and venous dilatation, reducing pre- and afterlo ad and myocardial work. GTN infu- sion (50mg in 50ml titrated from to 15ml/h) provides rapi d relief of unstable angina in in-patients. Rapid reversibility makes GTN especially useful in critically ill patients for angina and hypertensive crises. Prolonged administration (> 24h) results in tolerance to the nitrate and reduced ef \201 - cacy. Headache and tachycar dia are common side effects, and nitrates should be avoided in those with RV infarction and HOCM. Prolonged administration of IV nitrates can result in methaemoglobinaemia and possib ly resistance to heparin. Look for transdermal nitrate patches in hypoten- sive obtunded pa tients with a past history of ischaemic heart disease and remove (especially before de \201 brillation). Sublingual nitrates are normally avoided in critically ill patients due t o the unpredictable degree of hypotension. desperation include sodium bicarbonate for arrhythmia, magnesium (especially if QT prolonge d with sotalol), aminophylline, transvenous pacing, aortic balloon pump, haemodialysis, and even methylene blue to inhibit NO production and increase vascular tone. Calcium channel blockers These drugs are frequently used for angina and blood pres- sure co ntrol in patients who cannot tolerate B-blockade. There are two pharmacological (and functi onal) groups. The dihydropyridines (nifedipine, amlodipine, felodipine) reduce afterload an d cause coronary vasodilatation, whereas the non-dihydropyridines (diltiazem, verapamil) ar e also rate controlling. Systematic analysis does not show any bene \201 t for these drugs in preventing MI or mortality; therefore, B-blockers remain \201 rst line unless contrai ndi- cated. In the recovering critically ill, amlodipine has become commonly used as an ant ihypertensive due to its lack of effect on heart rate and conduction, and avoidance of B- b lockade \200\230in case \200\231 the patient deteriorates and requires catecholamine suppo rt; there is, however, no evidence that this is any safer than cautious B-blockade with an appropri- ate agent. Other antianginal drugs Opiates provide important symptomatic relief and should always be u sed to ameliorate the sympathetic drive in acute ischaemia. They do not provide outcome ben e \201 t. Potassium channel sensitizers such as nicorandil have an arterial and venous vas odilatory action but may also have a role in ischaemic pre-conditioning and myocardial prot ection. Its use in the critically ill patient remains exper- imental. Ranolazine is a fatty acid oxidase inhibitor which also pre- vents calcium overload in myocytes. Intensivists sh ould be aware that it causes prolongation of the QT interval. Ivabridine has a speci \201 c action on the sinus node pace- maker current, reducing heart rate. Its use in those intol er- ant of B-blockade is increasing. Pharmacokinetics and drug speci \201 cs Amlodipine is hepatically metabolized, has a peak effect at 6 \200\22312h and an elimination half-life of 30 \200\22350h if hepatic func- tio n is normal. Diltiazem has a half-life of 4h and is hepati- cally metabolized, but has acti ve metabolites and these are partially excreted in the urine. Nifedipine is hepatically met abolized to inactive metabolites; the half-life is 2 \200\2235h, but slow release preparati ons are usually used and these must not be crushed for NG tube administration; its use is b est avoided in critically ill patients. Verapamil is hepati- cally metabolized; its use in the critically ill is best avoided due to the risk of heart failure. Further reading Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2006 Guideline update on perioperative cardiovascular evaluation for noncardiac surgery: focused update on periopera tive beta-blocker therapy. Circulation 2006; 113: 2662 \200\22374. http://circ.ahajour- nal s.org/cgi/content/full/113/22/2662 Calcium channel blocker overdose These patients will be hypotensive and may or may not be b radycardic depending on the agent. An ABC approach plus speci \201 c therapy with calcium (10ml of 10% calcium chloride, repeated as necessary or followed by infusion at 0.5mEq calc ium/kg/h). Glucagon can also be used (see above). Vasopressors (noradrenaline) may be neces sary and also PDE inhibitors (only once pressors are initiated and can be titrated to count er hypotension). Insulin and glucose treatment has been used successfully (see above). Tran svenous pacing and aortic balloon pump may be nec- essary. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and u nstable angina: an overview. BMJ 1989; 299: 1187 \200\22392. 