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					                            Issues in the Use of Contrast Media in
                            Patients at High Risk for Contrast-Induced
                            Nephrotoxicity (CIN)
                            Release date: June 2003

                            Expiration date: June 2004

                            Estimated time to complete activity: 1.0 hours




Jointly sponsored by the Postgraduate Institute for Medicine
and Interlink Healthcare Communications.
This activity is supported by an educational grant from Amersham Health.
This activity has been planned and produced in accordance
with the ACCME Essential Areas and Policies.
    Target Audience
    This activity has been designed to meet the educational needs of
    radiologists, including interventional radiologists, interventional
    cardiologists, nephrologists, and radiologic technologists.


    Statement of Need/Program Overview
    The use of contrast media in radiologic procedures has continued to
    expand. The availability of both ionic and nonionic (including isosmolar)
    contrast has generated interest in reassessing the association of contrast
    with nephrotoxicity, particularly in high-risk patients, and evaluating
    clinically useful prophylactic measures.


    Educational Objectives
    Upon completion of this activity, participants should be better able to:

    • Identify issues in patients at high risk for CIN

    • Describe prophylactic strategies to lower the risk of CIN

    • Discuss recently published data on the use of contrast media in
      patients at high risk for CIN


    Method of Participation
    There are no fees for participating and receiving CME credit for this activity.
    During the period June 2003 through June 30, 2004 participants must:

    • Read the learning objectives and faculty disclosures

    • Study the educational activity

    • Complete the Post-Test by recording the best answer to each question
      in the answer key on the Evaluation Form

    • Complete the Evaluation Form

    • Fax the Evaluation Form with answer key to the Postgraduate
      Institute for Medicine



1
Faculty
Michael R. Rudnick, MD (Chair)
Associate Professor of Medicine
Chief, Division of Nephrology and Hypertension
University of Pennsylvania Health System—
Presbyterian Medical Center
Philadelphia, PA

Jeffrey A. Brinker, MD
Professor of Medicine and Radiology
The Johns Hopkins University
Baltimore, MD

Elliot K. Fishman, MD
Professor of Radiology and Oncology
Director, Diagnostic Imaging and Body CT
The Russell H. Morgan Department of Radiology
and Radiological Science
The Johns Hopkins University
Baltimore, MD

Warren Laskey, MD
Director, Cardiac Catheterization Laboratory
National Naval Medical Center
Bethesda, MD

Scott Trerotola, MD
Stanley Baum Professor of Radiology
Professor of Surgery
Associate Chair and Chief, Vascular and Interventional Radiology
University of Pennsylvania Medical Center
Philadelphia, PA




                                                                   2
    Physician Continuing Medical
    Education
    Accreditation Statement
    This activity has been planned and implemented in accordance with
    the Essential Areas and Policies of the Accreditation Council for
    Continuing Medical Education (ACCME) through the joint sponsorship
    of the Postgraduate Institute for Medicine and Interlink Healthcare
    Communications. The Postgraduate Institute for Medicine is accredited
    by the ACCME to provide continuing medical education for physicians.

    Credit Designation
    The Postgraduate Institute for Medicine designates this educational activity
    for a maximum of 1.0 category 1 credits toward the AMA Physician’s
    Recognition Award. Each physician should claim only those credits that
    he/she actually spent in the activity.

    Faculty Disclosure Statements
    Postgraduate Institute for Medicine has a conflict of interest policy that
    requires course faculty to disclose any real or apparent commercial financial
    affiliations related to the content of their presentations/materials. It is
    not assumed that these financial interests or affiliations will have an
    adverse impact on faculty presentations; they are simply noted here to
    fully inform participants.

    Elliot K. Fishman, MD
    Consultant: Amersham Health

    Michael R. Rudnick, MD
    Grants/Research Support: Amersham Health
    Consultant: Amersham Health
    Speakers’ Bureau: Amersham Health

    Scott Trerotola, MD
    Dr. Trerotola disclosed having no relationships with commercial entities
    related to his/her presentation materials.


3
Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the FDA.
The Postgraduate Institute for Medicine (PIM), Interlink Healthcare
Communications, and Amersham Health do not recommend the use
of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty
and do not necessarily represent the views of Postgraduate Institute for
Medicine, Interlink Healthcare Communications, and Amersham Health.
Please refer to the official prescribing information for each product for
discussion of approved indications, contraindications, and warnings.

Disclaimer
Participants may have an implied responsibility to use the newly acquired
information to enhance patient outcomes and their own professional
development. The information presented in this activity is not meant to
serve as a guideline for patient management. Any procedures, medications,
or other courses of diagnosis or treatment discussed or suggested in this
activity should not be used by clinicians without evaluation of their
patients’ conditions and possible contraindications on dangers in use,
review of any applicable manufacturer’s product information, and
comparison with recommendations of other authorities.




