**5. Reducing CM doses in CT-angiography of azotemic patients**

During the past decade, CTCA has become a clinical reality as a consequence of major advances in CT technology. Vascular enhancement in CT-angiography is dependent on a number of factors such as CM dose, injection rate, plasma volume, cardiac output (CO) and x-ray tube potential (Bae & Heiken, 2005; Fleischmann, 2003; Kormano et al., 1983; Kristiansson et al., 2010).

#### **5.1 CM distribution volume and injected dose rate**

The distribution volume of CM includes the plasma volume and the extravascular extracellular space, both related to body weight. By dosing CM in relation to body weight

Contrast Medium-Induced Nephropathy (CIN)

2007).

2009).

as discussed below.

Gram-Iodine/GFR Ratio to Predict CIN and Strategies to Reduce Contrast Medium Doses 203

However, the effective x-ray tube loading in terms of milliampere seconds (mAs) has to be increased by a factor four to keep image noise constant and results in 50% increase in radiation dose for the same reference object (Holmquist et al., 2009; Kristiansson et al., 2010). Thus, the diagnostic quality in terms of contrast-to-noise ratio (CNR) may be preserved. The increased radiation dose and risk of cancer induction may be of less concern in elderly azotemic patients with coronary artery disease and a limited survival time than the risk of CIN.

By combining CM dose tailored to body weight, a fixed injection time adapted to scan time, automatic bolus tracking, saline chaser, x-ray tube potential of 80 kVp and anticipating a decreased cardiac output in azotemic patients, it has been possible to halve the CM dose from 300 mg I/kg at 120 kVp and to 150 mg I/kg at 80 kVp when performing 16-row detector pulmonary CT-angiography in patients with eGFR <50 mL/min (Kristiansson et al., 2010). The median g-I/eGFR ratio was 0.3 and no CIN episodes were recorded. A total median dose of 10 grams of iodine was used, which is only 20-40% of non-body size related CM doses reported by those using 16-row detector for pulmonary CT-angiography at 120- 140 kVp (Bae et al., 2005; Holmquist et al., 2009; Holmquist & Nyman, 2006; Johnson et al.,

These principles should also be possible to adopt when performing CTCA in patients at high risk of CIN, especially with today's CT-equipments with many more detector rows,

The risk of CIN is related to the CM dose (Davidson et al., 2006; Freeman et al., 2002; Marenzi et al., 2009). Though there are numerous prophylactic studies on pharmacological agents, with hardly any unequivocally positive prophylactic effects so far (Stacul et al., 2006), studies on technical aspects of how to minimize the CM dose in coronary procedures

The average CM dose at PCA and/or PCI may range from 40 to 110 grams of iodine (Aspelin et al., 2003; Davidson et al., 2000; Laskey et al., 2007; Marenzi et al., 2009; Nyman et al., 2008; Rudnick et al., 1995; Worasuwannarak & Pornratanarangsi, 2010), while individual doses may range from 10 to inconceivable 500 grams of iodine (Marenzi et al.,

In a Letter to the Editor Kane et al. (2008) reported on utilizing biplane angiography for PCA resulting in a mean CM dose of only 8 grams of iodine (25 mL 320 mg I/mL), half the dose used for monoplane. Despite a higher CIN risk profile among patients examined with biplane, the incidence of CIN was significantly lower compared with those studied with monoplane. Freeman et al. (2002) proposed guidelines for high-risk patients including determination of the "maximum allowed radiocontrast dose", limit necessary images (i.e. left ventriculogram or other images) and excessive "puffs", and whenever possible consider staged diagnostic and therapeutic procedures with several days in between. Another option to reduce CM dose is to use a lower concentration than the perfunctory 320 to 370 mg I/mL

**5.4 Halved CM doses at CT-angiography in azotemic patients** 

more potent x-ray tubes and dual energy options.

are conspicuous by their almost total absence.

**6. Percutaneous coronary angiography and interventions** 

and using a fixed injection duration adapted to scan time, a fixed injected dose rate (mg I/kg/s) is obtained and vascular enhancement becomes essentially unrelated to body size (Awai et al., 2004a). When these principles are used, the choice of CM concentration is of no concern regarding CM enhancement (Awai et al., 2004b; Suzuki et al., 2004).

It may be anticipated that fixed CM doses irrespective of body weight have been adjusted to provide a proper enhancement in larger patients. Thus, dosing per kg implies that the risk of CIN may at least be reduced for low weight patients for the same enhancement as in a larger patient. In fact CM doses regarded sufficient for 80-100 kg patients could be halved for 40-50 kg patients to obtain the same degree of enhancement. A maximum dosing weight of 80-90 kg may be chosen, assuming that higher weights in most patients correspond to adipose tissue with minimal contribution to the distribution volume of CM.