184 S WADDY Antiplatelet agents (P2Y12) on the platelet surface and interrupt platelet acti- vation. Ticlopidine has a high er incidence of adverse effects (neutropenia and thrombotic thrombocytopenic syndrome) than clopidogrel and consequently is less commonly used. Platelets interact with a range of clotting factors, endothelial surfaces and tissue compon ents, as well as with each other to form a blood clot. Most of the time they are inactive a waiting stimulation, until there is vessel injury when they are appro- priately activated t o form a component of the blood clot plugging the gap. There are a variety of situations wh ere there is inappropriate activation or where we do things to the patient that result in u ndesirable platelet activation. There are a series of drugs that can be used to prevent thi s. Clinical use Acute coronary syndrome Clopidogrel is a key drug in the management of unstabl e angina and non-ST elevation MI (NSTEMI), and studies have demonstrated a reduction in vas cular events when clopidogrel is added to aspirin therapy for up to 12 months (MI reduced f rom 6.7 to 5.2% in the CURE study at 1yr). There is an increase in bleeding, and individual patient risks should be considered when starting this treatment (major bleeding increased from 2.7 to 3.7% in CURE). Clopidogrel is frequently used as \201 rst-line therapy in pat ients intolerant of or allergic to aspirin. Aspirin Acts by irreversibly acetylating cyclo-oxygenase type 1 (COX-1) found in platelets. This is achieved at low doses (usually 75mg daily) and prevents COX-1 from producing prost aglandin H2 which would otherwise be used in pro- duction of thromboxane A2 which is stored in platelets and acts as a local ampli \201 er of platelet activation. Post-coronary stenting Clopidogrel reduced the relative risk of in-stent thrombosis by 26.9 % at 1yr (absolute reduction of 3%) following percu- taneous coronary intervention (PCI) in the CREDO study (the control group was given clopidogrel for 3 months post- PCI and both g roups continued aspirin). Evidence suggests that pre-treatment with thienopyridines further reduces instent thrombosis provided the loading dose (300mg clopi- dogrel) is at least 6h before the procedure (it may be pos- sible to improve the outcomes when loading in advance is impossible by giving a larger loading dose, 600mg). Clinical use Coronary disease: aspirin is used in stable coronary dis- ease for primary and secondary prevention, and in unsta- ble disease for treatment of MI. The second internatio nal study on infarct survival (ISIS-2) demonstrated that 160mg aspirin daily reduced 5 week mortality by 23% in acute ST elevation myocardial infarc- tion (STEMI). This was the same as the reduction achieved by streptokinase (25%) and, used together, an odds reduc- tion of 42% is achieved (from 13.2 to 8.0% mortality). Aspirin is an important therapy! GI bleedin g: a past history of GI bleeding should not pre- vent the administration of aspirin acutely in STEMI. Cerebrovascular disease: aspirin is also used for second- ary prevention of cere brovascular disease, giving 22% odds reduction (from 21.4 to 17.8% in a pooled analysis of 21 trials). Issues in intensive care Cardiothoracics: there is evidence that clopidogrel ther- apy may signi \201 cantly increase bleeding post-operatively, incidence of return to theater and t ransfusion requirements in cardiothoracic surgery. If possible it should be suspended 5 day s before bypass surgery. This effect is mitigated if clopi- dogrel is started at least 4h p ost-operatively in those with low drain outputs, where there may be an outcome bene \201 t to starting clopidogrel. An assessment on an individual patient basis and their likelihood of having an unstable coro- nary event during drug suspension should be made. Non-cardiac surgery and medical patients: there are very few data. Individual assessment of coronary ri sk vs bleeding risk should be made. If the patient has had coro- nary stent implantation wi thin 1 month (bare metal stents) or 3 months (coated or drug-eluting stents) then only seve re or life-threatening bleeding should prompt cessation of clopidogrel as the risk of stent occlusion is signi \201 cant. Perioperative: platelet transfusion should only be used in the context of overt hemorrhage and not pre-emptively even if a decision to stop clopidogre l is made pre-operatively (neurosurgery may be an exception). There is only one reported ca se of clopidogrel overdose and that was without symptoms. Reversal: requires platelet trans fusion. Issues in intensive care GI bleeding is a major side effect of aspirin. This risk should be put in perspective. In a meta-analysis of 22 rand- omized trials of aspirin therapy, the i ncreased risk of major bleeding from aspirin was 70%, but this translates to an absolute an nual increase of only 0.13% in stable patients (769 patients need to be treated with aspiri n to cause one major bleed). Clearly these absolute risks will be greater in the intensive care population. Bronchospasm is seen in up to 10% of new users. Perioperative: in general, aspirin should