Newer drugs in intensive care

3 Newer drugs in intensive care KIN-LEONG KONG SALLY HAYNES JULIAN BION

Systems for monitoring the efficacy and safety of new drugs in the general population are now reasonably well-established, but it is only in the last few years that the pharmaceutical industry and the medical profession have recognized the need to assess drugs formally in critically ill patients, rather than making assumptions based on simple pharmacokinetic studies in patients with stable failure of single organ systems such as chronic renal failure or cirrhosis. Two examples have drawn attention to this problem: the hypnotic agent etomidate (Hypnomidate) and morphine-based opioids. Etomidate was used for infusion-sedation of critically ill patients by clinicians who assumed that its safety in anaesthetic practice would apply in intensive care; and it was not until Watt and Ledingham (1984) reported the association of such infusions with an increase in mortality in multiple trauma patients that the potent inhibitory effect of etomidate on adrenal cortical function was discovered (Lambert et al, 1983). Old drugs used in new surroundings are potentially even more hazardous, as they may escape the vetting procedures applied to new drugs: the accumulation of active morphine metabolites in renal failure (Osborne et al, 1986) is still not recognized by some clinicians. Some pharmaceutical companies are now applying for product licences specifically for intensive care, and this is a welcome development. In time it should be possible to develop a standardized approach to the investigation of new drugs in critically ill patients, but there are difficulties that need to be resolved. The assessment of drugs in patients with multiple organ failure (MOF) may be complicated by polypharmacy, changes in drug receptors, altered plasma protein and tissue binding, changes in regional blood flow and drug distribution, accumulation of either the parent compound or potentially active metabolites, and the effect of haemofiltration on drug clearance. Two particular difficulties include the measurement of tissue (as opposed to plasma) drug levels, and the absence of accurate non-invasive measures of hepatic blood flow and hepatocellular function. Pharmacodynamic studies, particularly those which use survival as an end-point, must stratify for severity of illness to reduce bias (Knaus et al, 1984). In this brief review, we have selected new drugs of relevance to intensive care practice, and have included some older compounds, which are either Baillibre's Clinical Anaesthesiology-Vol. 4, No. 2, September 1990 ISBN 0-7020-1465-6

305 Copyright 9 1990, by Bailli6re Tindall All rights of reproduction in an,/form reserved

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being used in new ways or for which there is new information. We hope that all companies making intensive care drugs will apply for critical care product licences, and would encourage them to work with clinicians to establish proper methods for assessing both new and established compounds. VASOACTIVE DRUGS The presentation of cardiovascular failure in critically ill patients depends on the underlying pathology, but the two commonest patterns are the highoutput/low-resistance hypotension typical of sepsis, and the low-output/ moderate-resistance hypotension seen in primary cardiac failure and many other conditions. Common to both is an inadequate oxygen delivery for the needs of the tissues. The newer compounds described here should not be seen as necessarily replacing agents such as adrenaline or noradrenaline for organ system support, and rational management must be based on proper haemodynamic measurement. There is still insufficient information about the effect of these drugs on regional perfusion and organ function in critically ill patients.

Dopexamine Dopexamine hydrochloride is a synthetic dopamine analogue designed for use in low cardiac output states. It combines systemic and renal arterial vasodilatation with inotropic activity. It is a potent direct [~2 adrenoceptor agonist, a weak indirect ~1 agonist by inhibition of noradrenaline reuptake, and has one-third the activity of dopamine at DA1 receptors in the splanchnic vasculature. It has no ~-agonist activity (Brown et al, 1985). It improves cardiac output by a combined inotropic and chronotropic effect without significantly increasing myocardial oxygen consumption, and has less dysrhythmogenic potential than other agents. Dopamine receptor agonism ensures that part of the increase in cardiac output is directed towards the renal circulation. Dopexamine is rapidly cleared from the plasma with a half-life of about 7rain in healthy volunteers (Neale et al, 1986). It undergoes hepatic sulphoxidation, and this inactive metabolite is cleared by the kidneys. The effect of renal failure is not known. Clinical studies in patients with chronic congestive cardiac failure (New York Heart Association Classes II to IV) and in patients recovering from cardiac surgery showed that infusions of dopexamine at 0.5-4 ~g kg-1 min-1 increased stroke volume, cardiac index, and heart rate, and decreased systemic vascular resistance (Dawson et al, 1985; Foulds, 1988). Magrini et al (1988) studied the effects of dopexamine hydrochloride infusion (3 p~gkg- i rain- i ) on the renal circulation in patients undergoing renal vein catheterization for renin estimation and confirmed that the increase in renal blood flow was due to direct vasodilatation as well as an increased cardiac output. Dopexamine, like all vasoactive drugs, is best administered via a central

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vein while monitoring its effect on cardiac output and systemic vascular resistance. However, it can be given by peripheral infusion into a large vein, and combined with its pharmacological profile it may find a useful role in the prophylaxis of organ system failure in patients with impaired physiological reserve and reduced tissue oxygen delivery who are receiving care on ordinary wards. Clinical experience with dopexamine in the intensive care unit is very limited. When given in doses exceeding 4 txg kg -1 min -1, significant sideeffects such as tachycardia, hypotension, nausea and vomiting may limit the usefulness of the drug. Tachyphylaxis may occur with long-term infusion (Colardyn and Vandenbogaerde, 1988). Vasodilator inotropes ('inodilators') in septic shock often require the concurrent administration of vasoconstrictors to maintain perfusion pressure, and the place of dopexamine in this condition has yet to be determined. P H O S P H O D I E S T E R A S E INHIBITORS

These drugs have been developed in the search for orally active inotropic drugs with a better therapeutic : toxic ratio than digoxin. They increase cyclic AMP levels in myocardium and vascular smooth muscle. This results in an increase in cardiac contractility, stroke volume, heart rate, and cardiac output, and a reduction in systemic and pulmonary arterial blood pressures. Peripheral vasodilatation reduces impedance to left ventricular ejection, and the increase in cardiac output is often achieved without an increase in myocardial oxygen consumption (Benotti et al, 1980). This profile is advantageous for patients with congestive cardiac failure, but the role of these drugs in cardiogenic or septic shock, either alone or in combination, has yet to be determined. Caution is required when using vasodilator drugs with a relatively long half-life in patients with a fixed low cardiac output as hypotension may be difficult to reverse, particularly in the presence of renal or hepatic failure when clearance may be impaired. Unlike catecholamines, the phosphodiesterase inhibitors do not cause down-regulation of [3-adrenergic receptors, so tolerance and tachyphylaxis are not seen. They may act synergistically with catecholamines (Gonzalez et al, 1988). Amrinone and milrinone

Amrinone and milrinone are bipyridine derivatives. They possess positive inotropic and, to a lesser extent, chronotropic actions on the heart and have potent vasodilator properties (Alousi and Johnson, 1986). Milrinone is 10 to 30 times more potent than amrinone (Alousi et al, 1983). In addition to phosphodiesterase inhibition, they enhance calcium flux across the cell membrane (Alousi and Johnson, 1986). Concentrations of cyclic AMP in vascular smooth muscle are also increased, leading to vascular dilatation and a reduction in peripheral and pulmonary vascular resistance. Both amrinone and milrinone are largely eliminated by renal excretion (Kullberg et al, 1981). In healthy volunteers milrinone has a plasma half-life

