Intravascular iodinated contrast media and the anaesthetist

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1 doi: /j x REVIEW ARTICLE Intravascular iodinated contrast media and the anaesthetist M. C. Dickinson 1 and P. C. A. Kam 2 1 Provisional Fellow, 2 Nuffield Professor of Anaesthetics, University of Sydney, Department of Anaesthetics, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia Summary The use of intravascular iodinated contrast media (ICM) in radiological investigations is common. Increasingly, anaesthetists and intensivists are involved in the care of patients undergoing these investigations. Whilst the use of ICM is generally safe there are important adverse effects that need to be recognised and measures instigated to prevent or treat these effects. In patients at risk of developing adverse reactions it is important to consider alternative modes of imaging so that ICM can be avoided. Strategies for the prevention of ICM nephropathy should be considered in all patients receiving ICM. Currently intravascular volume expansion with 0.9% saline has the strongest evidence base. The use of isotonic sodium bicarbonate combined with N-acetylcysteine appears promising in providing further benefits. Although the use of N-acetylcysteine alone has not been shown to significantly reduce the incidence of ICM nephropathy it is cheap, has few adverse effects and it would seem reasonable to continue its use in conjunction with intravascular volume expansion. The routine use of corticosteroid and antihistamine premedication is not always effective in preventing general adverse reactions.... Correspondence to: Professor P. C. A. Kam pkam@usyd.edu.au Accepted: 18 January 2008 Anaesthetists are being called upon more frequently to provide either sedation or anaesthesia for the patient undergoing radiological diagnostic or interventional procedures. Since their introduction in the 1950s, intravascular iodinated contrast media (ICM) are amongst the most widely used drugs, with about 75 million examinations being performed annually worldwide [1]. ICM have a good safety profile and adverse effects are generally mild and self-limiting. However, severe or life threatening reactions can occur. Anaesthetists must be aware of the risk factors for adverse reactions to ICM. The aims of this review are to summarize the common intravenous contrast media, their adverse reactions and strategies to minimise adverse reactions, prompt recognition and management of any reactions to ICM. Chemistry and pharmacology All currently used ICM are based on chemical alterations of the 2, 4, 6 tri-iodinated benzene ring [2]. The addition of the three iodine atoms at positions 2, 4 and 6 on the parent benzene ring side chains make the ICM less toxic and less lipophilic. The substituent at position 5 also influences the route of elimination. ICM are classified according to their chemical structure, osmolality, iodine content and ionisation [2]. Osmolality is dependent on the concentration of iodine necessary to obtain radiographic attenuation relative to the particles in solution. Ionic tendency is due to the presence of carboxyl side chains and is reduced by hydroxylation of these side chains. Contrast media molecules can exist in four different forms: ionic monomers, ionic dimers, non-ionic monomers and non-ionic dimers. (Table 1) The anion in ICM is triiodobenzoic acid, whilst the cation is usually Na +, Ca 2+ or methylglucamine (meglumine). Methylglucamine salts are better tolerated and more soluble than sodium or calcium salts, therefore ionic media are often presented as a combination of salts. In non-ionic contrast media the addition of an amide group to the -COOH side chain means that the molecule remains a single particle when in solution. Most newer generation agents are of the non-ionic type [2, 3]. Ionic ICM are strong acids because the -COOH group is directly linked to the triiodobenzene group, allowing the formation of salts that 626 Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland

2 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist Table 1 Intravascular iodinated contrast media physicochemical properties and uses. Ionisation Polymer Example Osmolality (mosm.kg )1 ) Route (use) Ionic Monomer Diatrizoate Hyper-osmolar ( mosm.kg )1 ) IA, IV (angiography) Ionic Dimer Ioxaglate Hypo-osmolar (600 mosm.kg )1 ) IA, IV (angiography) Nonionic Monomer Iohexol, Iopromide Hypo-osmolar ( mosm.kg )1 ) IA, IV (angiography) Nonionic Dimer Iodixanol Iso-osmotic (280 mosm.kg )1 ) IV (urography) IA, intra-arterial; IV, intravenous. are readily soluble in water. The anions contain the contrast producing properties, whilst the cations are essential for improving the solubility of iodinated acids and for attaining physiological ph. The positively and negatively charged species are partly responsible for the toxicity of ionic contrast media because they disrupt the electrical potential of the cell membrane [2]. The solubility of the non-ionic contrast media is due to the presence of hydrophilic side chains such as hydroxyl (-OH) and amide (-CONH) groups. The absence of electrical charge leads to less disruption of cell membrane electrical potential. In clinical practice, ICM are categorised according to their osmolality. High osmolality ICM (osmolality ranging from 1200 to 2400 mosm.kg )1 ) are ionic monomers consisting of a tri-iodinated benzene ring with two organic side chains (diatrizoate or iothalamate) and a carboxyl group conjugated with a sodium or meglumine cation. The ionisation of the carboxyl-cation bond makes the agent water soluble. Commonly used high osmolality ICM include iothalamate ion (Conray Ò ) and diatrizole ion (Hypaque Ò ). The three types of low osmolar compounds include (a) non-ionic monomers, (b) ionic dimers, and (c) nonionic dimers. Non-ionic monomers do not ionise in solution because they lack a carboxyl group, and are made water soluble by the addition of hydrophilic side chains at the 1, 3 and 5 positions. At a given iodine concentration non-ionic monomers have about half the osmolality of ionic monomers in solution. At normally used concentrations (25 76%) non-ionic monomers have osmolality between 290 and 860 mosm.kg )1, but are harder to inject because they have a higher viscosity. Common non-ionic monomers include iohexol (Omnipaque Ò ), iopromide (Ultravist Ò ), iopamidol (Isovue Ò ) and ioversol (Optiray Ò ). The non-ionic monomers are the ICM of choice because they are potentially less toxic in addition to their non-ionic nature and lower osmolality. The ionic dimers are synthesised by joining two ionic monomers and removing one carboxyl group. The only clinically used ionic dimer is ioxaglate (Hexabrix Ò ) that has an osmolality of 600 mosm.kg )1, and is used primarily for peripheral arteriography. Non-ionic dimers such as iotrol and iodixanol are iso-osmolar compounds and consist of two joined monomers. However their high viscosity limit their clinical usefulness. Whilst a meta-analysis has shown that the use of low osmolar agents is beneficial in patients with underlying renal disease [4], a recent study has shown an even lower incidence of radiocontrast nephropathy with iso-osmolar non-ionic dimers (280 mosm.kg )1 ) agents [5]. To achieve adequate contrast large volumes ( ml) of agent are injected either intravenously or intra-arterially within a short period of time, the patient receiving approximately g of contrast medium [6]. Its viscosity will influence the speed at which a contrast media can be injected. The viscosity increases rapidly with increasing concentration and decreasing temperature. Dimers are more viscous than monomers. Ideally, ICM should be warmed to 37 C to facilitate rapid intravascular administration. ICM are hydrophilic and demonstrate low protein binding. Following intravascular injection peak concentrations only last for a few seconds and 70% of the injected dose diffuses from plasma to the extracellular space within 2 5 min. In highly perfused tissues such as the liver, heart, lungs and brain the fall in plasma concentration is rapid. Diffusion into the extracellular space is slower in skin, fat and skeletal muscle. Complete equilibrium between plasma and the interstitial space occurs about 2 h after injection [7]. Most ICM are eliminated from plasma by the kidneys. The ICM molecules are filtered through the glomeruli without tubular reabsorption and are not metabolised before elimination [8]. This property is used to image the renal tract as the cleared molecules opacify the renal architecture, ureters and bladder. The elimination half-life following intravascular injection in patients with normal renal function is about two hours. In patients with renal impairment the excretion by the kidneys can last for several weeks [7, 8]. Gadolinium-based compounds Gadolinium (Gd) is a rare element that has seven unpaired electrons in ionic (Gd 3+ ) form and therefore has paramagnetic properties. Magnetic resonance Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland 627

