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Mark Twite, MA, MB, BChir, FRCP
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Luis Zabala, MD
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Contrast Agents and Pediatric Cardiac Catheterization

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Contrast Agents and Pediatric Cardiac Catheterization

By Luis M. Zabala, MD
UT Southwestern Medical School, Children’s Medical Center Dallas
 
Pediatric cardiac catheterizations, both diagnostic and interventional, are essential components of comprehensive care of congenital heart disease patients. Due to advances in technique, technology, and our understanding of pathophysiology many lesions, including patent ductus arteriosus, atrial and ventricular septal defects, collateral vessel burden, valve and vessel stenosis,  and conduction abnormalities, once thought to be amenable only to surgical intervention are now routinely successfully treated by interventional cardiologists. As a consequence, in large pediatric cardiac centers the number of interventional catheterization procedures performed has increased exponentially in the last 20 years.

Catheterization  procedures, both diagnostic and interventional, generally require performance of angiography with use of cine radiographic imaging and administration of contrast media. Opacification of blood with a water-soluble contrast agent allows for radiographic imaging of vascular structures and intracardiac chambers. Contrast solutions are basically classified into ionic media, which dissociate iodine into ionic particles in solution, and non-ionic media, which do not dissociate into particles but depend upon hydrophilic moieties in their molecules for solubility (low-osmolar or iso-osmolar contrast media).

Generally, those with ionic media require a significantly higher osmolality to achieve a sufficient iodine content to produce adequate angiography. It is these “hyperosmolar ionic” contrast agents that were associated with arrhythmias, pulmonary edema, hemodynamic alterations, cerebral and renal complications during the 1970s.  Radiographic media accounted for many of the complications and several deaths in the Cooperative Study on Cardiac Catheterization of 1968; an era during which morbidity and mortality in infants undergoing cardiac catheterization was relatively high (1,2). The risk of oliguria and anuria were greatest in infants, particularly those with decreased systemic blood flow, and largely related to renal toxicity. Ho and coworkers showed a clear relationship between type of contrast media used and mortality, meglumine derivatives proving safer than sodium derivatives, both hyperosmolar ionic agents (3). Its effects on hemodynamic variables are significant and immediate.

Romero et. al. reported significant hemodynamic alterations, with instantaneous increases in left ventricular (LV) end diastolic and end systolic volumes and LV end diastolic pressure after left ventricle injection of contrast media (Hypaque M-75%) in 1–3 month old conscious lambs (4). These changes were also accompanied by mild depression in LV contractility, systemic vasodilation and persistent augmentation of cardiac output and were attributed to acute volume expansion and sustained intravascular volume after contrast.

As an alternative, nonionic, less hypertonic, contrast agents were developed and widely adopted in the 1980s. These agents proved to provide equivalent angiographic quality while triggering less hemodynamic response following their administration. In a comparative study in children, evaluating the side-effects of non-ionic and ionic contrast media, Kunnen and coworkers showed a decrease in the incidence of discomfort, less changes in heart rate, decreased rhythm disturbances and overall better quality angiogram with non-ionic Amipaque when compared with ionic Isopaque Coronar for pediatric angiocardiography (5).

Furthermore, Pelech et al., demonstrated significantly less hemodynamic alterations in heart rate, blood pressure, and left ventricular diastolic pressure when using a non-ionic contrast agent, validating hemodynamic superiority (6). Due to their improved hemodynamic profile and reported favorable safety profile pediatric cardiac catheterization labs have largely moved toward sole use of non-ionic contrast media.

Complications and inherent toxicity from contrast agents are rare in pediatrics and much improved with new non-ionic agents. The most common induced complication of cardiac angiography is an intramyocardial injection with extravasation of contrast into the wall of the chamber or vessel as a consequence of the high-pressure injection. In the setting of a small isolated localized “stain” the treatment would entail managing the recognized hemodynamic implication. On the other extreme, pericardial effusion or tamponade may ensue, requiring active drainage.  Furthermore, there are inherent complications from the contrast agents themselves. The most common of these is a sensitivity or allergic reaction to iodine or to a specific contrast agent. Allergic reactions are extremely rare in the pediatric population. If an allergic reaction occurs unexpectedly, intravenous antihistamines, steroids and, when necessary, epinephrine may be needed. In the event that a child has a known allergy and requires angiocardiography, premedication with antihistamines and rapid-acting corticosteroid may be used. Thirty minutes after the premedication, a test dose 0.5 ml of contrast is given intravenously to assess response. At this point the procedure is allowed to continue with caution after balancing the risk of an allergic reaction versus the benefits of the intervention.
In addition to allergic reaction, all contrast agents have the potential for renal toxicity and central nervous system (CNS) toxicity.