Calculation of individual CM volumes and injection rates based on CM dose in milligram iodine/kg, concentration and injection duration can be easily done with a Microsoft Excel spreadsheet or using a dedicated computer program developed to calculate both eGFR and CM injection parameters from predefined CT protocols (OmniVis, GE Healthcare, Stockholm, Sweden).

#### **5.2 Cardiac output and vascular CM enhancement**

Arterial enhancement increases with decreasing CO (Bae et al., 1998) due to less dispersion and dilution of the CM bolus and at the same time poor cardiac function is an independent risk factor of CIN. Renal impairment may induce cardiac dysfunction and vice versa, the so called cardiorenal syndrome (Ronco et al., 2008). Since increasing age also predispose to decreasing renal function and cardiac diseases, many azotemic patients will have a reduced CO. Thus, it would be possible to decrease CM dose in most azotemic patients for the same vascular CM-enhancement as that obtained in patients with normal cardiac function. On the other hand a patient with no CIN risk factors and hyperkinetic circulation may need and tolerate a higher CM dose than normal to achieve diagnostic quality without jeopardizing renal function.

Since cardiac function may play a major role for CM-enhancement in CTCA and echocardiography results may be readily available in coronary patients, information of cardiac function should be used when tailoring the CM protocol. Another option is to use electrical velocimetry to measure CO, readily performed in the CT suite (Flinck et al., 2010). This has the advantage that measured CO will reflect cardiac function at the time of the CM injection. CO measured by echocardiography hours to days prior to CTCA may result in inadequate CM injection parameters, since CO is highly dependent on pulse rate and may vary considerably for number a of reasons.

#### **5.3 X-ray tube potential and iodine attenuation**

Attenuation of photons by iodine is highly dependent on the x-ray spectra used. As an example decreasing the x-ray tube peak kilovoltage (kVp) from commonly used 120 kVp for CT to 80 kVp brings the x-ray spectra closer to the k-edge of iodine (33.2 keV) and increases iodine attenuation by a factor 1.6 (Prokop, 2003). Thus, the CM dose may be reduced by a factor 1.6 while maintaining the attenuation at the same level as that obtained at 120 kVp. However, the effective x-ray tube loading in terms of milliampere seconds (mAs) has to be increased by a factor four to keep image noise constant and results in 50% increase in radiation dose for the same reference object (Holmquist et al., 2009; Kristiansson et al., 2010). Thus, the diagnostic quality in terms of contrast-to-noise ratio (CNR) may be preserved. The increased radiation dose and risk of cancer induction may be of less concern in elderly azotemic patients with coronary artery disease and a limited survival time than the risk of CIN.

#### **5.4 Halved CM doses at CT-angiography in azotemic patients**

202 Coronary Interventions

and using a fixed injection duration adapted to scan time, a fixed injected dose rate (mg I/kg/s) is obtained and vascular enhancement becomes essentially unrelated to body size (Awai et al., 2004a). When these principles are used, the choice of CM concentration is

It may be anticipated that fixed CM doses irrespective of body weight have been adjusted to provide a proper enhancement in larger patients. Thus, dosing per kg implies that the risk of CIN may at least be reduced for low weight patients for the same enhancement as in a larger patient. In fact CM doses regarded sufficient for 80-100 kg patients could be halved for 40-50 kg patients to obtain the same degree of enhancement. A maximum dosing weight of 80-90 kg may be chosen, assuming that higher weights in most patients correspond to adipose

Calculation of individual CM volumes and injection rates based on CM dose in milligram iodine/kg, concentration and injection duration can be easily done with a Microsoft Excel spreadsheet or using a dedicated computer program developed to calculate both eGFR and CM injection parameters from predefined CT protocols (OmniVis, GE Healthcare,

Arterial enhancement increases with decreasing CO (Bae et al., 1998) due to less dispersion and dilution of the CM bolus and at the same time poor cardiac function is an independent risk factor of CIN. Renal impairment may induce cardiac dysfunction and vice versa, the so called cardiorenal syndrome (Ronco et al., 2008). Since increasing age also predispose to decreasing renal function and cardiac diseases, many azotemic patients will have a reduced CO. Thus, it would be possible to decrease CM dose in most azotemic patients for the same vascular CM-enhancement as that obtained in patients with normal cardiac function. On the other hand a patient with no CIN risk factors and hyperkinetic circulation may need and tolerate a higher CM dose than normal to achieve diagnostic quality without jeopardizing

Since cardiac function may play a major role for CM-enhancement in CTCA and echocardiography results may be readily available in coronary patients, information of cardiac function should be used when tailoring the CM protocol. Another option is to use electrical velocimetry to measure CO, readily performed in the CT suite (Flinck et al., 2010). This has the advantage that measured CO will reflect cardiac function at the time of the CM injection. CO measured by echocardiography hours to days prior to CTCA may result in inadequate CM injection parameters, since CO is highly dependent on pulse rate and may

Attenuation of photons by iodine is highly dependent on the x-ray spectra used. As an example decreasing the x-ray tube peak kilovoltage (kVp) from commonly used 120 kVp for CT to 80 kVp brings the x-ray spectra closer to the k-edge of iodine (33.2 keV) and increases iodine attenuation by a factor 1.6 (Prokop, 2003). Thus, the CM dose may be reduced by a factor 1.6 while maintaining the attenuation at the same level as that obtained at 120 kVp.

of no concern regarding CM enhancement (Awai et al., 2004b; Suzuki et al., 2004).

tissue with minimal contribution to the distribution volume of CM.