not be suspended for operations, as this signi \201 cantly increases the r isk of perioperative coronary events, unless bleeding would be catastrophic, e.g. intracran ial surgery. Reversal of aspirin: requires platelet transfusion. Dipyridamole Inhibits adenosine deaminase and phosphodiesterase (PDE), resulting in accumul ation of adenosine and cAMP. It is used as a second-line agent in stroke prevention in conj unction with aspirin or in those intolerant of aspirin. It is also used in cardiac stress t esting due to its vasodilatory action. There are few reports of overdose, but hypotension a nd MI are reported. Dipyridamole has a half-life of 10h; more rapid reversal requires plate let transfusion. GpIIb/IIIa receptor antagonists There are two classes of agent: \200 \200 Antibody to the receptor (abciximab, ReoPro ) Small molecule inhibitors (tiro \201 ban, A ggrastat ; and epti \201 batide, Integrilin ) Clopidogrel Clopidogrel and ticlopidine are thienopyridines that block binding of ADP to th e type II low af \201 nity purine receptor 185 CHAPTER 11.8 Antiplatelet agents Platelet P2Y12 GpIIb/IIIa Abciximab Tirofiban Epoprostanol Fibrin Blocks binding Activation stimulates GpIIb/IIIa synthesis Adenylate cyclase TxA2 Inhibits platelet activatio cAMP Platelet COX 1 Arachadonic acid Aspirin Phosphodiesterase degradation ADP inhibits Released from platelet granules Dipyridamole Blocks receptor binding Clopidogrel Fig. 11.8.1 Mechansim of action of antiplatelet drugs. adenylate cyclase and increasing cAMP levels, which inhib- its platelet activation. It is u seful for its very rapid reversi- bility within a few minutes of stopping the infusion (hal f-life is 6min). Its use is limited by cost and profound vasodilata- tion (it is also used for pulmonary vasodilatation in idio- pathic pulmonary hypertension). These agents act by blocking the GpIIb/IIIa receptor on the platelet surface. This receptor binds \201 brin so is key to creating the meshwork of \201 brin and activated platelet s that forms the platelet plug of a clot. Abciximab has complex pharmacokinetics, but the k ey point is that the molecule takes days to clear from the plasma completely, and clinicall y platelet function takes 48h to recover from cessation of an infusion. Recovery of platel et function is much more rapid from the small mole- cule inhibitors (within a few hours). A bciximab can cause a unique form of thrombocytopenia occurring between 30min and 24h of adm inistration that results in a profound drop in platelets, believed to be due to the presenc e of \200\230pre-formed \200\231 antibodies to \200\230hidden \200\231 epitopes on platel ets. Confusingly pseudothrombocytope- nia can also be seen, but this recovers within 4h, an d differ- ent platelet counts are seen with different anticoagulants in the sampling tube, e.g. EDTA vs citrate. Both these are much less common with tiro \201 ban or epti \201 bat ide. Summary of indications Aspirin \200 Primary prevention in high risk patients (coronary and cerebrovascular) Secondary preventio n all patients Pre- and post-coronary stenting \200 Dipyridamole \200 Second-line therapy in cerebrovascular disease in combi- nation with aspirin Clopidogrel \200 Second-line therapy in high risk coronary disease in combination with aspirin Pre- and post -coronary stenting Alternative to aspirin in those intolerant Clinical use STEMI: should not be used in STEMI, where primary ther- apy is thrombolysis, u nless used prior to angiography and primary angioplasty stent. They are frequently used in the context of failed thrombolysis or re-infarction whilst awaiting transfer for rescue PCI. NSTEMI: meta-analysis shows that if the serum troponin is elevated and if PCI is plann ed, there is mortality and MI bene \201 t to using these drugs, and this bene \201 t is s till seen with concurrent clopidogrel therapy. Bleeding risk: is elevated especially with c oncurrent use of other agents. All the GpIIb/IIIa inhibitors require dose adjust- ment in p atients with renal failure, and use with caution in the elderly and with weight adjustment in smaller patients. Reversal: platelet transfusion, but tiro \201 ban and epti \201 bati de reverse within a few hours anyway. \200 GpIIb/IIIa inhibitors \200 STEMI: failed thrombolysis pending rescue PCI or pend- ing primary PCI NSTEMI: positive tro ponin, only if proceeding to PCI Caution in renal failure, elderly, small patients. \200 Further reading Bosch X, Marrugat J. Platelet glycoprotein IIb/IIIa blockers for per- cutan eous coronary revascularization, and unstable angina and non-ST-segment elevation myocardia l infarction. Cochrane Database Syst Rev 2001; (4): CD002130. ISIS-2 Collaborative Group. Randomized trial of intravenous strep- tokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lance t 1988; 2: 349 \200\22360. Epoprostenol (prostacyclin, PGI2, Flolan ) This is used in intensive care as a method of a nticoagula- tion for extracorporeal circuits. It acts by stimulating Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST- segment elevation. N Engl J Med 2001; 345: 494 \200\223502. 