Despite the many angiographic procedures performed in pediatric patients with complex congenital heart disease, there are few studies investigating contrast media as a risk of acute kidney injury (AKI). The exact incidence of nephrotoxicity related to contrast media in the pediatric population is unknown. Several authors have reported the incidence of Contrast Induced Nephropathy (CIN) to be 15 %-18.75% in the pediatric population, with a significant reduction in glomerular filtration after angiography (7,8,9). Subsets of pediatric patients with poor systemic perfusion and extreme cyanosis are likely to have abnormal renal function prior to contrast exposure and may be predisposed to further injury.  

In a recent study, Bianchi et. al. reported that the amount of contrast media used during the preoperative angiographic examination(16% relative risk increase for AFR per each additional grams per kilogram administered), age < 2 years and low postoperative cardiac output were risk factors for postoperative renal failure (10). In their series, 20% of patient received a dose of iodine contrast media > 5 g/kg (12.5 ml/kg when iodine concentration 400 mg/ml) exclusively associated with longer and more complex angiographic procedures. This is the first report demonstrating that a high contrast media load is a risk factor for operative ARF in children following surgical repair.

However, a clear relationship between timing of surgery after angiography and postoperative ARF could not be established. Furthermore, a recent study by Huggins et al. attempted to clarify the timing relationship and concluded that contrast administration within 48 hours prior to cardiopulmonary bypass was not an additional risk factor for the development of Acute Kidney Injury (AKI) in cyanotic congenital heart disease patients (11).  

In summary, a multitude of studies stress the deleterious effects of contrast media on renal function in pediatric patients and recently identify high dose contrast as clear modifiable risk factor for CIN in this population, despite the use of new agents. Known high risk patients, in particular, may benefit from hydration, both pre and post contrast administration (12,13). CNS toxicity is probably related to the osmolality of the agents, and occurs predominantly when large doses of contrast are being used. However, two recently published cases, reported contrast retention in the CNS following work-up for post catheterization seizure, despite using non-ionic agents (14,15). In both cases, large doses of contrast were used (7 cc/kg and 18 cc/kg), findings were transient and no permanent harm was recorded. As a general rule, toxicity of the contrast media decreases as osmolality approaches that of the serum. Developing nonionizing compounds and then combining two monomers to form a dimer have accomplished this.

Representative osmolalities
Serum: 290 mosm/kg H2O
High-osmolar: Ionic monomer: diatrizoate: 1570 mosm/kg H2O
Low-osmolar: Nonionic monomer: iohexol 240 (Omnipaque): 518 mosm/kg H2O  
Low-osmolar: Nonionic monomer: iohexol 300 (Omnipaque): 672 mosm/kg H2O
Iso-osmolar: Nonionic dimer: iodixanol 320 (Visipaque): 290 mosm/kg H2O

Additional modifications that have mitigated toxicity include: adding calcium ions (reduces cardiac toxicity), neutral pH (less vasodilation), and altering and distribution of –OH ions (decrease neural toxicity).

In addition to the type of contrast used, the total amount of contrast used is also important, as mentioned above. A maximum of 4 ml of contrast per kilogram of weight was arbitrarily established decades ago from clinical findings that the toxicity associated with ionic, hyperosmolar contrast agents increased significantly when larger volumes of contrast were used (16,17).

To date, there have been no scientific controlled studies performed on the toxic effects and safe volumes of ioninc and non-ionic contrast agents in the pediatric congenital population in relation to the duration of the study. Procedures in the  pediatric catheterization laboratory have evolved from being primarily diagnostic to largely interventional. This transition demands significantly more resources, contrast medium and procedure time.

A seminal paper by Senthilnathan et al. aimed at reporting adverse events rates (AE) attributed to contrast administration in the pediatric cardiac catheterization reported that 25% of their cases involved total contrast doses of >6 mL/kg. In this study of 2321 cases the occurrence of AEs potentially related to contrast administration was exceedingly low; 2 of 2321 patients or 0.09 %. These events were acute neurologic change and transient nephropathy. Interestingly, in the 50 cases (2.2%) with the highest dose (ranging from 10.8 – 16.8 mL/kg), chart audit could not find any AEs potentially related to contrast administration (e.g. allergic reaction, fever, contrast induced nephropathy, or neurologic sequelae) (18). In addition, they also reported that patients receiving high doses (top quartile; > 6 ml/kg) had more complex cardiac anatomy and underwent higher risk procedures requiring longer procedure times, potentially allowing for clearance in relation to the duration of the catheterization study.