**5.2 Cardiac output and vascular CM enhancement** 

vary considerably for number a of reasons.

**5.3 X-ray tube potential and iodine attenuation** 

Stockholm, Sweden).

renal function.

By combining CM dose tailored to body weight, a fixed injection time adapted to scan time, automatic bolus tracking, saline chaser, x-ray tube potential of 80 kVp and anticipating a decreased cardiac output in azotemic patients, it has been possible to halve the CM dose from 300 mg I/kg at 120 kVp and to 150 mg I/kg at 80 kVp when performing 16-row detector pulmonary CT-angiography in patients with eGFR <50 mL/min (Kristiansson et al., 2010). The median g-I/eGFR ratio was 0.3 and no CIN episodes were recorded. A total median dose of 10 grams of iodine was used, which is only 20-40% of non-body size related CM doses reported by those using 16-row detector for pulmonary CT-angiography at 120- 140 kVp (Bae et al., 2005; Holmquist et al., 2009; Holmquist & Nyman, 2006; Johnson et al., 2007).

These principles should also be possible to adopt when performing CTCA in patients at high risk of CIN, especially with today's CT-equipments with many more detector rows, more potent x-ray tubes and dual energy options.

#### **6. Percutaneous coronary angiography and interventions**

The risk of CIN is related to the CM dose (Davidson et al., 2006; Freeman et al., 2002; Marenzi et al., 2009). Though there are numerous prophylactic studies on pharmacological agents, with hardly any unequivocally positive prophylactic effects so far (Stacul et al., 2006), studies on technical aspects of how to minimize the CM dose in coronary procedures are conspicuous by their almost total absence.

The average CM dose at PCA and/or PCI may range from 40 to 110 grams of iodine (Aspelin et al., 2003; Davidson et al., 2000; Laskey et al., 2007; Marenzi et al., 2009; Nyman et al., 2008; Rudnick et al., 1995; Worasuwannarak & Pornratanarangsi, 2010), while individual doses may range from 10 to inconceivable 500 grams of iodine (Marenzi et al., 2009).

In a Letter to the Editor Kane et al. (2008) reported on utilizing biplane angiography for PCA resulting in a mean CM dose of only 8 grams of iodine (25 mL 320 mg I/mL), half the dose used for monoplane. Despite a higher CIN risk profile among patients examined with biplane, the incidence of CIN was significantly lower compared with those studied with monoplane. Freeman et al. (2002) proposed guidelines for high-risk patients including determination of the "maximum allowed radiocontrast dose", limit necessary images (i.e. left ventriculogram or other images) and excessive "puffs", and whenever possible consider staged diagnostic and therapeutic procedures with several days in between. Another option to reduce CM dose is to use a lower concentration than the perfunctory 320 to 370 mg I/mL as discussed below.

Contrast Medium-Induced Nephropathy (CIN)

should be less nephrotoxic than IA administration.

using dedicated GFR prediction equations.

and the following CM doses and concentrations:

tracking and a saline chaser.

150, ISSN 0033-8419 (Print)

Vol.15(Suppl 5), pp. E46-E59

will increase iodine attenuation.

days in between.

**7. Conclusion** 

**8. References** 

Gram-Iodine/GFR Ratio to Predict CIN and Strategies to Reduce Contrast Medium Doses 205

• Whenever possible consider staged diagnostic and therapeutic procedures with several

• Scientific evidence is lacking regarding the opinion that IV administration of CM

• Renal function should be estimated taking into account not only serum creatinine but also anthropometric (weight and height) and/or demographic (gender and age) by

• CM dose should be expressed in grams of iodine instead of simply volumes since it also takes into account concentration and serves as an index of diagnostic capacity. • A g-I/eGFR ratio ≥1.0 appears to a significant and independent predictor of CIN in

• If a CM examination is deemed necessary in patients at high risk of CIN, the author's goal is to keep the dose as low as reasonably achievable, preferably below a g-I/eGFR ratio of 0.5, which may be possible by applying a meticulous examination technique

• CT-angiography: 100-150 mg I/kg by using 80 kVp, mAs-compensation for constant CNR, fixed injection duration adapted to scan time, automatic bolus