                                                                              4
    Issues in the Use of Contrast Media in
    Patients at High Risk for Contrast-
    Induced Nephrotoxicity (CIN)
    Introduction
    Intravascular radiopaque contrast media (RCM) are used globally for the
    performance of a wide variety of diagnostic and interventional procedures
    such as urography, computed tomography (CT), digital subtraction angio-
    graphy, and cardiac catheterization. Over 16 million examinations using
    intravascular RCM were done in the United States alone in 1994.1
    Although the vast majority of radiographic examinations are completed
    without incident, adverse reactions to RCM can be, at least, unpleasant
    and, at worst, potentially life-threatening. One such adverse reaction is
    CIN, which can increase hospital costs and, in some high-risk patients,
    lead to dialysis and/or permanent renal damage.2

    This program will focus on CIN, the patients who are at increased risk
    of CIN, and clinical approaches to reduce its occurrence.

    Characteristics of RCM
    Ionic vs nonionic. Since the first description of intravenous contrast
    use in humans in 1919,2 contrast agents have gradually evolved from
    early, relatively toxic products such as sodium iodopyridone or sodium
    iodomethamate3 to the new nonionic isosmolar iodixanol. RCM are
    typically divided into categories—ionic contrast media are salts of sodium
    and/or meglumine, nonionic contrast media are organic compounds that
    do not dissociate in solution. Ionic contrast media require two molecules
    to deliver the same number of iodine atoms as nonionic contrast media
    deliver with one molecule (Figure 1).




5
Osmolality. The number of ions of a solute (eg, contrast medium) dis-
solved in a solution determines its osmolality. The osmolality of normal
human serum is 285 mOsm/L. High osmolar contrast media (HOCM)
have an osmolality range of approximately 1,400 to 3,000 mOsm/L; low
osmolar contrast media (LOCM) have an osmolality range of approximately
400 to 850 mOsm/L. With one exception all LOCM are nonionic
monomeric compounds. The lone ionic LOCM is ioxaglate. Recently,
a nonionic isosmolar dimer, iodixanol, has been introduced that has an
osmolality of 290 mOsm/L, essentially the same osmolality as that of
human serum.

Figure 1. Chemical structure of contrast agents.



                    I          I           I              I I            I
                               COO-Na+                     R             COO-Na+

  Iothalamate            I                          I              I
  Diatrizoate     Ionic Monomer                Ionic Dimer - Ioxaglate
  Metrizoate
                    I          I           I              I I            I
                                                           R
                            I                     I              I
                  Noionic Monomer -            Noionic Dimer - Iodixanol
                  Iohexol, Ioversol,
                  Iopamidol


Ideally, RCM should be water soluble, chemical and heat stable, biologically
inert (nonantigenic), of low viscosity, and low or isosmolar, excreted
selectively through the kidney, safe, and inexpensive.3 Selected properties
of RCM are shown in Tables 1–2. Lower osmolality may decrease some
adverse effects, hence the rationale to produce nonionic agents. Higher
osmolality may not only increase pain and other symptoms, but may also
increase adverse effects affecting the heart and kidney.1,3 While the wide
variety of contrast agents available in the marketplace today continues to
improve, physicians still must address the risk of adverse effects and find
ways to mitigate them.




                                                                                   6
    Table 1. Ionic Radiopaque Contrast Media4* (ACR 4.1, pp41–42)

    Trade Name       Composition    %      Iodine   Viscosity     Osmolality
                                   Salt   240–320   at 37ºC     (mOsm/kg H20)
                                          (mg/mL)

    Hypaque       Diatrizoate      60      282        4.1           1,415
    Meglumine 60% Meglumine
    (Amersham
    Health)

    Reno®-60         Diatrizoate   60      282        4.0           1,404
    (Bracco)         Meglumine

    Conray-60        Iothalamate   60      282         4            1,400
    (Mallinckrodt)   Meglumine

    Renograffin-60   Diatrizoate   52      292.5      4.0           1,450
    (Bracco)         Meglumine      8
                     Sodium

    Hypaque          Diatrizoate   50      300        2.43          1,515
    Sodium 50%       Sodium
    (Amersham
    Health)

    Hexabrix         Ioxaglate
    (Mallinckrodt)   Meglumine     39.3    320        7.5            600
                     Sodium        19.6




7
Table 2. Nonionic Radiopaque Contrast Media4* (ACR 4.1, pp41–42)


Trade Name          Composition    Iodine   Viscosity     Osmolality
                                  200–320   at 37ºC     (mOsm/kg H20)
                                  (mg/mL)

Omnipaque® 240      Iohexol        240        3.4           520
(Amersham Health)   51.8%

Optiray® 240        Ioversol       240        3.0           502
(Mallinckrodt)      50.9%

Ultravist®-240      Iopromide      240        3.0           502
(Berlex)

Isovue®-250         Iopamidol      250        3.0           524
(Bracco)            51%

Visipaque®-270      Iodixanol      270        6.3           290
(Amersham Health)

Isovue®-300         Iopamidol      300        4.7           616
(Bracco)            61.2%

Omnipaque®-300      Iohexol        300        5.5           651
(Amersham Health)   64.5%

Optiray® 300        Ioversol       300        5.5           651
(Mallinckrodt)      63.6%