186 M PALAZZO Diuretics and the critically ill Introduction Diuretics are frequently used in the critically ill, although the rationale fo r their use is not always logical. The most common reasons are for reduction of tissue or p ulmonary oedema, to promote urine output for oliguric states, to control ascites and occasi onally to change blood acid \200\223base balance to help weaning, such as with acetazola- m ide. The decompensated cirrhotic is characterized by vasodila- tation, arteriovenous \201 stul ae, and \202 uid and albumin loss through ascites, which all lead to reduced effective in tra- vascular volume. The latter stimulates compensatory sec- ondary sodium retention, olig uria and impaired water excretion. Appropriateness of diuretics for oedema \200 While diuretics may be an appropriate treatment for patients with hydrostatic pulmonary oed ema due to cir- culating hypervolaemia, they are less appropriate for the hyperpermeable pu lmonary congestion or oedema of in \202 ammatory states. Where oedema is largely driven by sodium retention and hyperaldosteronism, diuretics are appropriate and of value, although control of the driving mechanism such as myocardial dysfunction is likely to be more succes sful for oedema control. Diuretic therapy for hyperpermeability, pulmonary oedema of chest infection or aspiration pneumonitis may modestly improve oxygenation particularly if there is alveolar rather than interstitial oedema; however, the improvement is short lived becaus e defective permeabil- ity is not resolved. Large oxygenation improvement sug- gest a signi \201 cant hydrostatic component Diuretic therapy to achieve negative balance may in hyper permeability states result in circulating hypovolae- mia, renal dysfunction, a fall in card iac output and greater inotrope need, which are associated with poor out- comes. Paradoxica lly these patients may still continue to have peripheral oedema if the underlying in \202 ammation persists. There is a common belief that peripheral oedema is a marker for pulmonar y or internal organ oedema, and that \200\230dry \200\231 states improve tissue oxygenatio n. The improvement in survival rates associated with more aggressive resuscitation and \202 uid maintenance tech- niques suggests that the latter is a better overall haemo- dynam ic package. In critical illness, increased capillary permeability is com- mon. Oedema forma tion, particularly in subcutaneous and muscle tissue where the safety factors are not as we ll developed, is expected. Unresolved systemic in \202 am- mation will result in consecuti ve days of positive bal- ances struggling to achieve an appropriate circulating volume to m aintain multi-organ function in the face of permeability losses. The more rapidly the speci \201 c thera- pies of timely surgery or antibiotics are instituted to halt the in \202 a mmatory process, the less likely are oedema formation and multi-organ failure. It is notabl e that in the recovery phase of systemic in \202 ammation, when permeability tends back to normal, spontaneous diuresis occurs without haemodynamic perturbations and indeed diuretic s may be used to accel- erate losses of excess total body saline with little further haemod ynamic impact other than through unheralded rhythm changes consequent to large potassium an d magnesium losses. Tissue oedema, pulmonary oedema and ascites \200 Tissue oedema is the accumulation of \202 uid in the inter- stitial space. It results in circulating hydrostatic forces overwhel ming the protective safety factors described by Guyton. These relate lymphatic \202 ow, i nterstitial oncotic pressure and capillary hydrostatic pressure assuming normal endothelial permeability in a given tissue. In health, tissues have remarkably different capillary per - meabilities from each other. For example, brain has non- fenestrated capillaries while mu scle, subcutaneous tissue, intestines, kidneys and liver are progressively more per- meable . The variability between these components explains why it is considerably easier to develo p skin oedema than pulmonary oedema for a given hypervol- aemic state. In the critically il l, the tendency for greater capillary per- meability with systemic in \202 ammatory states exacerbates the tendency to oedema. Tissue and pulmonary leaki- ness result in oedema with modest capillary hydrostatic pressure rises. Pulmonary oedema may be hydrostatic, as it is with iatrogenic circulating hypervolaemia. This is more likely in those with unheralded ca rdiac dysfunction and uncommon in \202 uid-de \201 cient septic or haemorrhagic patients . It also follows the