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Curr Treat Options Cardio Med (2018) 20: 32

DOI 10.1007/s11936-018-0621-3

Coronary Artery Disease (D Feldman and V Voudris, Section Editors)

Prevention of Contrast
and Radiation Injury
During Coronary Angiography
and Percutaneous Coronary
Intervention
Arash Ehteshami Afshar, MD, MSc
Puja B. Parikh, MD, MPH, FACC, FAHA, FSCAI*
Address
*
Division of Cardiovascular Medicine, Department of Medicine, State University of
New York at Stony Brook, Stony Brook, NY, 11794, USA
Email: puja.parikh@stonybrookmedicine.edu

Published online: 22 March 2018


* Springer Science+Business Media, LLC, part of Springer Nature 2018

This article is part of the Topical Collection on Coronary Artery Disease

Keywords Cardiac catheterization I Contrast-induced nephropathy I Contrast-induced acute kidney injury I Radiation
injury

Abstract
Purpose of review In this review, we provide a summary of the recently published literature
on various methods of preventing contrast-induced acute kidney injury (CI-AKI) and
radiation-related injuries associated with cardiac catheterization and percutaneous coro-
nary intervention (PCI).
Recent findings The overall reported incidence of CI-AKI is declining, primarily due to
adaptation of a standardized definition for CI-AKI as well as implementation of pre-
procedural protocols to prevent or decrease the risk of CI-AKI. The implementation of
increasing awareness and establishing radiation protection culture has been shown to be
effective measures in reducing radiation exposure.
Summary Coronary angiography and PCI are valuable diagnostic and therapeutic tools in
cardiovascular medicine. Accurate imaging of the coronary arteries in cardiac catheteri-
zation is dependent on the use of intravascular injection of iodinated contrast media and
fluoroscopic imaging. Patients undergoing diagnostic and interventional cardiac cathe-
terization may be exposed to a substantial amount of contrast media and ionizing
radiation. Administration of contrast media is correlated with increased risk of CI-AKI,
and exposure to radiation is known to be associated with a spectrum of acute and chronic
tissue injuries.
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Introduction
Coronary angiography and percutaneous coronary in- acute and chronic tissue injuries. The enforcement of
tervention (PCI) are valuable diagnostic and therapeutic preventive measures, the application of improved angio-
tools in cardiovascular medicine. Administration of con- graphic equipment and techniques, and the introduc-
trast media during angiography and PCI is associated tion of newer generation of contrast media have reduced
with increased risk of contrast-induced acute kidney the risk of adverse post-procedural events. In this review,
injury (CI-AKI), also known as contrast-induced ne- we provide a summary of various methods for
phropathy (CIN). Radiation exposure from fluoroscopic preventing CI-AKI and radiation injury following coro-
imaging is known to be associated with a wide array of nary angiography and PCI.

Contrast-induced acute kidney injury


In recent years, the cardiovascular community has adopted a more unifying
definition for contrast-induced acute kidney injury (CI-AKI), also known as
contrast-induced nephropathy (CIN). According to the Kidney Disease Improv-
ing Global Outcomes guidelines, CI-AKI is defined as either an increase in
serum creatinine of 1.5 times or ≥ 0.3 mg/dL from the baseline within 48 h or
decrease in urine volume to less than 0.5 mL/kg/h for 6 h, after contrast
exposure [1]. The reported incidence of CI-AKI in the literature varies widely
depending on the definition of kidney injury, type of procedure, the amount
and type of contrast agent administered, and the presence or absence of risk
factors [2]. Traditionally, the incidence of CI-AKI after diagnostic coronary
angiography or percutaneous coronary intervention (PCI) is estimated to be
between 1 and 2% in the general population and over 20% in higher risk
subgroups [2–4]. Hospitalized patients in general are at increased risk of AKI
from etiology other than contrast media exposure [4], and therefore, during
hospitalization, their serum creatinine levels might significantly fluctuate even
in the absence of contrast exposure [5].