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of 0.94 h (Larsson et al, 1986). In patients with congestive cardiac failure, the elimination half-life of milrinone is about 2 h, and 5-8 h for amrinone (Edelson et al, 1986). In patients with chronic renal failure, milrinone clearance appears to be linearly related to creatinine clearance; the half-life increases to 3.25 h in severe renal impairment (Larsson et al, 1986). Most of the available clinical data on amrinone and milrinone are based on studies in patients with congestive cardiac failure. In these patients, the bipyridines seem to have ideal haemodynamic properties: cardiac output increases and filling pressure is reduced with minimal effects on myocardial oxygen demand. The recommended dosage for amrinone is an initial intravenous loading dose of 0.75 mg/kg given over 3-5 min, with a second equal dose 30 min later if required. This may be followed by a continuous infusion of 510 txgkg -1 min -1. The peak effect of amrinone occurs within 2min of a single intravenous dose and improvement in cardiac output lasts for up to 60 min. Oral therapy with amrinone has been discontinued due to serious side-effects, including thrombocytopenia, gastrointestinal intolerance and the aggravation of ventricular dysrhythmias (Wilmhurst and Webb-Peploe, 1983; Packer et al, 1984). Milrinone is also started as a loading dose, 25-50 ~xg/kg, at a rate of 100 fxg/s. This may be followed by a continuous infusion of 0.25-1.0 ~tgkg -1 min -1. The dosage of both drugs should be reduced in patients with renal failure, based on the creatinine clearance. Enoximone

Enoximone is an imidazolone (4-aroylimidazol-2-one) inodilator which is structurally unrelated to other compounds, but which like the bipyridines inhibits phosphodiesterase in the myocardium and peripheral vascular smooth muscle leading to a reduction in the breakdown of cyclic AMP (Uretsky, 1986). The positive inotropic and vasodilator properties of enoximone are not inhibited by a-adrenergic, [3-adrenergic, histaminergic or cholinergic receptor blockade. Enoximone may be given intravenously or orally. It has a rapid onset of action, with peak haemodynamic effects occurring within 10 to 30min. Intravenous treatment is started with 0.5-1.0 mg/kg given as a slow injection; further doses of 0.5mg/kg may be given similarly every 30rain until a satisfactory response is achieved or a total initial dose of 3.0 mg/kg is reached. Alternatively, a continuous infusion of 5-20 ~xgkg -I min -~ can be used, but caution must be exercised and the dose reduced in patients with hepatic or renal dysfunction because of the effects on metabolism and elimination. It is primarily eliminated via sulphoxide formation by the liver with subsequent renal excretion of the metabolite (Okerholm et al, 1987). Although less potent, this sulphoxide metabolite has positive inotropic and vasodilating properties (estimated in animal studies to be one-fifth to one-seventh of the parent drug). Enoximone has an elimination half-life of approximately 6 h, and the metabolite, 7h. Less than 0.5% of the intact drug and 80% of the metabolite are recovered in urine. Hepatocellular failure or hypoperfusion may therefore be expected to increase plasma concentrations of enoximone,

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and renal failure to increase levels of the active metabolite. Orally administered enoximone is readily absorbed, but the significant first-pass metabolism results in lowered systemic availability ranging from 50 to 60% in normal subjects. Enoximone has been recommended for acute or chronic congestive heart failure, in low-output states following cardiac surgery, and as supplementary support before cardiac transplantation. Clinical experience with its use is still rather limited and there has been no formal evaluation of its efficacy in septic shock. Potential advantages include an improvement in myocardial performance, a reduction in ventricular afterload, and in some instances, an increase in left ventricular compliance. Like the bipyridines it increases cardiac output with little or no effect on myocardial oxygen consumption (Amin et al, 1984). V A S O A C T I V E M E D I A T O R S AND MODIFYING DRUGS

Current theories about the pathogenesis of multiple organ failure are based on the principle that organ system damage is caused by a variety of mediators, which are released following a major physiological disturbance such as microbial infection, endotoxinaemia, or tissue hypoxia. These mediators include complement; activated circulating or tissue polymorphonuclear leukocytes (PMN) and their products, such as oxygen radicals, tumour necrosis factor (TNF), elastase, and interleukin-1 (ILl); activated T-lymphocytes which produce IL2; and the products of cell-membrane lipid oxidation, the arachidonic acid derivatives. Arachidonic acid is oxidized by cyclooxygenase to the prostaglandins and thromboxanes, and by lipoxygenase to the leukotrienes. These substances have diverse effects, and the subject has been reviewed by Oettinger (1987), Chiara et al (1989), and Marston et al (1989). Three classes of drugs are currently under investigation for their potential to modify the release or activity of these mediators: prostaglandins, cyclooxygenase inhibitors, and oxpentiphylline. Epoprostenol

Epoprostenol is a synthetic prostaglandin. It is an analogue of prostacyclin (PGI2), with similar physiological activity but greater chemical stability and a longer half-life (30 rain) than the naturally occurring substance. It is given by intravenous infusion by increasing the dose over several hours to a maximum of 10 ng kg -1 rain -1. Prostacyclin vasodilates the arteriolar side of the circulation, but has no effect on the postcapillary sphincter or the venous system (Higgs, 1982). It inhibits platelet aggregation (Whittle et al, 1978) and has some fibrinolytic activity (Szczeklik et al, 1983). It also exerts a 'cytoprotective' effect on various organs when cells are damaged directly or by drugs. It appears to mediate some of these effects by stimulating adenyl cyclase, thereby increasing intracellular cyclic AMP levels (Gorman et al, 1977), and by inhibiting the generation of neutrophil-derived oxygen free radicals (Fantone et al,

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1984), including those generated by infused adrenaline (HerbaczynskaCedro and Gordon-Majszak, 1986). It also produces splanchnic vasodilatation, thereby preserving gut blood flow (Kaijser, 1958). The main use of epoprostenol at present is to maintain filter patency during haemofiltration when anticoagulation with heparin presents problems. However, the combination of both agents is not as simple as it seems, since heparin enhances adrenaline-induced platelet aggregation (Thompson et at, 1973), and may impair the disaggregatory effect of epoprostenol (Machin et al, 1987). Apart from measuring the bleeding time, there is no simple way of assessing clinical effect. Phosphodiesterase inhibitors will potentiate the effect of epoprostenol on platelets (Romson et al, 1983). Epoprostenol has also been used to improve tissue oxygen uptake in critically ill patients: infusions of 5 ng kg -1 min -1 caused vasodilation with marked reductions in systemic vascular resistance, mean arterial pressure and pulmonary artery pressure. There was evidence of improved oxygen delivery and tissue uptake (Bihari et al, 1987). The significance of this in terms of improved survival has yet to be shown, and the cytoprotective effect could merely reflect improved tissue perfusion. Trials are being conducted at present to examine the efficacy of epoprostenol for renal prophylaxis in patients exposed to nephrotoxic agents such as cyclosporin. More research is required to define its role and cost-effectiveness in intensive care practice.