hypervolaemic state associ- ated with the hyperaldosteronism of cardi ac dysfunction or the mechanical perturbation associated with valvular incompetence or peri cardial constriction. Equally, a sig- nificant reduction in cardiac performance through abn ormal rhythms or deteriorating contractility may acutely or insidiously precipitate pulmona ry oedema through left atrial pressure rises. Ascites is a hallmark of patients with severe cirrhosis. Mechanical obstruction by slow portal vein \202 ow or thrombosis results in p eritoneal cavity \202 uid accumula- tion. This is the result of hepatic sinusoidal out \202 ow obstruction due to \201 brosis. Continuing \202 uid accumula- tion is halted by the dynamic balance between perito- neal hydrostatic pressure and the forces of transudati on. Reduction of the former by aspiration leads to a rapid re-accumulation of ascites. Cirr hotics also retain sodium, which promotes ascites and peripheral oedema. Two theories for s alt retention have been proposed although both result in increased aldosterone activity 1 Under \201 ll theory which suggests that splanchnic pooling and peripheral vasodilatatio n reduce the effective intravascular volume and stimulate secondary sodium retention. 2 Over \202 ow theory suggests primary sodium retention through intrahepatic hypertension and an ill-de \201 ned hepatorenal re \202 ex. The latter stimulates renal sympa- thetics , which promote sodium retention. Indications for diuretic therapy \200 Hydrostatic pulmonary oedema \200 Congestive card iac failure 187 CHAPTER 11.9 Diuretics and the critically ill \200 \200 response in doses between 25 and 100mg. It has a long duration of action and its active ele ments are spironol- actone and its metabolite canrenone. It is commonly combined with loop diuretics for its synergistic diuretic effect while sparing potassium losses. Its main use is to control hyperaldosteronism-driven oedematous states, typically cardiac, cirrhotic or nephrotic. It has been shown to reduce mortality associated with severe cardiac failure (EF s <35%) Hypertension Cerebral oedema Hyperaldosteronism-mediated oedema, nephrosis, cir- rhosis, co r pulmonale Peripheral oedema to promote mobility Promote urine output for renal function C hange arterial blood chemistry to aid weaning Help manage poor oxygenation in permeability pulmo- nary oedema \200 \200 \200 Amiloride Amiloride also acts at the collecting tubule, but prevents sodium uptake by the s odium pump and not by aldoster- one inhibition. Commonly used diuretics in the critically ill Thiazides Bendro \202 uazide This is a weak diuretic which produces a sustained daily diuresis by inhibiting sodium uptake in the corti cal thick ascending limb of the loop of Henle and in early distal tubules. It has to gain t ubular access by glomerular \201 ltra- tion to be active. It is used for long-term hypert ension management and uncommonly used in the acute phase of critical illness. Potassium canrenoate Potassium canrenoate is an IV aldosterone antagonist. It is a prodrug metabolized to the active canrenone. It is given in an equivalent dose range to spironolact one. The above drugs alone are not very powerful, but with loop diuretics they minimize the tendency to hypokalaemia. Carbonic anhydrase inhibitors Acetazolamide This is available as either IV or oral preparat ions. 250 \200\223 500mg 6 hourly is a modestly effective diuretic. By inhibi- tion of carb onic anhydrase in the proximal tubule it facilitates bicarbonate and sodium loss. The resul ting high sodium tubular content leads to greater potassium \200\223sodium exchanges in the distal collecting tubules and results in hypokalaemia. Consequently acetazolamide is one o f the few causes of hypokalaemic, hyperchloraemic metabolic acidosis. Acetazolamide can be used to provide a mild hyperchlorae- mic metabolic acidosis to correct metabolic alkalosis which is impeding weaning. Typically patients receiving loop diu- retics develop a mild met abolic alkalosis (chloride and K losses). They may also have a secondary metabolic alkalosi s that accompanies hypercarbia of hypoventilation. Such patients have apneoic episodes duri ng attempts at weaning if the pH > 7.45. Impaired weaning can be managed with a few days co urse of acetazolamide until pH is mildly acidotic. It should be noted that CSF pH might tak e a further 48h to correct; therefore, apneoa episodes on a ventilator may continue. Potass ium and magnesium losses will be large, and plasma concentrations should be kept at the hig h end of the nor- mal range. The diuretic effect of acetazolamide tends to tail off after a few days. Metolazone Metolazone is a powerful thiazide given in doses 5 \200\22310mg twice daily, but only available in oral preparations. It can provide signi \201 cant diuresis when loop di uretics are becom- ing ineffective. It can