Oxilan® 300         Ioxilan        300        5.1           585
(Cook)              62%

Ultravist® 300      Iopromide      300        4.9           607
(Berlex)

Optiray® 320        Ioversol       320        5.8           702
(Mallinckrodt)      67.8%

Visipaque®-320      Iodixanol      320        11.8          290
(Amersham)




                                                                        8
    Table 3. Radiopaque Contrast Media Typically Used in Cardiac Procedures

     Trade Name        Composition          %       Iodine      Viscosity      Osmolality
                                           Salt    (mg/mL)      at 37ºC      (mOsm/kg H20)

     Omnipaque–        Nonionic                      350           10.4            844
     350 (Amersham     iohexol
     Health)           75.5%

     Isovue–370        Nonionic            —         370           9.4             796
     (Bracco)          iopamidol
                       75.5%

     Hypaque–76        Ionic diatrizoate             370           8.32           2016
     (Amersham         meglumine           66
     Health)           sodium              10

    *Note: Tables 1–2 are not a complete listing of currently available ionic and nonionic
     contrast media.

    Adverse Effects of RCM
    Adverse reactions to intravascular HOCM occur in 5% to 12% of patients
    compared with a 1% to 3% incidence in those receiving LOCM. Reactions
    to RCM may include anaphylactoid, or pseudoallergic reactions (eg,
    urticaria, nasal congestion, laryngeal edema, bronchospasm); chemotoxic
    reactions (eg, cardiac depression, arrhythmia, renal tubular or vascular
    damage); osmotoxic reactions (eg, changes in plasma volume, vascular
    permeability, vasodilation, blood–brain barrier); and vasovagal reactions
    (eg, bradycardia, hypotension).4 Severe reactions, which include dyspnea
    (shortness of breath), sudden drop in blood pressure, cardiac arrest, and
    loss of consciousness occur in <0.004% of procedures with ionic RCM
    and in 0.001% of procedures with nonionic RCM.1

    CIN is an adverse effect associated with RCM that continues to receive
    considerable attention–particularly because it is relatively common in
    high-risk patients and has the potential for serious sequelae.




9
Clinical Features of Contrast Nephrotoxicity
Definition of CIN. The first challenge in evaluating CIN is to determine
what defines significant nephrotoxicity. In most studies, an increase in
serum creatinine of at least 0.5 mg/dL or 25% above baseline during the
48- to 72-hour period following contrast media exposure is considered
clinically significant,5 although not all clinicians are in agreement.
However, outcomes that represent clinically more severe forms of CIN such
as the need for dialysis or prolonged hospitalization due to renal toxicity,
are uncommon, and are generally not selected to define CIN clinically.

Historical perspective. CIN was first reported in 1928 when acute renal failure
was observed in some patients after the administration of iodopyridone.6
Subsequently, it was demonstrated that pre-existing renal insufficiency was
a risk factor for this complication.7 In the early 1950s, the first RCM to
use the benzene ring, Urokon, was introduced and was soon followed by
tri-iodinated agents that were less nephrotoxic. The advent of low osmolar
agents has further improved the safety profile of these agents.3,8 However,
nephrotoxicity still occurs in a number of patients, so an understanding of
its clinical course and what measures can be taken to prevent or reduce it
is important.

Clinical course. The clinical course of CIN typically shows an increase in
serum creatinine levels within 24 to 48 hours after intravascular contrast
administration with peak values occurring between 3 to 5 days. There is
usually complete return of the serum creatinine value to its precontrast
baseline value by 10 days.9,10 In more severe cases, the serum creatinine
may continue to rise for 5 to 10 days and, in rare cases, dialysis may be
needed. Although most cases of CIN are nonoliguric, oliguric CIN can
occur and is most typically seen in patients with diabetes and severe
pre-existing renal insufficiency. A rise in serum creatinine that occurs
more than 48 hours after contrast exposure should suggest a cause for
acute renal failure other than CIN, such as cholesterol embolization.




                                                                                  10
     Pathogenesis of CIN
     Although no one has clearly established what physiochemical property
     of contrast media has the most effect on the kidney, renal medullary
     hypoxia and direct cytotoxicity have been identified as key causes of
     CIN. As shown in Figure 2, there are several factors that affect medullary
     oxygenation: prostaglandins (PGs) and atrial natriuretic peptide (ANP)
     are known to increase renal medullary blood flow while endothelin,
     vasopressin, adenosine, and reductions in prostacyclin (PGI2) decrease
     blood flow. If there is systemic hypoxemia or increased blood viscosity,
     oxygen delivery to the renal medulla may also be reduced.11

     Figure 2. The effect of contrast media on acute renal failure.