Non-steroidal anti-inflammatory analgesics (NSAIAs) Is there a place for peripherally acting, non-steroidal anti-inflammatory analgesics in intensive care practice? NSAIAs act in either of two ways: some (like piroxicam) inhibit cyclooxygenase and thus prevent the conversion of arachidonic acid to the cyclic endoperoxides, including the cytotoxic vasoconstrictor thromboxane A2 (TXA2). Others inhibit endoperoxide isomerase and reductase to prevent the transformation of the cyclic endoperoxides to PGE2 and PGF2a. The combined effect is to block the biosynthesis of both vasoconstrictor and vasodilator substances, and on this basis NSAIAs have been used to modify the pulmonary response to sepsis with some success (Utsunomiya et al, 1982; Ogletree et al, 1986; Hanly et al, 1987). However, intrarenal production of prostaglandins and thromboxanes is well documented (Dunn and Zambraski, 1980); and although prostaglandins appear to have little influence on renal haemodynamics in normal subjects, under conditions of haemodynamic stress (as in critically ill patients) due to volume depletion, immunologic injury, hypoxia, or decreasedperfusion of any cause, prostaglandins exert a potent and essential protective effect on renal blood flow and oxygen delivery. Numerous clinical renal disorders have been reported secondary to NSAIAs, which block cyclooxygenaseproducts. NSAIAs can interfere with urine output and sodium excretion and impair diuretic action. They have also been associated with renal failure due to papillary necrosis, acute interstitial nephritis, and vasculitis (Garella and Matarese, 1984). Other adverse effects of NSAIAs include gastrointestinal ulceration and bleeding, inhibition of platelet function, marrow depression,

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and hepatotoxicity. In addition, NSAIAs have a wide range of drug interactions mainly as a result of competition for plasma protein binding. NSAIAs are therefore best avoided in critically ill patients, unless adequate renal perfusion can be guaranteed and there is a specific indication for their use, such as rheumatoid arthritis. Oxpentiphylline

This xanthine was originally introduced for the treatment of peripheral vascular disease because it lowers blood viscosity. More recently it has been shown to protect animals from experimental endotoxinaemia (Schonharting and Schade, 1989) by inhibiting messenger RNA-linked generation of tumour necrosis factor (TNF) from macrophages (Strieter et al, 1988). In nine human volunteers oxpentiphylline blocked TNF but not IL6 production in response to intravenous endotoxin; clinical responses such as fever and nausea were unaffected (Zabel et al, 1989). This agent may represent an alternative to recombinant anti-TNF antibody, but much more work is required, including an improved understanding of the actions and interactions of the various mediators released in sepsis. DRUGS USED FOR SEDATION AND ANALGESIA Midazolam

Midazolam is a water-soluble hypnotic imidazobenzodiazepine used as a premedicant, as a sedative, and for the induction of anaesthesia. It acts by binding to benzodiazepine receptors in the brain and spinal cord thereby facilitating the inhibitory actions of 7-aminobutyric acid (GABA). This results in hypnotic, anxiolytic, muscle-relaxant and anticonvulsant activity (Saidman, 1985). Midazolam is administered either as intermittent doses of 0.02-0.05 mg/kg or as a continuous infusion for sedation (0.024). 2 mg kg- 1h - 1). The efficacy of the drug should be monitored and patients' requirements reviewed regularly. This is especially important when the drug is infused because accumulation may occur leading to delayed recovery from sedation. Midazolam is extensively bound to plasma proteins. Its metabolism in man involves hydroxylation by hepatic microsomal enzymes and subsequent conjugation with glucuronic acid before renal excretion. The hydroxymetabolites have limited sedative activity (Ziegler et al, 1983). Although its elimination halfqife-ranges from 1 to 4h in healthy subjects, this may be increased unpredictably in critically ill patients (Dirksen et al, 1987). Firm evidence is lacking, but it is probable that midazolam accumulation is most likely to occur in septic patients with impaired liver blood flow, as this affects the clearance of all lipid-soluble drugs of high extraction ratio. Current practice of sedation in intensive care in the UK is that patients should be pain free and easily rousable from light sleep (Bion and Ledingham, 1987). Midazolam is a satisfactory hypnotic when used in patients who are not

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critically ill and who are receiving analgesia to relieve pain or discomfort, because of its cardiovascular stability (Westphal et al, 1987). In patients with multiple organ failure, however, the unpredictable half-life may cause concern. Moreover, midazolam is a potent amnesic agent, and it may produce a form of sedation in which verbal contact and hence cooperation is impaired: this may delay weaning from ventilation. Attempts to control agitated patients by increasing the dose of midazolam often cause over-sedation (Kong et al, 1989). It is probably best used in low-dose intermittent boluses to diminish anxiety, provided that other causes for distress have been identified and relieved.

Flumazenil (Anexate) Flumazenil, an imidazobenzodiazepine, is a specific competitive benzodiazepine antagonist, acting at the benzodiazepine receptor. The hypnotic and sedative effects of agonist drugs are rapidly reversed by flumazenil but resedation may occur, because of the short half-life of 50 min (Klotz et al, 1984; Roncari et al, 1986). Flumazenil is 50% protein bound, two-thirds of which is to albumin. It is rapidly eliminated by hepatic biotransformation, primarily to the inactive carboxylic acid form. The recommended initial dose is 200 txg given intravenously over 15 s. If the desired level of consciousness is not obtained within 60 s, further doses of 100 Ixg each can be repeated at 60 s intervals up to a maximum total dose of 2 mg. If drowsiness recurs, an intravenous infusion of 100-400 ~xg/h may be required to maintain arousal. Numerous clinical studies have demonstrated the efficacy and safety of flumazenil in reversing benzodiazepine sedation following short procedures. Flumazenil has also been recommended for use in the intensive care unit for the reversal of benzodiazepine sedation, either to facilitate weaning from the ventilator or to assess cerebral function. The potential dangers of its use include the precipitation of convulsions in epileptics and withdrawal symptoms in patients dependent on benzodiazepines. Resedation may also occur. Caution is recommended in its use in patients with severe head injury, since rapid reversal of midazolam sedation by flumazenil has been shown to increase the intracranial pressure leading to dangerous decreases in cerebral perfusion pressure (Chiolero et al, 1988). It has no clinical or EEG effect on hepatic encephalopathy in the absence of administered benzodiazepines (our unpublished data). Flumazenil has an obvious and useful role in the treatment of benzodiazepine overdose (O'Sullivan and Wade, 1987). Its wider usage is likely to follow the pattern of the opioid antagonist, naloxone; to be used for good reasons with specific indications.

Propofol Propofol (2,6-di-isopropylphenol) is a short-acting intravenous anaesthetic agent introduced for the induction and maintenance of anaesthesia; it is now being assessed for long-term infusion sedation in intensive care.

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Propofol is 97% bound to plasma proteins. It is a highly lipophilic drug and following a single induction dose (2.5mg/kg), it has been shown to distribute rapidly and extensively from blood into brain and tissues. Unconsciousness occurs in about 30 s. The volume of distribution at steady state is 3291/kg and the clearance 1.81 I/rain (Kay et al, 1986). Propofol is rapidly metabolized by the liver primarily to its inactive glucuronide and sulphate conjugates. Metabolites are excreted in the urine. It is possible that extrahepatic mechanisms contribute to the metabolism of propofol (Servin et al, 1986). Given as an infusion at 1 - 3 m g k g - l h -1, propofol has been shown to produce a controllable level of sedation with rapid recovery in patients receiving intensive therapy (Grounds et al,- 1987; Newman et al, 1987). A recent multicentre study comparing midazolam with propofol for sedation in the intensive care unit confirmed the usefulness of propofol sedation and demonstrated shorter arousal times, but failed to show a difference in quality of sedation (Aitkenhead et al, 1989). Although Beller et al (1988) have shown that the continuous infusion of propofol for sedation in ICU patients does not lead to cumulative effects or tachyphylaxis, there is as yet no information available on the pharmacokinetics in patients with multiple organ failure. Following infusions of propofol of up to 96 h, adequate recovery with response to commands was obtained in most patients by 10 min (Beller et al, 1988). When used for sedation in the critically ill, it should be remembered that experience with this drug is still limited. Its cardiovascular effects are more significant than those of other intravenous sedatives. Prolonged infusions of propofol will increase serum triglyceride and cholesterol concentrations. A substantial proportion of patients' calorie requirements may be contained in the fat content in the propofol infusion (Gottardis et al, 1989). In patients on fluid restriction, the large volumes of sedative infused may also pose clinical problems; these will be resolved by the introduction of a 2% formulation. ANALGESICS The most commonly employed opioids in intensive care practice in the UK are papaveretum and morphine (Bion and Ledingham, 1987). Morphine-based opioids are metabolized by the liver to morphine 3- and 6-glucuronides, which are excreted by the kidneys. Morphine 6-glucuronide is twenty times as potent as the parent compound (Shimomura et al, 1971) and will accumulate in renal failure with the potential for prolonged ventilatory (Osborne et al, 1986) or central nervous depression. Like other lipid-soluble drugs, morphine is dependent on liver blood flow for hepatic clearance (Macnab et al, 1986). In high doses opioids impair immune responses in animals (Gungor et al, 1980; Tubaro et al, 1983), and their safety in critically ill patients cannot be assumed from experience ga!ped in the operating theatre. Interest has therefore centred around short-acting synthetic opioids with inactive metabolites.