In summary, the original rule of 4 cc/kg of body weight was established with older ionic hyperosmolar contrast agents and is probably too rigid and irrelevant when considering the new non-ionic iso-osmolar agent. Current contrast agents likely allow for higher contrast doses in excess of 4cc/kg for the most complex population. Today there is no “absolute maximum” contrast dose established in the pediatric congenital heart disease literature nor one single max dose honored in clinical practice by all institutions for these new agents.

Technically, it would be very difficult to offer a safe alternative catheter palliation without routinely going over 6 mL/kg in our most complex patients. However, until more safety data is documented with these new agents, it seems prudent to educate all caregivers involved with this patient population and limit the high dose of contrast exposure to those complex patients requiring interventions that demand extended length of time for the procedure, possibly allowing contrast clearance during the procedure.

References:

  1. Braunwald E: Deaths related to cardiac catheterization. Circulation 37 (suppl III): III-17, 1968.
  2. Swan HJC: Complications associated with angicardiogram. Circulation 37 (suppl III): III-81, 1968.
  3. Ho CS, Krovetz LJ, Rowe RD: Major complications of cardiac catheterization and angiography in infants and children. Johns Hopkins Med J 1972;131: 247.
  4. Romero TE, Higgins CB, Kirkpatrick S, Friedman WF. Effects of contrast material on dimensions and hemodynamics of the newborn heart: A study of conscious newborn lamb. Invest Radiol 1977;12: 510-514.
  5. Kunnen M, Devloo-Blancquaer A. Comparative study in angiocardiography in children, evaluating the side effects on non-ionic and ionic contrast media. Diagn Imaging 1979;48: 228-234.
  6. Pelech AN, Allard SM, Hurd RT, Giddins NG, Collins GF. A comparison of iohexol and diatrizoate-meglumine in children undergoing cardiac catheterization. Invest Radiol 1991:26;665-670.
  7. Ajami G, Derakshan A, Amoozgar H, Mohamadi M, Borzouee M, Bariratnia M, Abtahi S, Cheriki S, Soltani M. Risk of nephropathy after consumption of nonionic contrast media by children undergoing cardiac angiography: a prospective study. Pediatr Cardiol 2010;31:668-73.
  8. Niboshi A, Nishida M, Itoi T, Shiraishi I, Hamaoka K. Renal function and cardiac angiography. Indian J Pediatr 2006;73:49-53.
  9. Zo’o M, Hoermann M, Balassy C, Brunelle F, Azoulay R, Pariente D, Panuel M, Le Dosseur P. Renal safety in pediatric imaging: randomized, double blind phase IV clinical trial of iobitridol 300 versus iodixanol 270 in multidetector CT . Pediatr Radiol 2011;41:1393-400.
  10. Bianchi P, Carboni G, Pesce G, Isgro G, Carlucci C, Frigiola A, Giamberti A, Ranucci M. Cardiac catheterization and postoperative acute kidney failure in congenital heart pediatric patients. Anesth Analg 2013;117(2):455-61.
  11. Huggins N, Nugent A, Modem V, Rodriguez JS, Forbess J, Scott W, Dimas VV. Incidence of acute kidney injury following cardiac catheterization prior to cardiopulmonary bypass in children. Catheter Cardiovasc Interv. 2014 (ahead of print)
  12. Solomon R, Werner C, Mann D, D’Elia J, Silva P.. Effects of saline, mannitol and furosemide on acute disease in renal function induced by radio contrast agents. N Engl J Med 1994;331:1416-1420.
  13. Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P, Hewett J. A randomized prospective trial to assess the role of saline hydration on the development of contrast nepphrotoxicity. Nephron Clin Pract 2003;93:29-34
  14. Frye RE, Newburger JW, Nugent A, Sahin M. Focal seizures and cerebral contrast retention after cardiac catheterization. Pediatr Neurol 2005;32:213-216.
  15. Sansone V, Piazza L, Butera G, Meola G, Fontana A. Contrast-induced seizure after cardiac catheterization in a 6 year-old child. Pediatr Neurol 2007;36:268-270
  16. Stanger P et al., Complications of cardiac catheterization of neonates, infants and children. A three-year study. Circulation 1974; 50(3): 595-608.
  17. Fox KM, Patel RG, Bonvicini M, Taylor JF, Graham GR. Safe amounts of contrast medium for angiography in neonates and infants. Eur J Cardiology 1977;5:373-380.
  18. Senthilnathan S, Gauvreau K, Marshall A, Lock J, Bergersen L. Contrast administration in pediatric cardiac catheterization. Dose and Adverse Events. Catheter Cardiovas Interv 2009;73:814-820

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