                                              Contrast Media




                                                                           ¡
              ¡¡¡




                                    ¡¡




                    PG                  Endothelin      Systemic            Osmotic Load
                    ANP                 Vasopressin     Hypoxemia          Distal Tubule
                                                       ¡
                                   ¡




                    Adenosine           PGI2             Blood Viscosity
                        ¡




                                                       ¡




                                                                           ¡
                                         ¡




                            Blood Flow                     O2 Delivery         O2 Consumption


             Direct Cellular Toxicity                  Renal Medullary Hypoxia


                                Contrast Media Nephrotoxicity


     Adapted with permission from Heyman SN et al. Exp Nephrol. 1994;2:153-157.11

     Effect of osmolality on the kidney. With one exception, iodixanol, all
     currently available radiopaque contrast media for intravascular use are
     hyperosmolar relative to human serum. Administration of hyperosmolar
     RCM increases delivery of NaCl to the ascending limb of the loop of
     Henle (ie, RCM act as “osmotic diuretics”). This may result in increased
     active reabsorption of NaCl, a process which requires increased oxygen
     expenditure thus further contributing to medullary hypoxia.11,12 The increase
     in NaCl reabsorption also leads to adenosine triphosphate (ATP) hydrolysis
     and increased adenosine production, which can cause renal vasoconstric-
     tion and hence CIN.13



11
In addition, there is in vitro evidence that hyperosmolality can increase
programmed cell death (apoptosis) of kidney cells, which also contributes
to the pathogenesis of CIN.14 These observations may explain why the
incidence of CIN is lower with LOCM than with HOCM and possibly lower
still with isosmolar media than with LOCM.9,15

Risk Factors for CIN: Impact on Incidence

CIN is uncommon in “low-risk” patients who are defined as not having
pre-existing renal insufficiency. The mean incidence of CIN in the low-risk
population is approximately 3%, based on data from both retrospective
and prospective studies.8,9,16

Nephrotoxicity almost exclusively occurs in patients with pre-existing
renal insufficiency.16,17 In patients with pre-existing renal insufficiency
with or without diabetes mellitus (“high-risk” patients), the incidence of
CIN is much greater, reaching 9% to 50% in patients with both comor-
bidities.9,15 In a study of patients undergoing coronary angiography, CIN
occurred in 21.6% of high-risk patients and in 7.9% of low-risk patients.17
Diabetes mellitus alone is probably not a significant risk factor; however,
the incidence of CIN is much higher in azotemic patients with diabetes
than in azotemic patients without diabetes (Table 4).

Thus, patients with chronic renal insufficiency and diabetes mellitus are
at the greatest risk for CIN.




                                                                              12
     Table 4. CIN in Patients Who Have Renal Insufficiency (RI) With and
     Without Diabetes Mellitus (DM)

        Reference                   (+) RI (-) DM         (+) RI (+) DM
                                      n/N (%)                n/N (%)

        Rudnick et al,8 1994         15/296 (5)             43/213 (20)

        Harris et al,10 1991           5/76 (7)               3/25 (12)

        Barrett et al,34 1992         6/213 (3)               6/36 (17)

        Moore et al,28 1992           4/117 (3)               8/43 (19)


     Other factors that may be implicated in the development of CIN include:
     dehydration and absence of preventative measures, large volume of injected
     contrast medium, severe congestive heart failure, and prior history of
     contrast media-associated acute renal failure (Figure 3).

     Figure 3. CIN: contributing factors.
                    Diabetes         Chronic Renal        Contrast
                    Mellitus         Insufficiency         Volume




                                    Contrast Media
                                    Nephrotoxicity




                    Absence of                            Radiologic
                                       HOCM in
                    Preventive                            Procedure
                                      CRF patients
                     Regimens



     It has also been shown that the incidence of CIN increases as serum
     creatinine levels increase: 0% at <1.5 mg/dL (normal)18,19; 50% to 75%
     at 1.6 to 4.5 mg/dL (moderate CIN)18-20; 90% to 100% at >4.5 mg/dL
     (severe CIN).18,20




13
Effect of CIN on Mortality
As with any medical procedure or adverse reaction, the key issue is the
ultimate effect on patient outcome. In a large analysis (>16,000 patients)
of in-hospital patients who underwent RCM procedures, 183 developed
CIN. The mortality rate was 34% compared with only 7% in a matched
cohort of patients without CIN.21 Increased mortality in patients who
develop CIN versus those who do not has been substantiated in several
additional studies.22-24 However, due to the association of higher cardio-
vascular comorbidities in patients who developed CIN versus those who did
not, it is not possible at this time to determine if CIN directly contributes
to mortality or is simply a marker for patients with severe illnesses.23

Role of Osmolality in CIN
HOCM versus LOCM. Although high or low osmolar contrast media (CM)
have not been conclusively shown to differentially affect the kidneys in
patients with normal renal function,9,25 the osmolality of contrast agents
may be a factor in patients with pre-existing renal insufficiency. The data
strongly support a kidney-sparing effect with LOCM (Figure 4).10,17,26-28

Figure 4. Incidence of CIN (SCr ≥1 mg%) stratified by risk factor.