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Alfentanil

Alfentanil was the first drug to obtain a product licence specifically for use in intensive care units. It is a derivative of fentanyl with one-quarter of the potency, but has a shorter onset and duration of action. It is 92% protein bound, is less lipophilie than fentanyl, and hence has a smaller volume of distribution. Its peak effect occurs about 90 s after injection. It is rapidly metabolized by the liver to inactive metabolites and has an elimination half-life in healthy subjects of 90 rain (Bower and Hull, 1982). There has been a single reported instance in a critically ill patient of prolonged elimination of alfentanil following infusion, the cause of which was not determined (Yate et al, 1986). The detailed pharmacokinetics of the drug in patients with multiple organ failure are still not known, and it is hoped that information will be provided soon to confirm clinical reports (Cohen and Kelly, 1987) of the usefulness of alfentanil infusions. In view of the cost of alfentanil, and the absence of evidence demonstrating its superiority over conventional opioids in patients without major organ system impairment, its use should probably be confined to patients at risk of (or with established) hepatic or renal impairment, or those in whom cardiovascular stability is of major importance such as patients with raised intracranial pressure or marked impairment of cardiac function. Suitable infusion rates range from 0.05 to 2.0 ~gkg-lmin -1. It has been used in combination with benzodiazepines to provide effective sedation of ventilated patients in the intensive care unit (Yate et al, 1986; Cohen and Kelly, 1987), but benzodiazepines should not be prescribed without specific indications for their use, particularly in the more severely ill patients. N E U R O M U S C U L A R BLOCKING DRUGS

Muscle relaxants have in the past been confused with sedative drugs. As recently as 1980, Miller-Jones and Williams showed that neuromuscular blocking agents were used to 'calm' ventilated patients. Their use is now less common in intensive care (Bion and Ledingham, 1987) perhaps in part because of an appreciation of their disadvantages (Willatts, 1985). Neuromuscular blocking agents may, however, be useful in patients with reduced pulmonary compliance as in the adult respiratory distress syndrome, when control of intracranial pressure is important, and in patients with tetanus. Many factors may affect the degree of neuromuscular blockade in critically ill patients, such as acid-base disturbances, electrolyte imbalance, pre-existing neuromuscular disease and drug interactions. Regular monitoring of neuromuscular transmission is desirable. The ideal muscle relaxant for use in intensive care would have a short half-life, good cardiovascular stability, no histamine release, no accumulation, and a means of elimination that is independent of hepatic and renal function. Pancuronium was widely used in the past but its vagolytic effect and delayed clearance in hepatic and renal failure have resulted in the introduction of newer agents: those based on the steroid nucleus (vecuronium), and the benzylisoquinolines (atracurium, mivacurium).

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Veeuronium

Vecuronium is a non-depolarizing muscle relaxant with a high affinity for both pre- and post-junctional receptors at the neuromuscular junction. It has a short to medium duration of action (25-35 rain). The recommended initial dose is 80-100 ixg/kg body weight with incremental doses at 30-50 ixg/kg every 30 rain, or an infusion may be used at 50-80 ~g kg -1 h -1. In man, following a single dose, the plasma clearance rate is 5.2 ml kg -1 min -~ and the elimination half-life is 71 rain. Only 10-25% of the injected dose is excreted in the urine, the predominant route of excretion being through the bile. Most is excreted unchanged with a small amount of metabolism to the 3-OH, 17-OH, and 3,17 di-OH metabolites, which are all physiologically inactive. The major advantage of vecuronium is its notable lack of side-effects. Vecuronium has no blocking action on the cardiac vagus or autonomic ganglia. Of all the muscle relaxants in use, vecuronium has the least potential for histamine release (Basta and Savarese, 1983), and has little effect on the cardiovascular system. However, problems may be encountered with its use in critically ill patients, particularly if the drug is given by continuous infusion. Although early reports showed that renal failure does not significantly alter its pharmacokinetics (Miller et al, 1983), subsequent investigations revealed prolonged kinetic and dynamic properties of drug (Lynam et al, 1986; LePage et al, 1987) which may lead to prolonged paralysis in patients with renal failure in the ICU (Smith et al, 1987). The duration of action of vecuronium is also prolonged in patients with cirrhosis (Hunter et al, 1985). Caution is therefore recommended in patients with multiple organ failure, and if used it should be administered in small intermittent doses, not by infusion. Atracurium

Atracurium is a non-depolarizing neuromuscular blocking agent with short to medium duration of action. It comes close to being the ideal neuromuscular blocking agent for use in critically ill patients. Of currently available competitive neuromuscular blocking drugs, atracurium has the shortest elimination half-life (20 rain) which is unaffected by hepatic or renal failure (Ward and Neil, 1983). It has been shown to be the least cumulative (Ali et al, 1983). The elimination of atracurium is unique and depends upon a combination of chemical and enzyme-mediated hydrolysis, and pH- and temperature-dependent 'Hoffman' destruction of the bis-quarternary molecule to yield the tertiary amine laudanosine, and other metabolites (Stenlake et al, 1983). Atracurium may be administered as intermittent doses of 0.3-0.6 mg/kg body weight or a loading dose of 0.3-0.6 mg/kg may be given followed by an infusion at 0.3-0.6 mg kg -1 h -1. Although clinical studies suggest that infusions of atracurium are safe and useful in the management of the critically ill patient (Griffiths et al, 1986; Wadon et al, 1986), concern has been expressed about laudanosine, which is cleared by the kidneys and accumulates in patients with renal impairment. Laudanosine enters the cerebrospinal fluid (Eddleston et al, 1989) and has