3 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist Anaesthesia, 2008, 63, pages contrast media, such as gadolinium, function indirectly through their alteration of the local electromagnetic field. The unpaired electron causes proton relaxation enhancement (protons relax faster) and this enhances the image contrast. This trait makes gadolinium useful for Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA). However free Gd 3+ ions are highly toxic and have low solubility. Chelating Gd 3+ with polybasic organic substances reduces Gd toxicity as well as increases its water solubility. Gd-chelate contrast media are cleared from the body by glomerular filtration and therefore caution should be taken in patients with renal disease. The attenuation of X-rays by gadolinium-based MRI contrast agents, e.g. gadobutrol (Gadovist Ò ) and dimeglumine gadopentetate (Magnevist Ò ), in the range used for digital angiography (approximately 70 kv) is approximately the same as for iodine. In the range used for computerized tomography examinations (approximately 120 kv) the attenuation of gadolinium is approximately double that of iodine. Therefore, theoretically, gadolinium could substitute iodine as a radiographic contrast medium. However, the properties of gadolinium being used in the setting of MRI differ from that in the setting of X-ray examinations. The dosage required for MRI examinations is safe and not nephrotoxic, whilst the high doses required to provide equivalent X-ray attenuation to iodinated contrast media are nephrotoxic [9]. The European Society of Urogenital Radiology (ESUR) does not approve the use of gadolinium-based contrast media for radiographic examinations [9]. Adverse reactions to iodinated contrast media Adverse reactions to ICM may be classified as acute or delayed reactions. The adverse reactions to ICM are related to chemotoxicity, ionic toxicity and osmotoxicity of the specific compound used. Chemotoxicity increases as the hydrophobic nature of the ICM increases and causes a release of vasoactive substances, complement activation, fibrinolysis, inhibition of platelet aggregation, direct neurotoxicity, and decreased myocardial contractility and conduction. Ionic toxicity occurs as a result of the direct effects of anionic contrast medium or its conjugated cation on cellular membranes or cellular function. Osmotoxicity causes pain on injection, disruption of the blood barrier, vagal stimulation, emesis, decreased myocardial contractility, decreased myocardial fibrillation threshold, increased pulmonary artery pressure and vasodilation and decreased peripheral vascular resistance. In rare circumstances ICM can precipitate an exacerbation of myasthenia gravis (caused by increased neuromuscular blockade) [10] or iodine induced thyrotoxicosis [11]. The incidence of any adverse reaction to high osmolality ICM is about 15% and approximately 3% of patients receiving low osmolarity ICM. Most of these adverse reactions are usually mild and do not require treatment. The prevalence of adverse reactions is lower with low compared with high osmolality ICM by a factor of five for mild reactions and a factor of ten for very severe reactions [12]. The incidence of severe reactions with non-ionic agents is 0.04% and that of very serious reactions is 0.004%. Fatal reactions to ICM are rare (1 : ), and there is no difference in mortality between the two types. Adverse reactions to iodinated contrast media are more likely to develop in patients with a history of previous reaction to contrast media, a history of asthma or atopy or those who are medically unstable or debilitated [3, 13], cardiac and renal disease, dehydration, extremes of age, haematological and metabolic conditions such as sickle cell anaemia and phaeochromocytoma, and certain medications including b blockers, aspirin and non-steroidal anti-inflammatory drugs, and interleukin-2. A history of atopy increases the incidence of severe reactions to iodinated contrast media by a factor of three, whilst a history of a previous adverse reaction increased the incidence by a factor of five. A history of asthma increases the incidence of a severe adverse reaction by a factor of between six and ten [3]. The majority of acute adverse reactions are either idiosyncratic (i.e. a genetically determined, qualitatively abnormal reaction to a drug, related to a metabolic or enzyme deficiency) or anaphylactoid (i.e. a reaction due to non-specific complement activation and histamine release) [14]. Idiosyncratic reactions usually begin within 20 min of injection. Although these are frequently referred to as anaphylactic reactions they are not true hypersensitivity reactions because IgE antibodies are not involved, prior sensitisation is not required, and they do not consistently recur in a given patient [14]. The mechanisms of these adverse reactions involve activation of the complement, fibrinolytic and kinin systems, the release of histamine and other mediators such as serotonin, prostaglandins, bradykinins, leukotrienes, adenosine and endothelin and direct cellular effects. Both types of reaction are unpredictable, and not dose dependent. The symptoms may be mild, moderate or severe. Mild symptoms include flushing, pruritus, rhinorrhoea, urticaria, nausea and vomiting and diaphoresis. Moderate symptoms include persistent vomiting, diffuse urticaria, facial oedema, mild bronchospasm, dyspnoea, palpitations and abdominal cramps. Severe reactions include life threatening ventricular tachycardia, hypotension, severe bronchospasm, laryngeal oedema, convulsions and death. 628 Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland

4 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist ICM can cause increased vagal tone causing hypotension and bradycardia. High osmolarity ICM can precipitate ventricular tachy-arrhythmias (by lowering ventricular threshold), decrease myocardial contractility and cause peripheral vasodilation. Massive fluid shifts from infusion of an osmotic load can precipitate pulmonary oedema. The cardiovascular signs and symptoms may be caused by the release of vasoactive mediators. Delayed reactions occur more than 1 h after the administration of intravascular contrast media, but within 7 days. They are usually mild in nature and symptoms may include fever, rashes, pruritus, flushing, dizziness, nausea and vomiting, diarrhoea and arthralgia and occur after administration of both ionic and nonionic preparations. Delayed allergy-like reactions associated with skin manifestations are more common following the intravascular non-ionic dimers and as a consequence the non-ionic dimer has been withdrawn. The reported incidence of delayed reactions varies between 2% and 8% [3]. Patients who have been treated with interleukin-2 are prone to delayed reactions to ICM. Radiocontrast nephropathy, the use of iodinated contrast media in patients using metformin and those who are pregnant or lactating is considered separately below. Prevention of adverse reactions Various studies have shown that the use of non-ionic iodinated contrast media reduces the incidence of general adverse reactions when compared with the use of ionic agents combined with corticosteroid prophylaxis [15, 16]. The prophylactic use of corticosteroids and antihistamines, either alone or in combination, in patients at high risk of general adverse reactions to iodinated contrast media is widely used. Typically two doses of oral corticosteroids are given approximately 12 h and 1 2 h prior to the administration of ICM in combination with an oral dose of antihistamine. However, the use of a prophylactic regimen remains contentious [15, 16]. A recent meta-analysis [17] examined the use of pharmacological agents to prevent severe general reactions. The authors concluded that life threatening anaphylactic reactions to iodinated contrast media are rare and that a large number of unselected patients need to receive an oral double dose of methyl-prednisolone to prevent a single potentially life-threatening reaction. There was limited evidence to show that the prophylactic use of antihistamines was effective. The efficacy of drug combinations or the use of premedication in patients with a history of allergic reactions remains unproven. The authors recommended that physicians should not rely on the efficacy of premedication and that the routine use of prophylaxis should be abandoned [17]. Treatment of adverse reactions Mild reactions are usually self-limiting and the treatment is symptomatic. Antihistamines, corticosteroids, bronchodilators and antiemetics may be required. Intravenous access must be retained as rarely symptoms may persist or worsen. The patient should be observed until a full recovery is made. Severe reactions require a systematic ABC approach to symptoms. Severe bronchospasm requires high flow oxygen, nebulised b 2 agonists and, if no improvement is seen, intramuscular adrenaline. Severe hypotension requires the resuscitation team, high flow oxygen, rapid infusion of intravenous fluids, hydrocortisone and vasopressors. Critical care support may be necessary. Although life-threatening anaphylactic reactions to iodinated contrast media are rare it is essential that all personnel involved with the administration of intravascular iodinated contrast media are fully trained in cardiopulmonary resuscitation and that the appropriate equipment and drugs are available at all times. Nephropathy Radiocontrast nephropathy is a condition associated with an increase in creatinine by more than 25% over the patient s baseline or an absolute increase of > 44 mmol.l )1 is required to diagnose renal impairment due to ICM within 3 days of the intravascular administration of ICM [18]. Serum creatinine