                     30                                                     27

                     25
                                          s Iohexol
                     20                   s Diatriziate
           Percent




                     15                                                12
                     10          7.1                             7.4
                           3.2                             4.1
                     5
                                       0.0 0.0   0.7 0.6
                     0
                             Total     Group 1   Group 2   Group 3 Group 4
                          P<0.002      ( - )RI   ( - )RI   ( )RI   ( )RI
                                       ( - )DM   ( )DM     ( - )DM ( )DM


(SCr=serum creatinine; RI=renal insufficiency; DM=diabetes mellitus)17




                                                                                 14
     A meta-analysis of 25 trials revealed that the risk of having more than
     a 0.5 mg/dL increase in serum creatinine level following contrast
     exposure was 40% lower with LOCM than with HOCM. In patients
     with pre-existing renal insufficiency, the odds ratio was even greater.29

     Isosmolar contrast media versus LOCM. The recent development of
     the isosmolar nonionic contrast agent iodixanol has led to additional
     comparative studies to demonstrate reduced renal effects.15,30 In a recently
     published report (the NEPHRIC study), 129 patients with diabetes and
     impaired renal function were prospectively randomized to receive either
     iodixanol or iohexol for coronary angiography.15 Iodixanol was shown to
     be less nephrotoxic than iohexol based on both the standard definition
     of CIN (SCr >0.5 mg/dL) and a more rigorous definition of CIN (SCr >1.0
     mg/dL) (Figure 5). The risk of developing CIN was 11 times higher with
     iohexol compared with iodixanol, using the standard definition.

     Although data are still limited, these studies suggest that the isosmolar
     nonionic RCM iodixanol may be less nephrotoxic than low osmolar agents
     for the “high-risk” patient.

     Figure 5. The effect of iodixanol (isosmolar, nonionic) vs iohexol
     (LOCM, nonionic) on CIN (the NEPHRIC study).



                                  30
                                              26.2%          s Iodixanol
                                  25                         s Iohexol

                                  20
                    Percent CIN




                                                                    15.4%
                                  15

                                  10

                                  5    3.1%
                                                               0%
                                  0
                                        Peak Scr >0.5          Peak Scr >1.0
                                           mg/dL                  mg/dL

     Aspelin P, Aubry P, Fransson S-G, et al. Nephrotoxic effects in high-risk patients
     undergoing angiography. N Engl J Med. 2003;348:491-499.15



15
Prophylactic Strategies to Reduce CIN
Type, Volume, and Timing of Contrast Media
The type and volume of contrast media are important factors that affect
the incidence of CIN. Logically, the less volume used the better, but more
concentrated contrast media should not necessarily be chosen simply
to reduce the volume without considering the effects of the higher
concentration. It is important to select the lowest concentration that will
provide adequate radiopacity for the type of procedure being performed.
As previously noted, in patients with normal renal function, there is little
effect on the incidence of CIN with use of either HOCM or LOCM.
Conversely, in patients with pre-existing renal insufficiency, the use of
LOCM,17 and possibly isosmolar contrast15 is beneficial. When multiple
procedures are needed in 1 patient, increasing the time between
procedures will help give the kidneys more recovery time and reduce
the incidence and severity of CIN. If a patient is taking nonsteroidal
anti-inflammatory drugs (NSAIDs), the NSAIDs should be discontinued
prior to a contrast procedure to also help reduce nephrotoxicity.

Hydration
Hydration is the simplest and least expensive treatment to reduce the
incidence of CIN. The value of hydration as a prophylactic strategy may
be due to increased beneficial effects on the kidneys, such as decreased
activity of the renin–angiotensin system, augmentation of diuresis and
sodium excretion, and reduction in renal vasoconstriction by dilution of
contrast media.31 Although hydration is generally well accepted, there are
few clinical data to support timing, amount, or type of hydration. Most
studies have used either normal or half-normal saline at a rate of 1 mL/kg/hr
starting 12 hours before contrast and continuing for 12 hours after contrast.
Studies have shown that normal saline is superior to half-normal32 and
that normal saline is also superior to unrestricted oral fluids.33 Hydration
is recommended for all patients and is particularly important in patients
who have pre-existing impaired renal function in the presence or absence
of diabetes as well as in patients who have had previous episodes of CIN.


                                                                                16
     Mannitol and Furosemide
     Although mannitol and furosemide were at one time considered to
     be potentially useful in the prevention of CIN, a prospective study5
     demonstrated that saline alone was superior to either agent as a
     prophylactic strategy in CIN. Based on findings such as these, neither
     agent is recommended today.

     Acetylcysteine
     As indicated in preclinical studies, an antioxidant such as acetylcysteine
     (NAC) may help reduce CIN by decreasing the presence of oxygen-free
     radicals generated by contrast media35 and/or by its ability to reduce renal
     vasoconstriction.36

     Reported clinical data have been inconsistent regarding the ability of
     NAC to reduce the incidence of CIN. In the studies that showed benefit,
     patients with renal insufficiency who underwent radiographic procedures
     using LOCM and hydration as prophylaxis, received NAC (600 mg; total
     of 4 doses) both before and after RCM administration.37-39

     Other studies, however, that used similar study designs to those described,
     have not been able to demonstrate a clinically beneficial role for NAC in
     CIN. NAC was unable to prevent or minimize renal dysfunction compared
     with either saline alone or placebo.40-42

     Reasons for the lack of consistent findings in these studies are unclear at
     the present time. However, a large, randomized trial primarily designed to
     evaluate the prophylactic value of NAC will be needed before any definitive
     statements can be made. Despite the conflicting data, the relative safety
     and inexpensive cost of NAC favor its use at the present time.