be used for resistant peripheral oedema, and in the critically ill can help provide a diuresis in those with non-oliguric chronic renal fai lure. Loop diuretics Frusemide Frusemide is a powerful short-acting agent very commonly used eith er to improve pulmonary function consequent to cardiac failure or less effectively to \200 \230dry out lungs \200\231 in those with pulmonary congestion or oedema related to systemic or localized pulmonary in \202 ammation. Frusemide is also use to accelerate oedema clear ance in those in the recovery phase of critical illness. In addition, it is increasingly us ed as an infusion to drive a diuresis to maintain renal function. Infusions can be effectiv e in low doses, starting in diuretic-naive kidneys from 1mg/h. It acts by enzymatic inhibit ion of cortical and medullary thick ascending loop of Henle Na+ K+ 2Cl \200\223 co-transpor ter. This tubular cell brush border-sited enzyme facilitates the movement of sodium into th e tubular cell; sodium is then is pumped out of the cell into the interstitium by energy- d ependent Na+ K+ ATPase. Consequently, frusemide reduces tubular energy requirements. Like t hiazides, frusemide increases delivery of sodium- and chloride-rich \201 ltrate to distal tubular potassium and hydro- gen ion-secreting sites. The diuretic-driven plasma volume co ntraction causes an increase in aldosterone secretion which promotes sodium exchange for K+ and H+ ions at these sites. The loss of chloride and the cation exchanges result in hypoka laemia and a mild metabolic alkalosis. Magnesium losses are also substantial. A further con sequence of large quantities of chloride and sodium reaching distal tubules is stimulation of the juxta- glomerular apparatus which results in renin- and adenosine- mediated afferent glomerular arteriolar vasoconstriction. Osmotic diuretics Mannitol Mannitol is commonly used as pulse therapy to reduce cer- ebral oedema and improve ICP control. It does not cross the blood \200\223brain barrier and provi des an osmotic gradient for cerebral cellular and extracellular water movement to the vascu lar space. Theoretically it would be expected that mannitol is more effective for managemen t of cytotoxic cerebral oedema (white and gray matter cellular swelling due to ischaemia) t han vasogenic (capillary permeability, interstitial) oedema, which affects mainly white mat ter. Mannitol promotes diuresis by gaining access to the renal tubule. It has a molecular w eight of 182Da and is readily \201 ltered. It inhibits sodium and water uptake in all par ts of the tubule by it osmotic effect. Aldosterone antagonists Spironolactone This is available only as an oral preparation; it is a competi- tive antagonist of aldosterone with a linear diuretic 188 M PALAZZO Hypovolaemia and renal impairment may follow continu- ous aggressive therapy (>6 pulses/day ) in the absence of urine loss replenishment. Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg 1992; 77: 584 \200\2239. Pitt B, Zannad F, Remme WJ, et al. The effect of spir onolactone on morbidity and mortality in patients with severe heart failure. Randomized Ald actone Evaluation Study Investigators. N Engl J Med 1999; 341: 709 \200\22317. Further reading Better OS, Schrier RW. Disturbed volume homeostasis in patients Rocco VK, Ware AJ. Cirrhotic ascites. Pathophysiology, diagnosis with cirrhosis of the liver. Kidney Int 1983; 23: 303 \200\22311. and management. Ann Intern Med 1986; 105: 572 \200\22385. Guyton A. Textbook of medical physiology, 8th edn. New York: Elsevier, 1991. This page intentionally left blank 190 J CORDINGLEY Levosimendan of 25% or more in PCWP) was achieved by 28% of the levosimendan patients and 15% of the dob utamine patients (P = .022). Interestingly, a subgroup analysis demonstrated that the use o f -blockers enhanced the hemodynamic effects of levosimendan but reduced the hemodynamic effects of dobutamine. In the LIDO study, levosimendan treatment was also associated with a signi \201 cant decrease in mortality. At 31 days, all-cause mortality was signi \201 ca ntly lower with levosimendan compared with dobutamine (hazard ratio 0.43 [95% CI 0.18-1.00] P = .049). The patients were also followed retrospectively for 180 days and this analysis revealed that 26% of the levosimendan patients had died, compared with 38% in the dobutamin e group (hazard ratio 0.57 [95% CI 0.34-0.95] P = .029). The most studied calcium sensitizer, levosimendan, has recently been introduced in many cou ntries for the treat- ment of acutely decompensated chronic heart failure (HF) and has both positive inotropic and vasodilatatory effects. It differs from classic inodilators because of its ability to improve myocardial ef \201 ciency, enhancing myo \201 lament response to calcium (Ca2+) and leading to increased myo- cardial contraction without increasing intr acellular