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been shown to produce convulsions in dogs at plasma concentrations of 17 ixg/ml. However, recent studies (Yate et al, 1987; Parker et al, 1988) have shown that despite the use of large doses of atracurium for a considerable period in patients with renal dysfunction, the concentrations of laudanosine did not exceed 5 txg/ml. In cirrhosis, the terminal half-life of laudanosine is prolonged but clearance unaltered, because of an increase in the volume of distribution. The importance of laudanosine accumulation and the effect of haemofiltration on clearance are not yet clear. Atracurium also releases histamine, and bolus doses above 0.5 mg/kg are likely to cause hypotension and tachycardia (Basta et al, 1982; Pokar and Brandt, 1983). Mivacurium Mivacurium has been designed for continuous intravenous infusion. The double ester linkages allow rapid hydrolysis by plasma cholinesterases at a rate 90% that of suxamethonium (Basta et al, 1985); it may also undergo hepatic microsomal hydrolysis. In consequence the effective duration of action (15min) and plasma half-life (17min) are slightly shorter than atracurium, and the plasma clearance substantially faster (55 ml kg -1 min-1) (DeBros et al, 1987). The degree of hypotension attributed to histamine release is similar to that caused by atracurium in healthy individuals (Savarese et al, 1985). Prolongation of block might be expected in patients with reduced plasma cholinesterase levels and liver disease; further studies are required. GASTROINTESTINAL DRUGS The role of antacid drugs in intensive care practice is still not clearly defined. Critically ill patients may have alkaline gastric contents despite the absence of H2 receptor blocking drugs (Stannard et al, 1988), and stress ulceration may occur in patients receiving adequate doses of such drugs (van den Berg and van Blankenstein, 1985). Patients receiving H2-receptor blockers have a higher incidence of nosocomial pulmonary infections than those in whom gastric acidity is maintained (Driks et al, 1987; Tryba, 1987) as a result of retrograde oropharyngeal colonization from the gut (Garvey et al, 1989). Bacterial growth is inhibited by acid conditions. Nevertheless, in the majority of ICUs H2 receptor blockers are prescribed routinely without measurement of gastric pH. Omeprazole Omeprazole is a substituted benzimidazole, structurally similar to the H2 receptor antagonists. It represents a new class of drug, which blocks H+/K + ATPase (the 'proton pump' of the parietal cells) in the gastric mucosa. This prevents acid secretion in response to any stimulus (Clissold and CampoliRichards, 1986). It also reduces the total volume of gastric juice secreted and inhibits pepsin output, but these are minor effects compared to its acid inhibition.

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The usual dose is 20-40 mg daily orally but higher doses may be used. After administration as enteric coated granules, omeprazole is fairly well absorbed with a bioavailability of 70% (Regardh, 1985). Omeprazole is quickly degraded in an acid environment (Adams et al, 1988). This makes oral absorption very variable. Repeated doses appear to increase its bioavailability as the drug takes effect (Howden et al, 1984). Once absorbed it is almost completely metabolized to inactive metabolites, which are rapidly excreted mainly in urine. Omeprazole is 95% protein bound (Adams et al, 1988); the plasma half-life is approximately one hour but the duration of action is much longer. This is probably due to uptake of omeprazole into the parietal cells (Clissold and Campoli-Richards, 1986). With intravenous administration, higher doses are required. This may be due to a local effect in the stomach or the formation of an active metabolite in the gut (Walt et al, 1985). Omeprazole is not removed by dialysis (Howden et al, 1985), and impaired renal function has been shown to reduce urinary excretion of metabolites (Naesdal et al, 1986). In patients with impaired liver function the half-life is prolonged to over 2.5h, but with a once-daily dosage accumulation does not occur (Andersson et al, 1986; McKee et al, 1988). There have been few adverse effects associated with omeprazole. Nausea, diarrhoea, dizziness, colic, and paraesthesia have been reported but such symptoms have been mild and transient. Rats given 400 times the therapeutic dose for 2 years developed enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids within the gastric mucosa (Astra Pharmaceuticals data on file). There is no evidence of carcinogenicity in man. Like cimetidine, omeprazole inhibits the cytochrome P450 enzyme system giving the potential for a number of drug interactions, but there are insufficient data at present. Appropriate monitoring of the affected drug should be carried out if an interaction is suspected. Omeprazole is indicated for the treatment of reflux oesophagitis, peptic ulcers refractory to other treatment, and the Zollinger-Ellison syndrome. An intravenous formulation is undergoing trials to assess its suitability for use in ICU patients (Van Deeventer et al, 1988). It may prove useful in patients with gastric bleeding despite H2 receptor blockade, but this has yet to be shown. Sucralfate

Sucralfate is a non-absorbable aluminium salt of sucrose octasulphate, which has been shown to be effective in the treatment of peptic ulcers (Hollander, 1981). It works by forming a protective layer over the base of the ulcer (Bighley and Geising, 1981). Sucralfate is administered orally, 1 g 6-hourly. The tablets disperse in water and can be administered as a suspension via a nasogastric tube. The drug is not significantly absorbed (Bighley and Geising, 1981), but aluminium toxicity has been reported in a patient with end-stage renal disease (Robertson et al, 1989). Few adverse effects are reported. The most frequently reported are

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gastrointestinal effects such as constipation, diarrhoea, and nausea. The most likely potential interaction is interference with absorption of other drugs. Although indicated only for treatment, studies by Borrero et al (1984, 1985, 1986) and Bresalier et al (1987) have shown that sucralfate may be effective in preventing gastric bleeding. It has also been shown to protect against acute ethanol injury and to increase some prostaglandin levels (Cohen et al, 1989). In intensive care, interest has centred around the ability of the drug to protect against ulceration while preserving gastric acid secretion, thereby inhibiting gastric bacterial colonization (Tryba, 1987). Sucralfate may present an alternative to selective antibiotic decontamination of the gut and oropharynx in intubated patients, and is likely to replace the more expensive H2 receptor blocking drugs for prophylaxis of stress ulceration.

Cisapride Cisapride is a piperidinyl benzamide, chemically related to metoclopramide. It is a prokinetic agent which probably acts indirectly by facilitating acetylcholine release in the myenteric plexus of the gut (Megens et al, 1986; Schuurkes et al, 1986). It can be used to treat gastro-oesophageal reflux, gastroparesis and nausea. It can also reverse morphine-induced delay in gastric emptying (Rowbotham andNimmo, 1987) and may be used as an aid to nasogastric feeding in critically ill patients. After oral administration, cisapride is rapidly absorbed, with maximum plasma concentrations after 2 hours. It is 98% protein bound (Meuldermans et al, 1988). The half-life is about 7 h (Barone et al, 1987). The bioavailability is low (40-50%) because of marked first-pass hepatic metabolism (Van Peer et al, 1988). Hepatic oxidation produces three metabolites (mostly norcisapride) with negligible activity (Janssen Pharmaceutical). Excretion of unchanged cisapride and the metabolites occurs equally in urine and faeces. Detailed studies have yet to be published, but it appears that age and hepatic cirrhosis tend to delay clearance, and repeat doses may cause accumulation (Van Peer et al, 1988). On theoretical grounds, clearance may be delayed if hepatic blood flow is reduced. The effect of renal failure has not been properly determined; it is possible that faecal excretion might compensate for impaired renal clearance. Of importance is the absence of dopamine receptor blocking activity on in vitro testing (Schuurkes et al, 1987); this gives the drug a theoretical advantage over other agents such as droperidol or metoclopramide in patients at risk of renal failure who are receiving dopamine. Side-effects are related to pharmacological effects, and include diarrhoea and cramps. No drug interactions have been reported but cisapride has the potential to affect absorption of drugs by enhancing gastric emptying and reducing gut transit time. The dose is 5 mg three times a day orally, increasing to 10 mg; 2.5 mg should be employed in hepatic insufficiency. A suspension is available.