peaks by 3 7 days, and the creatinine level returns to baseline in 7 14 days. In patients with normal renal function the incidence of radiocontrast nephropathy is from 0% to 5%. In those with pre-existing renal impairment the incidence in several prospective controlled studies was found to be between 12% and 27% [19]. In one study in which patients with diabetic nephropathy were undergoing coronary angiography the incidence was as high as 50% [22]. The risk factors associated with radiocontrast nephropathy are summarised in Table 2. Pathophysiology It is caused by a combination of pre-existing haemodynamic disturbances, renal vasoconstriction mediated by adenosine and endothelin, and direct toxic effects. After an injection of ICM, transient vasodilatation is followed by a prolonged vasoconstriction of the renal vasculature and normal renal blood flow returns within 1 2 h. Direct toxic effects on the tubular cells are considered to be the main factors in the pathophysiology of ICM induced nephropathy. The particles of contrast media are not absorbed by the tubular cells and reduce water and sodium reabsorption from the tubules. The marked natriuresis and diuresis produced by high osmolality Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland 629

5 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist Anaesthesia, 2008, 63, pages Table 2 Risk factors for radiocontrast nephropathy [26]. Risk factor Odds ratio (95% CI) Patient-related factors Pre-existing renal dysfunction Serum Creatinine level mmol.l ) ( ) mmol.l ) ( ) 265 mmol.l ) ( ) Diabetes mellitus 5.47 ( ) Use of intra-aortic balloon pump 1.94 ( ) Myocardial infarction 1.85 ( ) Congestive heart failure 1.53 ( ) Hypertension 1.20 ( ) Low effective circulatory volume 1.19 ( ) Age (1-year increment) 1.02 ( ) Contrast medium related factors Volume of contrast medium (per 100 ml) 1.12 ( ) Low versus high osmolality contrast medium 0.50 ( ) in patients with pre-existing renal dysfunction ICM activate the tubuloglomerular feedback mechanism, leading to vasoconstriction of the glomerular afferent arterioles and causing a decrease in the glomerular filtration rate and renal arteriolar vasoconstriction. Renal hypoperfusion, along with the osmotic stress induced by ICM, predisposes to ischaemic renal parenchymal injury. Activation of the tubuloglomerular feedback mechanism is dependent on the osmolality of the contrast medium. Low osmolar preparations, which are still hypertonic to blood, may also stimulate this mechanism. Iso-osmolar preparations, which only induce a mild natriuresis and diuresis, do not [19]. Contrast agents also stimulate the endothelial cells to release vasoactive substances such as endothelin, prostaglandins and adenosine causing local renal vasoconstriction and exacerbating the effects of hypoperfusion [20]. ICM are also toxic to renal epithelial cells and cause increased intrarenal production of oxygen free radicals and activation of apoptosis in cells of the thick ascending limbs of loops of Henle in the renal medulla. Radiocontrast nephropathy is a form of acute tubular necrosis. Ischaemic acute tubular necrosis and renal atheroembolic disease are the main differential diagnoses to consider in patients developing a nephropathy following the administration of ICM. Ischaemic acute tubular necrosis is associated with a history of episodic or sustained hypotension and a urinary fractional excretion of sodium of > 1%. Radiocontrast nephropathy is not usually associated with hypotension and typically the fractional excretion of sodium is < 1%. Renal atheroembolic disease is much less common and is due to the embolization of cholesterol crystals from disrupted atherosclerotic plaques frequently associated with angiography. Athero-embolic disease usually occurs days to weeks after a procedure, compared with an hour to days for radiocontrast nephropathy, and is often associated with systemic manifestations such as mesenteric and digital ischaemia [21]. Clinical course The clinical course of radiocontrast nephropathy is characterised by an increase in serum creatinine and a decrease in creatinine clearance reflecting a decrease in the glomerular filtration rate. This increase in creatinine often peaks 3 4 days after the administration of ICM and usually returns to baseline within days [23]. Although the course of radiocontrast nephropathy is typically benign it may increase the risks of other complications and prolong the patient s stay in hospital. In one study the mortality amongst hospital inpatients with radiocontrast nephropathy was 34% compared with 7% in a control group that underwent the same procedure without developing nephropathy [24]. In patients with