calcium concentration. Levosimendan displays Ca2+ dependent binding to the N-terminal domain of cardiac troponin C with higher af \201 nity at high Ca2+ concentration and lower af \201 nity at low Ca2+ c oncentration. By stabilizing the Ca2+-troponin C (TnC) complex, levosimendan inhibits tropo nin I (TnI) effect and prolongs the actin-myosin cross-bridge association rate. Thus, the p ositive inotropic effect is obtained without an increase of intracellular calcium concentra tion or a signi \201 - cant increase of myocardial oxygen demand, usually seen with other inotropes. In addition, levosimendan is safe in patients with acute coronary syndromes and it improves the function of stunned myocardium in patients who undergo percutaneous coronary intervent ion. Importantly, the inodilatory effects of levosimendan are accentuated by concomitant us e of beta blocking agents in the LIDO trial. In the Randomized Multicenter Evaluation of In travenous Levosimendan Ef \201 cacy (REVIVE) trial, levosemindan signi \201 cantly improv ed a com- posite of clinical signs and symptoms of acute decompen- sated heart failure over \201 ve days as assessed by patients and their physicians. In the Survival Of Patients W ith Acute Heart Failure In Need Of Intravenous Inotropic Support (SURVIVE) study a statisti cally signi \201 cant difference was seen early, especially in patients chronically treate d with a beta blocker, but it was not evident in 180-day survival. Levosimendan also increases cyclic Adenosine Mono- phosphate (cAMP) due to phosphodiesteras e inhibition but the contribution of the cAMP system to its action appears to be rather sma ll. Levosimendan is associated with an increased rate of relaxation and reduced relaxation time , thus improving diastolic performance. The bene \201 cial effects of levosimendan are also related to its vasodilatatory effect m ediated by a Potassium-ATP- channel opening effect in cardiac and smooth muscle cells in an ATP-dependent manner and levosimendan-induced decrease in right and left ventricular after load seems to be bene \201 cial in failing hearts. Drug Use Treatment with Levosimendan is usually initiated with a 10 minute loading bolus of 3 to 6 mcg/kg followed by a 24h continuous infusion of 0.05 to 0.2 mcg/kg/min. If the pati ent has hypotension, one should either skip the loading dose or associate Norepinephrine in low dose. Most patients show improvement in hemodynamic function during the next 24h, usua lly heralded by a signi \201 cant increase in urine output and a signi \201 cant decrease in the PCWP. This diu- retic effect is often the cause of electrolyte imbalance that has b een associated with arrhythmia. Magnesium and potassium should be pre-emptively administrat ed in order to prevent arrhythmia unless there is a contra-indication such as renal failure . Levosimendan improves coronary blood \202 ow, decreases myocardial oxygen extraction, and improves ischaemic myocardium performance. This was \201 rst shown in animals and health y humans, but was later shown in patients with congestive HF, acute myocardial infarction ( AMI), after PCI of AMI patients with LV dysfunction and after coronary artery bypass grafti ng (CABG) where, despite improved cardiac performance, it did not increase myocardial oxyge n consumption or change myocardial substrate utilization. Levosimendan has a half-life of approximately 1.3 hours. The drug is metabolized by the liv er and has two active metabolites, OR-1855 and OR-1896, with long half-lives (75-78 hours), that are excreted by the kidney and prolong the duration of the hemodynamic effects of the ir parent compound. This long half-life is markedly increased in patients with severe chron ic renal failure or end-stage renal disease undergoing haemodialysis as compared with healt hy subjects. As a powerful vasodilator, levosimendan may be a harm- ful drug. Although this drug has a m inor in \202 uence on myo- cardial oxygen demand per se, in patients with active ischemia or obstructive CAD, levosimendan induced hypo- tension, especially in the hypovolemic patie nt, may precipi- tate tachycardia, aggravate ischemia, and increase myocardial damage, wors ening long term prognosis. Hypotensive patients or patients with active ischemia are not go od can- didates for levosimendan administration and should have these problems addressed \201 rst. Clinical Studies Several clinical trials have shown the bene \201 cial effect of levosimen dan on short-term hemodynamic and clinical signs in patients with AHF. Kivikko et al (DATE) reported a 30% increase in CO and a 50% decrease in PCWP after 24 hours infusion in class III-IV heart failure patients. The Levosimendan Infusion versus DObutamine (LIDO) study enr olled 203 patients with severe low-output heart failure and compared the effects of levosim endan with those of dobutamine in a double blind fashion over 24 hours. The primary end poi nt of hemodynamic improvement (an increase of 30% or more in cardiac output, and a decrease In countries where it is available, early levosimendan infusion can be considered for patie nts who remain symp- tomatic with dyspnea at rest despite initial therapy, partic- ularly t hose with a history of chronic heart failure, chronically treated with beta-blockers. It ha s also been used to restore right or left ventricular function in patients after cardiac su rgery, in unresponsive cardiogenic shock after heart transplantation primary graft failure, and RV dysfunction in acute respiratory distress syndrome patients. 