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ANTIMICROBIAL DRUGS Antibiotic therapy should form part of a general policy for the control of infection within intensive care units. Such policies must routinely involve microbiologists in clinical management, so that ward and laboratory information is properly coordinated, and patterns of colonization or resistance within the unit can be identified. The choice of a particular antibiotic will depend upon this information as well as a knowledge of likely pathogens, the effect of hepatic or renal failure on antibiotic clearance, the degree of tissue penetration of the drug, and its relative cost-effectiveness (see also Chapter 2). At present, gram-negative infections remain the most significant problem, but Staphylococcus epidermidis, viral, or nosocomial fungal infections are a particular risk in the growing number of immunosuppressed patients receiving hospital care. Ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic chemically related to nalidixic acid. It inhibits bacterial DNA-gyrase, preventing cell protein synthesis and DNA replication (Woolfson and Hooper, 1985). It is a bactericidal, broadspectrum antibiotic with particular activity against gram-negative organisms. It is effective against Enterobacteriaceae, Haemophilus influenzae, Neisseria, and Pseudomonas aeruginosa (Neu, 1987). It has some activity against Legionella, but is relatively ineffective against streptococci and anaerobes for which specific agents should be used. It is active against methicillin-resistant Staphylococcus aureus, although resistance has occurred (Isaacs et al, 1988). An outbreak in a leukaemia unit of Staphylococcus epidermidis resistant to ciprofloxacin was controlled by withdrawal of the drug (Oppenheim et al, 1989). In six patients with hepatic encephalopathy, oral ciproftoxacin markedly reduced faecal gram-negative bacteria and systemic endotoxinaemia without causing colonization-resistance with other microbes (Esposito et al, 1988). However, Pseudomonas resistance has occurred with oral ciprofloxacin (Scully et al, 1986) and cross-resistance may develop to other quinolones (Barry and Jones, 1984) or to antibiotics that inhibit protein synthesis such as erythromycin (Lewin et al, 1988). Ciprofloxacin can be administered orally (250-750mg) or parenterally (200 rag) twice a day. By either route the half-life is 3-4 h; the volume of distribution is high at over 21/kg (Hoffken et al, 1985). Forty per cent is protein bound but the effect of reduced serum albumin has not been studied. It is concentrated in bile and the prostate, and penetrates pelvic tissues, peritoneal fluid, sputum and bone (Terp and Rybak, 1987). Half is eliminated by renal filtration and tubular secretion (Hoffken et al, 1985); biliary excretion is also likely to be important. Hepatic cytochrome P450 metabolizes the remainder (Rubinstein and Segev, 1987). Severe renal impairment (creatinine clearance < 10 ml/min) increases the half-life (Wenk et al, 1988). In three of the patients studied, concurrent hypotension increased the half-life to 10.4-24h, which the authors attributed to reduced hepatic blood flow. Gasser et al (1988) recommend a

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50% reduction in dosage if the creatinine clearance is less than 50 ml/min, but, when possible, plasma levels should be monitored. Less than 30% of a single dose is removed by haemodialysis over 4h (Bergan et al, 1985; Boelaert et al, 1985), but peritoneal dialysis appears to be ineffective (Fleming et al, 1987). Clearance by haemofiltration with dialysis (CAVHD) is not known, but is likely to be similar to that achieved by haemodialysis. A number of drugs are known to interact with ciprofloxacin: antacids reduce oral absorption, and the drug reduces clearance of warfarin and theophylline. The interaction with theophylline appears to be related to competitive inhibition of cytochrome P450, causing a marked rise in serum theophylline levels (Nix et al, 1987; Holden, 1988). The nephrotoxicity of cyclosporin may be enhanced by ciprofloxacin (Elston and Taylor, 1988). Other adverse effects include nausea, diarrhoea, elevated liver enzymes, eosinophilia and arthralgia (Shacht et al, 1988).

Imipenem Imipenem is the first of a new class of ~-lactam antibiotics, the carbapenems. It binds to all penicillin-binding proteins (PBP) with an especially high affinity for PBP2; it has a low affinity for PBP3 (Spratt et al, 1977) to which cephalosporins bind. It is bactericidal, causing rapid cell swelling and lysis. It has a broader spectrum of activity than the third-generation cephalosporins and is effective against gram-negative bacteria including Pseudomonas aeruginosa and anaerobes but excluding Pseudomonas maltophilia, and against gram-positive bacteria with the exception of methicillin-resistant Staphylococcus aureus (Jones, 1985) and Streptococcus faecium. It is active against bacteria which produce [Mactamase, and may in fact induce [3lactamase production by Pseudomonas aeruginosa, thereby reducing the efficacy of [3-1actam antibiotics against this organism. In a study of 135 patients with proven bacteraemias of mixed origins, only 14 failed to respond to imipenem (Eron, 1985), and in other studies of relatively small numbers of patients the drug has proved to be of similar or better efficacy than other agents alone or in combination. The combination of broadspectrum activity and potency has encouraged use of the drug for 'blind' monotherapy of serious infections. However, this runs the risk of selecting out those resistant organisms mentioned above. Whenever possible, antibiotic therapy should be specific, and informed. In its commercial preparation, imipenem is combined with cilastatin in equal proportions. Cilastatin is a dehydropeptidase inhibitor with no intrinsic antibiotic activity; it is structurally related to imipenem, and prevents renal metabolism of imipenem by a dehydropeptidase in the brush border of the renal tubules. This increases urinary concentrations of the antibiotic, making it more effective in the treatment of urinary tract infections. High doses of imipenem can cause proximal tubular necrosis in laboratory animals. This effect is abolished by the coadministration of cilastatin, presumably because the two compounds compete for the same tubular sites (Birnbaum et al, 1985). Following intravenous administration, imipenem and cilastatin have

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plasma half-lives of 50 rain. Imipenem half-life is unaffected by the presence of cilastatin (Verpooten et al, 1984), which merely increases urinary concentrations of imipenem. Approximately 66% of imipenem and 75% of cilastatin are excreted unchanged in urine, and the remainder is excreted as inactive metabolite. Less than 2% is excreted in faeces (Norrby et al, 1984). In neonates, the half-life of imipenem is doubled, and that of cilastatin may increase six-fold (Freij et al, 1985). In renal failure the half-life of imipenem is increased to 170 min and cilastatin to nearly 800 rain. Both are effectively removed by haemodialysis (Verpooten et al, 1984), and it is likely that both would be cleared by CAVHD. The dosage interval should be increased in renal failure, but this would not appear to be necessary for patients receiving effective dialysis. The effect of high levels of cilastatin in critically ill patients is unknown. No drug interactions have been reported for imipenem. The side-effects are similar to those of other [3-1actam antibiotics: elevation of hepatic enzymes, diarrhoea and phlebitis. Seizures following imipenem administration have been reported (Brotherton and Kelber, 1984). Though the mechanism is uncertain, it is thought to be related to high drug levels in the cerebrospinal fluid, and caution must be exercised in prescribing imipenem to patients with renal failure not receiving dialysis. Fiuconazole

Fluconazole is a new bis-triazole antifungal agent, which acts by inhibiting the fungal cytochrome P450-mediated enzyme lanosterol C14 demethylase. This deprives the fungus of ergosterol which is an important constituent of the cell membrane (Shaw et al, 1987). Its main advantages are the relative lack of serious side-effects and good tissue penetration, while retaining at least equal potency compared with ketoconazole and amphotericin B. Clinical reports are inevitably based on small numbers of patients: fluconazole has been used successfully for a variety of infections with Candida species, including prosthetic cardiac valves (Isalska and Stanbridge, 1988) and funguria (Graybill et al, 1988). It is also effective against cryptococcal meningitis (Van't Wout et al, 1988). The dose ranges from 50 to 400 mg in a once-daily dose, orally or intravenously, depending on the site and severity of infection. After oral administration, fluconazole is well absorbed, with a bioavailability approaching 100%. There is no evidence of first-pass metabolism. The volume of distribution is 0.651/kg and autoradiography studies have shown that fluconazole is extensively distributed throughout the body, including penetration into saliva and CSF. It has a half-life of 24 h, the drug being excreted unchanged in urine (Brammer and Tarbit, 1987). Renal impairment will have a marked effect on the clearance of fluconazole, and either the dose should be reduced or the dose interval increased. Van't Wont et al (1988) found that haemodialysis had a limited effect on clearance in one patient. Another study found that haemodialysis removes about 50% (Pfizer data on file). Fluconazole appears to be relatively free from adverse effects with nausea, headache and abdominal discomfort being the most frequently