17
Dopamine and Fenoldopam
Dopamine. Stimulation of renal arterial dopamine D1 receptors results
in vasodilation of these vessels. Therefore, several studies have evaluated
dopamine as a prophylactic agent to prevent CIN, although with inconsis-
tent results.43,44 The failure to demonstrate a consistent benefit may be
due to the nonselectivity of dopamine for the D1 receptors.

Fenoldopam. Fenoldopam is a selective D1 receptor agonist that is
approved for the management of severe hypertension. Although initial
studies suggested a potential benefit for fenoldopam in preventing CIN,45-48
the results of a large, double-blind, randomized trial that compared
fenoldopam with placebo in high-risk patients demonstrated that
fenoldopam was unable to prevent CIN.49

Theophylline
Experimental and clinical studies have demonstrated that the
nonselective adenosine receptor antagonist, theophylline, inhibits
contrast media-induced renal vasoconstriction.13 Furthermore, several
studies suggest a beneficial effect of theophylline in reducing CIN.
Patients who received oral theophylline starting at least one hour
before contrast administration demonstrated prevention or attenuation
of reductions in creatinine clearance induced by both HOCM and LOCM
compared with placebo.50,51 The possibility of theophylline causing tachy-
arrhythmias in this setting is of potential concern especially in patients
with coronary artery disease undergoing coronary angiography.




                                                                               18
     Gadolinium as an Alternative Agent
     In patients with renal insufficiency or severe allergy to iodinated contrast
     media, gadolinium can be considered as a substitute for use in angiography.52
     Although typically considered only for magnetic resonance imaging,
     gadolinium—a rare earth paramagnetic material—is mildly radiopaque
     and can be used as a substitute for low-concentration iodinated contrast
     media. Gadolinium-DTPA at a concentration of 0.5 mmol/mL is equiva-
     lent to a 12.5% to 25% dilution of standard iodinated contrast material
     (eg, iohexol). Although it is extremely rare to see severe reactions to
     gadolinium, headache, nausea, and flushing can occur.4 The attractiveness
     of gadolinium in patients with renal insufficiency is its relative lack of
     nephrotoxicity.4,50

     At the present time, investigators who advocate the use of gadolinium
     during angiography in patients with renal insufficiency recommend that
     the total dose of gadolinium not exceed 0.3 to 0.4 mmol/kg body weight
     (about 40 to 50 mL for a 70-kg patient),50 which is adequate for many
     types of angiographic examinations. Studies that require larger volumes
     of contrast can still be accomplished when gadolinium is supplemented
     with CO2.

     Summary
     Physicians must carefully assess each patient who undergoes an intravascu-
     lar procedure that uses iodinated RCM. Patients at increased risk of adverse
     clinical events such as nephrotoxicity must be recognized and appropriate
     strategies for mitigating this risk must be implemented. Currently, hyration is
     the most widely recommended prophylactic measure to reduce the incidence
     of CIN. Patients who are at highest risk for developing CIN are those with
     existing renal insufficiency and diabetes mellitus. The development of
     LOCM has significantly reduced adverse reactions compared with HOCM
     and the availability of new isosmolar contrast media may have an even
     better tolerability and reduced nephrotoxicity profile. As new products and
     clinical management strategies emerge and with careful further study, the
     incidence and severity of adverse sequelae will hopefully continue to
     diminish, resulting in improved patient care.