pre-existing advanced renal failure, renal function may not recover to baseline and the need for dialysis after nephrotoxicity due to contrast media may be permanent. Risk factors The patients who are at the highest risk of developing radiocontrast nephropathy are those with pre-existing renal impairment and diabetes. The risk is directly proportional to the baseline serum creatinine level and increases further in the presence of diabetic nephropathy [19, 22]. Radiocontrast nephropathy developed in one third of patients who underwent percutaneous coronary interventions and who had a serum creatinine level of 177 mmol.l )1 or greater [25]. High osmolar ICM are more nephrotoxic than low osmolar preparations particularly in patients with pre-existing renal impairment. In a recent study in high risk patients undergoing coronary angiography an iso-osmolar preparation was associated with a lower incidence of radiocontrast nephropathy compared to low osmolar preparations [5]. Large volumes of contrast media and the route used may also affect the degree of impairment seen. ICM are less nephrotoxic when they are administered intravenously than when given intra-arterially via the renal arteries or the aorta proximal to the renal arteries. Dehydration and congestive cardiac failure associated with a reduction in renal perfusion exacerbate the ischaemic insult of contrast media [26]. Other predictors of developing radiocontrast nephropathy that are associated with reduced renal perfusion include the presence of hypertension, acute myocardial infarction within 24 h before the administration of the contrast agent, 630 Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland

6 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist haemodynamic instability and the use of an intra-aortic balloon pump during percutaneous coronary intervention (see Table 2) [26]. In the elderly patient, the reduction in renal mass, function and perfusion predisposes them to developing renal impairment. The concurrent use of nonsteroidal anti-inflammatory drugs and aminoglycosides potentiate the direct nephrotoxic effects of ICM. Prevention and treatment Radiocontrast nephropathy is a preventable form of acute renal failure. Many investigations requiring the use of intravascular ICM are elective, allowing adequate time for at risk patients to be identified and plans made to minimise the effects ICM have on the kidneys. The European Society of Urogenital Radiology Guidelines [18] suggest that high risk patients are well hydrated, that low- or iso-osmolar compounds are used, that nephrotoxic drugs should be stopped for at least 24 h prior to the study and that alternative imaging techniques that do not require the administration of ICM should be considered. High osmolar ICM should be avoided, as should large doses of ICM, mannitol and loop diuretics. Multiple studies within a short time period should be avoided. We consider here some treatment options. Intravenous volume expansion Animal models have demonstrated that intravascular fluid depletion predisposes to the development of radiocontrast nephropathy. Augmentation of the intravascular volume decreases the incidence of radiocontrast nephropathy. Solomon et al. [27] compared the efficacy of three preventative regimens in 78 moderate risk patients. Saline (0.45%) was infused at 1 ml.kg )1.h. )1 for 12 h preceding and following the administration of radiocontrast media, alone or combined with either mannitol or furosemide. The incidence of radiocontrast nephropathy was significantly lower in patients receiving saline alone (11%) compared with those treated with saline and mannitol (23%) or saline and furosemide (40%). This indicated that volume expansion provided better protection against radiocontrast nephropathy than a regimen involving a forced diuresis. A later study [28] that compared the infusion of 0.45% saline to 0.9% saline in 1620 patients undergoing coronary angiography showed that patients who received 0.9% saline had a lower incidence of radiocontrast nephropathy. This suggested that the augmented degree of volume expansion with an isotonic fluid provided greater protection than volume expansion with 0.45% saline. A randomised controlled trial [29] with a small sample size compared the incidence of radiocontrast nephropathy in patients treated with either intravenous isotonic saline or isotonic sodium bicarbonate. The incidence of radiocontrast nephropathy was significantly lower in the sodium bicarbonate group (1 60 vs 8 59, p = 0.02). The authors suggested that bicarbonate provided superior protection by increasing renal medullary ph and reducing the levels of phdependent free radicals. The REMEDIAL