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reported (Pfizer data on file). Unlike ketoconazole it does not seem to be hepatotoxic but there have been reports of elevated liver enzymes (Pfizer data on file) although the significance of these is not clear. Jaundice has also been reported (Holmes and Clements, 1989). Despite its mode of action, fluconazole appears to have little effect on human cytochrome P450 enzymes (Shaw et al, 1987). Interactions have been reported with warfarin, and with tolbutamide although this had no clinical significance. There are contradictory reports about interactions with cyclosporin (Collingnon et al, 1989; Ehninger et al, 1989). Drug level monitoring of the affected drug should be carried out if an interaction with fluconazole is suspected. Ribavirin

Ribavirin is a synthetic triazole nucleoside that inhibits a broad range of DNA and RNA viruses in vitro. Two possible mechanisms have been suggested, both of which can only occur after intracellular phosphorylation: inhibition of inosine monophosphate dehydrogenase, or competitive inhibition of guanyland methyl-transferases preventing incorporation of guanosine triphosphate into viral mRNA (Fernandez et al, 1986). Ribavirin has been administered orally for HIV infection (Crumpacker et al, 1987) with some clinical and laboratory improvement. In patients with Lassa fever, it reduces mortality if given within 6 days of onset (McCormick et al, 1986). In the UK its licensed indication is for respiratory syncitial virus (RSV) infections in children. In infants so affected, a randomized double-blind trial in which the drug was given by aerosol for 20 h/day for an average of 3 days resulted in a clinical improvement, better oxygenation, and reduced viral shedding (Breese Hall and McBride, 1983). There is conflicting evidence of its value in influenza, and if used it should be given by aerosol (Buchdahl et al, 1985). Following oral or intravenous administration, the plasma half-life is 24 h. Nebulized ribavirin is administered in a concentration of 20 mg/ml over 8-20 h, but plasma levels rise progressively and accumulation has occurred when ribavirin was given for 8 h on 3 consecutive days (Connor et al, 1984). Ribavirin accumulates in red blood cells, where it has a half-life of 40 days. It enters the CSF during long-term oral therapy, but does not penetrate wellinto neural tissue. It is metabolized to 1,2,3-triazole carboxamide which is excreted in the urine (Catlin et al, 1980). Reversible haemolysis (McCormick et al, 1986) and anaemia (Crumpacker et al, 1987) have been reported. Ganciclovir

Ganciclovir is indicated for the treatment of life- or sight-threatening cytomegalovirus (CMV) infections in immunocompromised patients. It is a deoxyguanosine analogue, structurally very similar to acyclovir but with greater activity against CMV. The drug itself is inactive but after conversion to ganciclovir-triphosphate it acts both as an inhibitor of, and a false substrate for, CMV-DNA-polymerase and causes viral DNA chain termination. The enzymes responsible for the phosphorylation are not known. CMV does not appear to encode for viral thymidine kinase, which is known

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to be important for the phosphorylation of acyclovir (Fletcher and Balfour, 1989); CMV does not respond to acyclovir for this reason. The normal dose is 10 mg kg -1 day -I in two divided doses. Ganciclovir is administered by intravenous infusion over one hour, the drug being poorly absorbed orally with a bioavailability of 3 % (Jacobson et al, 1987). Following administration it is rapidly distributed throughout the body with good penetration into the lung, liver, brain and CSF (Shepp et al, 1985; Fletcher et al, 1986). No metabolites of ganciclovir have been identified and clearance is dependent on renal elimination. Urinary recovery of the unchanged drug exceeds 90% over 24 h (Laskin et al, 1987). The elimination half-life is about 2.5 h in patients with normal renal function, but may be as long as 29 h in renal insufficiency (Laskin et al, 1987). In renal failure the manufacturers recommend dose reduction and a once-daily dosage. Haemodialysis has been reported to remove ganciclovir (Fletcher and Balfour, 1989). Ganciclovir causes a number of adverse effects. The most important is neutropenia, which occurs in about 30% of patients (Fletcher and Balfour, 1989). It is not clear if this is an idiosyncratic response or dose related. The neutropenia occurs 2 weeks after starting treatment and resolves within 3 weeks of stopping. Other side-effects include elevation in liver aminotransferases, thrombocytopenia, mental changes and phlebitis. Zidovudine

Zidovudine is a dideoxynucleoside and is the first antiretroviral agent to be used for the treatment of the acquired immunodeficiency syndrome (AIDS). Its efficacy was shown in a randomized double-blind trial (Fischl et al, 1987) that was terminated as it was felt it would be unethical to deny active treatment to the patients on the placebo arm. Zidovudine acts by inhibiting viral reverse transcriptase (Yarchoan et al, 1989). Zidovudine is administered orally and is well absorbed from the gut with a bioavailability of 63%. The half-life is only 1.1 h, so the drug must be given 4-hourly. Seventy-five per cent undergoes hepatic glucuronidation to an inert metabolite. The remaining drug and the metabolite are excreted in the urine (Yarchoan et al, 1989). Zidovudine has been administered by continuous infusion to children aged from 14 months to 12 years (Pizzo et al, 1988). The optimal dose was found to be 0.9-1.4mg kg -1 h -1. The effect of hepatic failure has not been studied but might be expected to prolong the half-life. In a patient receiving maintenance haemodialysis the half-life was 2.9h and there was accumulation of the metabolite (Deray, 1988); a dose of 100rag every 8h was equivalent to the normal dose in a patient with normal renal function. Zidovudine therapy causes a number of adverse effects including nausea, myalgia, anaemia and bone marrow suppression (Richman et al, 1987). There has been a case report of postural hypotension related to the drug (Loke et al, 1990). The concurrent use of paracetamol has been associated with more frequent haematological side-effects. Cholestasis and hepatitis, and grand mal seizures have also been reported (Dubin and Braffman, 1989; Routy et al, 1989). Neutropenia was also noted in a renal transplant patient