191 CHAPTER 11.10 Levosimendan References Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute hear t failure syndromes. Am J Cardiol. 2005; 96(6A): 68G-73G. Michaels AD, McKeown B, Kostal M, et al. Effects of intravenous levosimendan on human coron ary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circu lation 2005; 111(12): 1504-9. De Luca L, Proietti P, Celotto A, et al. Levosimendan improves hemodynamics and coronary \202 ow reserve after percutaneous coronary intervention in patients with acute myocardial infarc- tion and left ventricular dysfunction. Am Heart J 2005; 150(3): 563-8. De Luca L, Colucci WS, Nieminen MS, et al. Evidence-based use of levosimendan in different clinical settings. Eur Heart J. 2006; 27(16): 1908-20. Kass DA, Solaro RJ. Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation 2006; 113(2): 305-15. Follath F, Cleland JG, Just H, et al. (2002) Ef \201 cacy and safety of intravenous levosi mendan compared with dobutamine in severe low-output heart failure (the LIDO study): a rand omized double- blind trial. Lancet 2002; 360(9328): 196-202. Givertz MM, Andreou C, Conrad CH, Colucci WS. Direct myocar- dial effects of levosimendan i n humans with left ventricular dys- function: alteration of force-frequency and relaxation- frequency relationships. Circulation 2007; 115(10): 1218-24. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dob- utamine for patients with acu te decompensated heart failure: the SURVIVE Randomized Trial. Jama 2007; 297(17): 1883-91. Morelli A, Teboul JL, Maggiore SM, et al. Effects of levosimendan on right ventricular afte rload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 20 06; 34(9): 2287-93. Toller WG, Stranz C. Levosimendan, a new inotropic and vasodila- tor agent. Anesthesiology 2006; 104(3): 556-69. This page intentionally left blank 193 Chapter 12 Gastrointestinal drugs Chapter contents H2 blockers and proton pump inhibitors 194 Antiemetics 196 Gut motility agents 198 Antidiar rhoeals 200 Constipation in critical care 202 194 K DELL H2 blockers and proton pump inhibitors Physiology of acid secretion There is continual basal acid secretion and an increase after meals, from the parietal cells in the body and fundus of the stomach. The dominant mechanis m for acid secre- tion is mediated by histamine from enterochromaf \201 n cells, in turn s timulated by gastrin, released from antral G cells in response to amino acids. Other stimul i acting on parietal cells include acetylcholine, gastrin, calcium and pituitary adenylate cyclase-activating polypeptide. Lansoprazole is a weak inducer of cytochrome P450, affect- ing the metabolism of phenytoin, theophylline and warfarin. Pantoprazole does not inhibit or induce the cytochrome P450 sys tem. Pathophysiology of stress ulcers Factors contributing to mucosal disease \200 Defects in gastric glycoprotein mucus. This is contrib- uted to by re \202 uxed bile salts and uraemic toxins. Gastric acid hypersecretion. Although acid secretion in most criticall y ill patients is normal or subnormal, in patients with head injuries and extensive burns t here can be hypersecretion. Ischaemia. Even with apparently normal systemic circula- tion, visceral perfusion can be decreased, decreasing secretion of mucus and bicarbonate. Helicob acter pylori infection. This has not been well stud- ied in the critically ill. Pharmacology Histamine receptor-2 blockers (H2Bs) \200 \200 can cause bradycardia on rapid injection have a short half-life, resulting in an elevated p H for 4 \200\2238h after an intravenous bolus possess a degree of renal elimination and the refore require dose adjustment with renal impairment cimetidine is known to be an enzyme in hibitor increasing the plasma levels of many drugs, e.g theophylline, metro- nidazole, diaz epam and phenytoin exhibit tachyphylaxis or tolerance. Coagulation effects In vitro studies have shown at a pH of 6.4 the effectiveness of coagula tion and platelet aggregation is halved. A further drop in pH to 5.4 results in practical c essation of coagula- tion and platelet aggregation activity. Clot lysis by pepsin is inhibi ted if pH is >4. The literature has suggested aims of treatment are: \200 \200 