trial compared the use of three different fluid and antioxidant regimens; 0.9% saline infusion combined with N-acetylcysteine, sodium bicarbonate infusion combined with N-acetylcysteine and 0.9% saline combined with ascorbic acid and N-acetylcysteine [30]. They concluded that the strategy of volume supplementation by sodium bicarbonate plus N-acetylcysteine seemed to be superior to the combination of 0.9% saline with N-acetylcysteine alone or with the addition of ascorbic acid in preventing radiocontrast nephropathy in patients at medium to high risk. N-acetylcysteine N-acetylcysteine reduces renal damage by scavenging oxygen free radicals (produced as a result of toxic damage to renal tubules) in addition to direct vasodilation effects on the renal medullary circulation mediated by the release of nitric oxide. Several meta-analyses have been conducted to systematically analyse the efficacy of the antioxidant properties of N-acetylcysteine. Three of these four meta-analyses showed some reduction in the incidence of developing radiocontrast nephropathy from the use of N-acetylcysteine but with varying levels of efficacy. The largest, and most recent of the studies [31] analysed the results of 16 prospective clinical trials with a total of 1538 patients and concluded that the heterogeneity of the current literature limited any meaningful conclusions to be drawn on the benefit of N-acetylcysteine for radiocontrast nephropathy. However the use of N-acetylcysteine is simple, cheap and has few adverse side effects so it would seem reasonable to continue its use as an adjunct to intravascular volume expansion until further evidence is available. Diuretics Furosemide may reduce renal ischaemia by reducing the metabolic demands in the thick ascending limb of the loop of Henle via inhibition of the sodium-potassiumchloride co-transport. Mannitol increases renal medullary blood flow and is a free radical scavenger. However, the use of furosemide and mannitol in addition to intravascular volume expansion are associated with an increased incidence of radiocontrast nephropathy compared with the use of intravascular volume expansion alone [27]. The natriuretic and vasodilator properties of atrial natriuretic peptide do not reduce the incidence of radiocontrast nephropathy [32]. Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland 631

7 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist Anaesthesia, 2008, 63, pages Dopamine receptor agonists Low-dose (< 2 lg.kg )1.min )1 ) dopamine increases renal blood flow and inhibits sodium reabsorption in the proximal tubule, inducing a natriuresis. Studies have shown that dopamine does not reduce the incidence of radiocontrast nephropathy and that it may be detrimental to patients with underlying diabetes [33]. Fenoldopam is a selective dopamine-1 receptor agonist that increases blood flow to both the cortex and the medulla of the kidney and it is suggested that it may be useful in the prevention of radiocontrast nephropathy. However, studies evaluating the benefits of fenoldopam were either poorly designed or underpowered. Therefore the use of fenoldopam to prevent radiocontrast nephropathy currently has no evidence base. Theophylline The role of theophylline as an adenosine antagonist has been postulated as a potential preventative agent against the development of radiocontrast nephropathy. Preliminary studies have yet to show any clinical benefit and further trials are needed to evaluate the usefulness of the drug in the prevention of radiocontrast nephropathy [34]. Calcium channel blockers Although calcium channel blockers have potentially beneficial vasodilator effects in addition to the reduction in intracellular calcium in tubular epithelial cells following anoxia, studies have failed to demonstrate any clinical benefit in the prevention of radiocontrast nephropathy and their use is not currently recommended [35]. Drugs altering renal perfusion Non-selective non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors decrease the production of vasodilator prostaglandins in the kidney. The European Society of Urogenital Radiology [18] recommends that these drugs should be discontinued prior to investigations requiring ICM. There is currently inadequate data to support the continuation or discontinuation of angiotensin converting enzyme inhibitors and angiotensin-ii receptor blockers in patients at risk from developing radiocontrast nephropathy. Renal replacement therapy Both haemodialysis and haemofiltration have been investigated as methods to prevent and treat radiocontrast nephropathy [36]. Haemodialysis removes all watersoluble iodinated contrast media, but does not prevent radiocontrast