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on concurrent immunosuppressive therapy, and resolved when the dose of zidovudine was reduced to 100 mg 8-hourly (Erice et al, 1988). After a study of 36 weeks treatment in 38 patients (Flegy et al, 1989) it was suggested that neutropenia should not be a contraindication to treatment with the drug. REFERENCES Adams MH, Ostrosky JD & Kirkwood CF (1988) Therapeutic evaluation of omeprazole. Clinical Pharmacology 7: 725-745. Aitkenhead AR, Pepperman ML, Willatts SM et al (1989) Comparison of propofol and midazolam for sedation in critically ill patients. Lancet ii: 704-709. Ali HH, Savarese JJ, Basta SJ et al (1983) Evaluation of cumulative properties of three new non-depolarizing neuromuscular blocking drugs BW A444U, atracurium and vecuronium. British Journal of Anaesthesia 55: 107S. Alousi A A & Johnson DC (1986) Pharmacology of the bipyridines: amrinone and milrinone. Circulation 73(supplement 3): 3-10. Alousi AA, Stankus GP, Stuart JC et al (1983) Characterization of the cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissue from several animal species. Journal of Cardiovascular Pharmacology 5: 804. Amin DK, Shah PK, Hulse Set al (1984) Myocardial metabolic and haemodynamic effects of intravenous MDL-17043, a new cardiotonic drug, in patients with chronic severe heart failure. American Heart Journal 108: 1285-1292. Anderson T, Olsson R & Skanberg I (1986) Pharmacokinetics of omeprazole in patients with liver cirrhosis. Acta Pharmacologica et Toxicologica Supplement 5: 203. Barone JA, Huang Y-C, Bierman RH et al (1987) Bioavailability of three oral dosage forms of cisapride, a gastrointestinal stimulant agent. ClinicalPharmacology 6: 640-645. Barry AL & Jones RN (1984) Cross resistance among cinoxacin, ciprofloxacin, DJ 6783, enoxacin, nalidixic acid, norfloxacin and oxolinic acid after in vitro selection of resistant populations. AntimicrobiaI Agents and Chemotherapy 25: 775-777. Basta SJ & Savarese JJ (1983) Comparative histamine releasing properties of vecuronium, atracurium, tubocurarine and metocurine. In Agoston S (ed.) Clinical Experiences with Norcuron, CCPll, pp 183-184. Amsterdam: Excerpta Medica. Basra SJ, Ali HH, Savarese JJ et al (1982) Clinical pharmacology of atracurium besylate (BW33A): a new non-depolarising muscle relaxant. Anesthesia and Analgesia 61: 723. Basta SJ, Savarese JJ & Ali HH (1985) The neuromuscular pharmacology of BW 1090U in anesthetized patients. Anesthesiology 63: A318. Belier JP, Pottecher T & Lugnier A (1988) Prolonged sedation with propofol in ICU patients: recovery and blood concentration changes during periodic interruption in infusion. British Journal of Anaesthesia 61: 583-588. Benotti JR, Grossman W, Braunwald E et al (1980) Effects of amrinone on myocardial energy metabolism and haemodynamics in patients with severe congestive heart failure due to coronary disease. Circulation 62: 23. Bergan T, Dalhoff A & Thorsteinsson SB (1985) A review of the pharmacokinetics and tissue penetration of ciprofloxacin. Proceedings of a workshop at the 14th International Congress of Chemotherapy, Kyoto, Japan, pp 23-26. Hong Kong: Seiber and McIntyre. Bighley LD & Geising D (1981) Duodenal ulcer, gastric ulcer: sucralfate, a new therapeutic concept. In Caspary WF (ed.) Sucralsate: A New Therapeutic Concept, pp 3-12. Baltimore: Urban and Schwanzenburg. Bihari D, Smithies M, Gimson A e t al (1987) The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients. New England Journal of Medicine 317: 397-403. Bion JF & Ledingham IMcA (1987) Sedation in intensive care--a postal survey. Intensive Care Medicine 13: 215-216. Birnbaum J, Kahan FM, Kropp H et al (985) Carbapenems, a new class of betalactam antibiotics. American Journal of Medicine 78 (6A): 3-21. Boelaert J, Valke V, Schurgers Met al (1985) The pharmacokinetics of ciprofloxacin in patients with impaired renal function. Journal of Antimicrobial Chemotherapy 16: 87-93.

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Borrero E, Margolis IB, Banks S e t al (1984) Antacid vs sucralfate in preventing acute gastrointestinal bleeding. American Journal of Surgery 148: 809-812. Borrero E, Banks S, Margolis IB et al (1985) Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who are critically ill. American Journal of Medicine 79 (supplement 2C): 62-64. Borrero E, Ciervo J & Chang JB (1986) Antacid vs sucralfate in preventing acute gastrointestinal bleeding in abdominal aortic surgery. Archives of Surgery 121: 810812. Bower S & Hull CJ (1982) Comparative pharmacokinetics of fentanyl and alfentanil. British Journal of Anaesthesia 54: 871. Brammer KW & Tarbit MH (1987) A review of the pharmacokinetics of ftuconazole (UK49858) in laboratory animals and man. In Fromtling RA (ed.) Recent Trends on the Discovery, Development and Evaluation of Antifungal Agents. South Africa: Prous Science Publishers. Breese Hall C & McBride JT (1983) Aerosolized ribavirin treatment of infants with respiratory syncytial virus infection. New England Journal of Medicine 308: 1443-1447. Bresalier RS, Grendell JH, Cello JP & Meyer AA (1987) Sucralfate suspension versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients. American Journal of Medicine 83: 110--116. Brotherton TJ & Kelber RL (1984) Seizure like activity associated with imipenen. Clinical Pharmacy 3: 536-540. Brown RA, Dixon J, Farmer JB et al (1985) Dopexamine: a novel agonist at peripheral dopamine receptors and beta-2 adrenoceptors. British Journal of Pharmacology 85: 599608. Buchdahl RM, Taylor D & Warner SO (1985) Nebulised ribavirin for adenovirus pneumonia. Lancet ii: 1070-1071. Catlin DM, Smith RA & Samuels AI (1980) 14C-Ribavirin distribution and pharmacokinetic studies in rats, baboons and man. In Smith RA, Kirckpatrick W (eds) Ribavirin--A Broad Spectrum Antiviral Agent, pp 83-98. New York: Academic Press. Chiara O, Giomarelli PP & Casini A (1989) Acute lung injury: role of lipid peroxidation. In Vincent JL (ed.) Update in Intensive Care and Emergency Medicine, vol. 8, pp 33-38. Berlin: Springer Verlag. Chiolero RL, Ravussin P, Anderes JP et al (1988) The effects of midazolam reversal by R0 15-1788 on cerebral perfusion pressure in patients with severe head injury. Intensive Care Medicine 14: 196-200. Clissold SP & Campoli-Richards DM (1986) Omeprazole: a preliminary review of its pharmacodynamics and pharmacokinetic properties and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome. Drugs 32: 15-47. Cohen AT & Kelly DR (1987) Assessment of alfentanil by intravenous infusion as long-term sedation in intensive care. Anaesthesia 42: 545-548. Cohen MM, Bowdler B, Gervaise Pet al (1989) Sucralfate protection of human gastric mucosa against acute ethanol injury. Gastroenterology 96: 292-298. Colardyn FA & Vandenbogaerde JF (1988) Use of dopexamine hydrochloride in intensive care patients with low-output left ventricular heart failure. American Journal of Cardiology 62: 68C-72C. Collignon P, Hurley B & Mitchell D (1989) Interaction of fluconazole with cyclosporin. Lancet i: 1262. Connor JD, Hintz M, Van Dyke K et al (1984) Ribavirin pharmacokinetics in children and adults during therapeutic trials. In Smith RA, Knight V, Smith JAD (eds) Clinical Applications ofRibavirin, pp 10%123. New York: Academic Press. Crumpacker C, Heagy W, Bubley G e t al (1987) Ribavirin treatment of the acquired immunodeficiency syndrome (AIDS) and the acquired immunodeficiency syndrome related complex (ARC). Annals oflnternal Medicine 107: 664-674. Dawson JR, Thompson DS, Signy Met al (1985) Acute haemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist, in patients with chronic heart failure. British Heart Journal 54: 313-320. DeBros F, Basta SJ & Ali HH (1987) Pharmacokinetics and pharmacodynamics of BWB1090U in healthy surgical patients receiving N20/O2 isoflurane anesthesia. Anesthesiology 67: A609.

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