• Coronary arteriography and interventions: 140-200 mg I/mL, especially in thinner patients in whom automatic or manual down-regulation of the x-ray tube potential

Altmann DB, Zwas D, Spatz A, Bergman G, Spokojny A, Riva S, Sanborn TA (1997). Use of

Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ (2003). Nephrotoxic

Awai K, Hiraishi K, Hori S (2004a). Effect of contrast material injection duration and rate on

Awai K, Inoue M, Yagyu Y, Watanabe M, Sano T, Nin S, Koike R, Nishimura Y, Yamashita Y

*Radiology,* Vol.233, No.3, (2004 Dec), pp. 682-688, ISSN 0033-8419 (Print) Bae KT, Heiken JP (2005). Scan and contrast administration principles of MDCT. *Eur Radiol,*

Bae KT, Heiken JP, Brink JA (1998). Aortic and hepatic contrast medium enhancement at CT.

after angiography. *J Interv Cardiol,* Vol.10, pp. 113-119

(2003 Feb 6), pp. 491-499, ISSN 1533-4406 (Electronic)

No.3, (1998 Jun), pp. 657-662, ISSN 0033-8419 (Print)

the contrast volume estimated creatinine clearance ratio to predict renal failure

effects in high-risk patients undergoing angiography. *N Engl J Med,* Vol.348, No.6,

aortic peak time and peak enhancement at dynamic CT involving injection protocol with dose tailored to patient weight. *Radiology,* Vol.230, No.1, (2004 Jan), pp. 142-

(2004b). Moderate versus high concentration of contrast material for aortic and hepatic enhancement and tumor-to-liver contrast at multi-detector row CT.

Part II. Effect of reduced cardiac output in a porcine model. *Radiology,* Vol.207,

coronary interventions but it may also be valid for CT-angiography.

#### **6.1 Iodine concentration iso-attenuating with gadolinium CM**

Attenuation increases with the atomic number (Z) of the atom (iodine, Z = 53; gadolinium, Z = 64). At photon energies between the k-edge of iodine (33.2 keV) and that of gadolinium (50.2 keV), iodine attenuates roughly twice as many photons as does gadolinium (Nyman et al., 2002). At all other photon energies the opposite prevail. Thus, a gadolinium (Gd) CM may be used as an x-ray CM. Before the advent of nephrogenic systemic fibrosis (NSF) (Thomsen, 2009), some investigators reported on the use of Gd-CM in a variety of diagnostic angiographic and interventional procedures (Spinosa et al., 2002; Strunk & Schild, 2004) including PCA (Barcin et al., 2006; Briguori et al., 2006; Gupta & Uretsky, 2005; Sarkis et al., 2003; Voss et al., 2004) in patients at risk of CIN due to its perceived non-nephrotoxicity (Prince et al., 1996). However, the non-nephrotoxicity of Gd-CM has been proved wrong (Buhaescu & Izzedine, 2008; Ergun et al., 2006; Sam et al., 2003). In fact, Gd-CM may have a higher, both general and renal, toxicity than I-CM in concentrations and volumes causing the same attenuation as Gd-CM (Elmståhl et al., 2004; Elmståhl et al., 2008; Nyman et al., 2002).

Moreover, the maximum dose of Gd-CM according to the manufacturers' recommendations is only 0.2-0.3 mmol/kg, though average doses used for x-ray angiographic procedures have ranged from 0.2-0.8 mmol/kg. However, average clinical I-CM doses of 40-100 grams of iodine, results in about 4-10 mmol/kg in a 75 kg individual. Thus, the use of Gd-CM is limited in terms of volume and radiodensity (Nyman et al., 2011). Despite this, diagnostic satisfactory PCA has been achieved with 1.0M Gd-CM (Briguori et al., 2006; Voss et al., 2004) or 2:1 (Barcin et al., 2006; Sarkis et al., 2003) and 1:1 mixtures (Gupta & Uretsky, 2005) of 0.5M Gd-CM and I-CM.

Angiographic experiments with a 30 cm thick water-equivalent phantom at 70 and 95 kVp indicate that iodine concentrations at 60 and 80 mg/mL, respectively, are iso-attenuating with 0.5M Gd-CM (Nyman et al., 2011). The attenuation of the 1.0M Gd-CM and the mixtures between 0.5M Gd-CM and I-CM at 320 or 350 mg I/mL would correspond to about 140-200 mg I/mL of a pure I-CM at 70-95 kVp, concentrations that are commercially available. Thus, it seems possible to perform coronary procedures with half or even one third of the standard concentrations, not at least in thinner patients patients in whom automatic or manual down-regulation of the x-ray tube potential will increase attenuation by iodine.

Precautions and techniques to save contrast media during PCA/PCI in azotemic patients are summarized as follows:


• Whenever possible consider staged diagnostic and therapeutic procedures with several days in between.