nephropathy when either used prophylactically prior to the administration of ICM or when started immediately after their administration. In addition haemodialysis can cause some degree of haemodynamic instability and hypovolaemia, which may worsen the renal injury associated with radiocontrast media. Haemofiltration provides hydration with high volumes of isotonic fluid without causing fluid overload. A recent study compared haemofiltration, initiated prior to the administration of ICM media and continued for up to 24 h after the investigation, with isotonic saline volume expansion [36]. The study found that 50% of patients in the intravenous saline group developed a 25% increase in their baseline serum creatinine concentration compared with 5% in the haemofiltration group (p < 0.001). However, the use of serum creatinine concentration as an endpoint is questionable as it is directly lowered by haemofiltration. Therefore, although it cannot be recommended for all patients it may be deemed justifiable in those patients with advanced renal disease requiring angiographic procedures. Metformin-induced lactic acidosis About 90% of metformin, a biguanide that is used in the treatment of type II diabetes, is excreted by the kidneys in 24 h. Renal insufficiency (GFR< 70 ml.min )1, or serum creatinine > 140 mmol.l )1 ) leads to the retention of metformin in the tissues and this may precipitate the development of lactic acidosis [3, 18, 23, 26]. Whilst ICM have the potential to reduce renal function, and to precipitate metformin induced lactic acidosis, there is no conclusive evidence to suggest that this occurs in patients with a normal serum creatinine (< 130 mmol.l )1 ). However, the complication is observed in type II diabetic patients with abnormal renal function before the administration of contrast media [3]. In these patients, if the serum creatinine is normal, a low volume (< 100 ml) of contrast agent can be administered intravenously and no special precaution is needed. However if more than 100 ml of contrast agent or the intra-arterial route is required, metformin should be withheld for 48 h after the procedure. If contrast injection is necessary in a diabetic patient who has a raised creatinine, metformin should be withheld 48 h before and 48 h after the contrast is administered and the renal function reassessed before recommencing metformin therapy. In any event it is most likely that the diabetic medication would be changed in the light that metformin is contraindicated in the presence of renal impairment. Pregnancy and lactation Mutagenic or teratogenic effects have not been described after the administration of ICM. Free iodide in radiographic contrast media administered to the mother can 632 Journal compilation Ó 2008 The Association of Anaesthetists of Great Britain and Ireland

8 M. C. Dickinson and P. C. A. Kam Æ Intravascular iodinated contrast media and the anaesthetist potentially depress fetal thyroid function. Therefore the thyroid function in the neonate should be evaluated during the first week after birth if ICM have been administered to the pregnant mother. Only tiny amounts of ICM given to a lactating mother reach the milk and it is not necessary to stop breast feeding following the use of these agents [37]. Conclusion Acute adverse reactions occur less often with the use of low osmolality contrast media than with high osmolality agents, adverse reactions are not totally eliminated. Various radiological societies and colleges [38] have issued guidelines to radiologists to provide general advice on relevant precautions on the use of ICM and offer management advice in the event of an adverse event. Although radiologists and sometimes surgeons are the primary physicians who administer ICM, anaesthetists are frequently involved in procedures associated with the use of ICM and therefore should be able to recognise and differentiate the various types of reactions to ICM so that appropriate treatment can be instituted rapidly and effectively. An accurate history of individual patients is essential to enable the identification of risk factors for radiocontrast nephropathy so that preventative measures can be instituted. The most effective prophylactic method of preventing radiocontrast nephropathy is hydration and correction of the volume status of the patient at risk because pharmacological agents used to prevent it are at most partially effective. Anaesthetists should identify and withhold potentially nephrotoxic agents prior to the procedure and focus on the preoperative volume status of the patient so that the patient is normovolaemic when the ICM is administered. 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