19
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                                                                                                20
     19. Harkonen S, Kjellstrand CM. Intravenous pyelography in nonuremic diabetic patients.
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     27. Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunc-
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     28. Moore RD, Steinberg EP, Powe NR, et al. Nephrotoxicity of high-osmolality versus
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     29. Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and low-
         osmolality iodinated contrast media. Radiology. 1993;188:171-178.
     30. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment.
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     31. Erley CM. Does hydration prevent radiocontrast-induced acute renal failure? Nephrol
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     32. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated
         nephropathy: randomized comparison of 2 hydration regimens in 1620 patients
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     33. Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role
         of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract.
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     34. Barrett BJ, Parfrey PS, Vavasour HM, et al. Contrast nephropathy in patients with
         impaired renal function: high versus low osmolar media. Kidney Int.
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     35. Bakris GL, Lass N, Gaber AO, Jones JD, Burnett JC Jr. Radiocontrast medium-induced
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21
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    renal microcirculation: studies in rats. Kidney Int. 2003;63:634-641.
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    N Engl J Med. 2000;343:180-184.
38. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography-
    related renal tissue injury (the APART trial). Am J Cardiol. 2002;89:356-358.
39. Shyu K-G ,Cheng J-J, Kuan P. Acetylcysteine protects against acute renal damage in
    patients with abnormal renal function undergoing a coronary procedure. J Am Coll
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40. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent-associated
    nephrotoxicity. J Am Coll Cardiol. 2002;40:298-303.
41. Durham JD, Caputo C, Dokko J, et al. A randomized controlled trial of N-acetylcys-
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42. Allaqaband S, Tumuluri R, Malik AM, et al. Prospective randomized study of N-acetyl-
    cysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy.
    Cathet Cardiovasc Interv. 2002;7:279-283.
43. Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and aminophylline on
    contrast-induced acute renal failure after coronary angioplasty in patients with
    preexisting renal insufficiency. Am J Cardiol. 1999;83:260-263.
44. Kapoor A, Sinha N, Sharma RK, et al. Use of dopamine in prevention of contrast
    induced acute renal failure–a randomized study. Int J Cardiol. 1996;53:233-236.
45. Madyoon H, Croushore L, Weaver D, Mathur V. Use of fenoldopam to prevent radio-
    contrast nephropathy in high-risk patients. Cathet Cardiovasc Interv. 2001;53:341-345.
46. Tumlin JA, Wang A, Murray PT, Mathur VS. Fenoldopam mesylate blocks reductions in
    renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of
    contrast nephropathy. Am Heart J. 2002;143:894-903.
47. Kini A, Sharma SK. Managing the high-risk patient: experience with fenoldopam, a
    selective dopamine receptor agonist, in prevention of radiocontrast nephropathy during
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48. Chamsuddin AA, Kowalik KJ, Bjarnason H, et al. Using a dopamine type 1A receptor
    agonist in high-risk patients to ameliorate contrast-associated nephropathy. AJR.
    2002;179:591-596.
49. Stone GW, McCullough P, Tumlin J, et al. A prospective, randomized, placebo-controlled
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    induced nephropathy: the CONTRAST trial. J Am Coll Cardiol. 2003;41(suppl A): 83A.
50. Katholi RE, Taylor GJ, McCann WP, et al. Nephrotoxicity from contrast media: attenu-
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51. Huber W, Ilgmann K, Page M, et al. Effect of theophylline on contrast
    material–induced nephropathy in patients with chronic renal insufficiency: controlled,
    randomized, double-blinded study. Radiology. 2002;223:772-779.
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    ventional radiology: A useful alternative to iodinated contrast media for angiography.
    Radiology. 2002;223:319-325.
                                                                                                22
                                                               CME BOOKLET—POST-TEST
                               Issues in the Use of Contrast Media in Patients at High Risk for Contrast-Induced Nephrotoxicity (CIN)

1. Nonionic contrast media require only 1 molecule to deliver the same                 9. Which of the following statements about the NEPHRIC study are true?
   number of iodine atoms as ionic contrast media deliver with 2 molecules.               a) The study included 129 patients with diabetes and impaired renal function
                                                                                             prospectively randomized to receive either iodixanol or iohexol for coronary
   A) true          B) false
                                                                                             angiography.
2. Which of the following statements about osmolality are true?                           b) The risk of developing CIN was 11 times higher with iohexol than with
                                                                                             iodixanol, based on the standard definition of CIN (SCr >0.5 mg/dL) and
   a) High osmolar contrast media (HOCM) have an osmolality range
                                                                                             a more rigorous definition of CIN (SCr >1.0 mg/dL).
      of approximately 1,400 to 3,000 mOsm/L.
                                                                                          c) Although data are still limited, the study suggests that the isosmolar,
   b) Low osmolar contrast media (LOCM) have an osmolality range
                                                                                             nonionic radiopaque contrast media (RCM) iodixanol may be less
      of 400 to 850 mOsm/L.
                                                                                             nephrotoxic than low osmolar agents for high-risk patients.
   c) Human serum has an osmolality of approximately 285 mOsm/L.
                                                                                          d) The NEPHRIC study data were published in the New England Journal
   A) a and b       B) b and c          C) a and c        D) a, b, and c                     of Medicine (Aspelin et al), Volume 348, No. 6.

3. Which of the following observations may explain why the incidence of                   A) a and b       B) a and c        C) a, b, and c      D) a, b, c, and d
   CIN is lower with LOCM than with HOCM, and possibly lower still with
   an isosmolar contrast medium than with LOCM?                                        10. Which of the following statements about the use of hydration as
                                                                                           treatment to reduce the incidence of CIN are true?
   Hyperosmolality may:
                                                                                          a) Hydration increases the activity of the renin–angiotensin system.
   a) Increase apoptosis of kidney cells
                                                                                          b) Hydration augments diuresis and sodium excretion.
   b) Decrease delivery of NaCl to the ascending limb of the loop of Henle
                                                                                          c) Hydration reduces renal vasoconstriction by dilution of contrast media.
   c) Increase reabsorption of NaCl, resulting in increased adenosine
      production and subsequent renal vasoconstriction                                    d) Hydration is recommended for all patients, and is particularly important
                                                                                             in patients who have pre-existing impaired renal function or those who
   d) Contribute to medullary hypoxia, as a result of reabsorption of NaCl
                                                                                             have had previous episodes of CIN.
   A) b and c       B) a, b, and c      C) a, c, and d    D) a, b, and d
                                                                                          A) a, b, and c B) b, c, and d      C) a, b, and d      D) a, b, c, and d
4. In most studies, an increase in serum creatinine of at least ____ mg/dL during
   the 48- to 72-hour period following contrast media exposure is considered a         11. Although mannitol and furosemide were once considered potentially useful
   clinically significant indicator of nephrotoxicity.                                     for preventing CIN, a prospective study demonstrated that saline alone was
                                                                                           superior to either agent as a prophylactic strategy.
   A) 0.05          B) 0.2              C) 0.5            D) 0.10
                                                                                          A) true          B) false
5. Although it has not been clearly established what physiochemical property of
   contrast media has the most effect on the kidney, ________ and ___________          12. Which of the following statements about the use of gadolinium as an
   have been identified as key causes of CIN.                                              alternative contrast agent are true?
   A) Renal medullary hypoxia/direct cytotoxicity                                         a) Gadolinium can be considered as a substitute for use in angiography
   B) Renal medullary hypoxia/indirect cytotoxicity                                          in patients with renal insufficiency or severe allergy to iodinated
                                                                                             contrast media.
   C) Renal cortical hypoxia/direct cytotoxicity
                                                                                          b) Gadolinium-DTPA at a concentration of 0.5 mmol/mL is equivalent to a
6. In patients with pre-existing renal insufficiency with or without diabetes melli-         12.5% to 25% dilution of standard iodinated contrast material (iohexol).
   tus, the incidence of CIN is much greater in patients with both comorbidities.         c) Although it is extremely rare to see severe reactions to gadolinium,
                                                                                             headache, nausea, and flushing can occur.
   A) true          B) false
                                                                                          d) Studies that require larger volumes of contrast can still be accomplished
7. In addition to pre-existing renal insufficiency and diabetes mellitus, which              when gadolinium is supplemented with CO2.
   of these factors can also contribute to CIN?                                           A) a and b       B) a, b, and c    C) a, b, and d      D) a, b, c, and d
   a) Dehydration
   b) The use of HOCM in chronic renal failure patients                                13. Which of the following statements about other prophylactic strategies for
   c) Severe congestive heart failure                                                      reducing the risk of CIN are true?
   d) Large volume of injected contrast medium                                            a) Several studies have evaluated dopamine, a D1 agonist, as a prophylactic
                                                                                             agent to prevent CIN, although with inconsistent results, possibly due to
   A) a, b, and c B) b, c, and d        C) a, c, and d    D) a, b, c, and d
                                                                                             the nonselectivity of dopamine for the D1 receptors.
8. The risk of having more than a 0.5 mg/dL increase in serum creatinine                  b) Results of a large, double-blind, randomized trial that compared fenoldopam
   level following contrast exposure was significantly __________ with LOCM                  to placebo in high-risk patients demonstrated that fenoldopam was unable
   than with HOCM.                                                                           to prevent CIN.
                                                                                          c) Several studies suggest that theophylline may have a beneficial effect in
   A) higher        B) lower
                                                                                             reducing CIN; however, it may cause tachyarrhythmias in patients with
                                                                                             coronary artery disease undergoing coronary angiography.
                                                                                          A) a and b       B) b and c         C) a, b, and c

                                                                                       14. An antioxidant such as acetylcysteine (NAC) may help reduce CIN by
                                                                                           decreasing the presence of oxygen-free radicals generated by contrast
                                                                                           media; however, clinical data have been inconsistent regarding the ability
                                                                                           of NAC to reduce the incidence of CIN.
                                                                                          A) true          B) false
                                    CME BOOKLET—EVALUATION FORM (PHYSICIAN CREDIT)
          PIM Project ID # 021167-ES-5 Issues in the Use of Contrast Media in Patients at High Risk for Contrast-Induced Nephrotoxicity (CIN)
 The Postgraduate Institute for Medicine (PIM) respects and appreciates your opinions. To assist us in evaluating the effectiveness of this activity
 and to make recommendations for future educational offerings, please take a few minutes to complete this evaluation form. Please note that a
 certificate of completion is issued only upon receipt of your completed evaluation form.

 Please answer the following questions by circling the appropriate rating: 5 = Outstanding 4 = Good 3 = Satisfactory 2 = Fair 1 = Poor

 Extent to Which Program Activity Met the Identified Objectives
 Upon completion of this activity, participants should be able to:
 • Identify issues in patients at high risk for contrast-induced nephrotoxicity (CIN)                                               5        4       3       2       1
 • Describe prophylactic strategies to lower the risk of CIN                                                                        5        4       3       2       1
 • Discuss recently published data on the use of contrast media in patients at high risk for CIN                                    5        4       3       2       1

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 Objectives were related to overall purpose/goal(s) of activity                                                                     5        4       3       2       1
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