Pathogenesis and risk factors


Iodinated contrast media consists of a water-soluble carbon-based molecule
that binds to iodine atoms [6]. The iodine atoms absorb X-ray radiation,
ultimately resulting in radio-opacity in medical imagery. Animal studies
have demonstrated that iodinated contrast media can cause vasoconstric-
tion and direct cellular injury mediated by oxidative stress, ischemia, high
osmotic nephrosis, and viscosity. After arterial injection, the contrast-
induced vasoconstriction leads to the outer medullary layer blood flow
reduction in the kidneys, resulting in ischemia of the proximal and distal
tubules. Iodinated contrast media does not directly affect glomeruli and
freely filters through but is then reabsorbed owing to its water-soluble
properties and causes direct oxidative stress and cell injury in the proximal
tubules [2, 7]. Moreover, high concentrations and stasis of contrast in the
tubulointerstitial space induce ongoing damage to the adjacent cells [6].
These injuries trigger the tubuloglomerular feedback, which in turn reduces
the filtration rate in the first 24 to 48 h after exposure to contrast media [8].
Curr Treat Options Cardio Med (2018) 20: 32 Page 3 of 13 32

Micro-showers of atheroembolic material to the renal circulation from


contrast injection and catheter manipulation may also contribute to AKI
following coronary angiography and/or PCI [9].

Prognosis
The majority of the patients with clinically evident CI-AKI will have complete
and relatively rapid recovery of renal function, approximately 8 to 10 days after
exposure to contrast. However, in patients with underlying kidney disease, even
lower doses of iodinated contrast can cause a significant reduction in estimated
glomeruli filtration rate (eGFR) leading to azotemia, volume overload, electro-
lyte abnormalities, and occasionally, the need for dialysis. Residual renal dys-
function may persist especially among patients with underlying kidney disease.
CI-AKI is associated with prolonged hospital stay, mortality, and increased costs
[10]. Even a small, reversible increase in serum creatinine correlated with
increased risk of mortality. However, most of the patients in these observational
studies had unadjusted underlying risk factors which could have potentially
increased the mortality, independent of the renal dysfunction [11–13]. In a
recent study of more than 5000 patients undergoing elective PCI, after adjust-
ment for multiple confounders, persistent CI-AKI after 1-year follow-up corre-
lated with long-term mortality only in patients with chronic kidney disease
(CKD) but not in those without CKD [14]. The difference in reported short and
long-term mortality rates may be accounted for by the lack of a standardized
definition of CI-AKI and heterogeneity of reporting criteria in various reports.
The question of whether CI-AKI is the cause or a marker of a higher mortality
rate remains to be thoroughly investigated.

Prevention of CI-AKI
The first step in the prevention of CI-AKI is to identify patients at increased risk
of kidney injury from contrast media agent administration. Identifying high-
risk patients will allow the use of the pre-procedural intervention that could
mitigate the risk of CI-AKI. A comprehensive systematic review of literature in
2015 identified 12 prediction models for CI-AKI in patients receiving contrast
for cardiac procedures [15]. Although some of these models were excellent in
predicting CI-AKI in the study settings, none of them were evaluated in clinical
practice, which limits their external validity [16]. Furthermore, because some of
these models incorporated variables like contrast volume that are obtainable
only after the procedure, the practical application of these models is debatable.
Nevertheless, models with good discriminative ability included pre-existing
CKD, age, diabetes mellitus, heart failure or impaired ejection fraction, and
hypotension or shock as major risk factors [3, 16].

Pre-procedural withdrawal of medications


Although there is no randomized trial that investigated the pre-procedural
withdrawal of medications, it is reasonable to hold non-steroidal anti-inflam-
matory drugs (NSAIDs) 24–48 h before the procedure and to avoid re-
introduction until it is evident that CI-AKI has not occurred. The effect of
discontinuing antihypertensive drugs, angiotensin-converting enzyme inhibi-
tors and angiotensin II receptor blockers, diuretics, and metformin remains
unclear [17, 18].
32 Page 4 of 13 Curr Treat Options Cardio Med (2018) 20: 32

Dosage and type of contrast media


It is suggested that higher volumes (9 100 mL) of iodinated contrast medium
are associated with a higher risk for CI-AKI [19]. However, in high-risk patients,
even a very small dose of contrast can increase the risk CI-AKI [20]. Some recent
studies are challenging the association between contrast media exposure and
risk of CI-AKI [21]. An analysis of hospitalization data in the USA through 2009
demonstrated that the incidence of AKI was not significantly different among
patients who received contrast media, mainly for computed tomography (CT)
imaging for a wide variety of indications, compared to those who did not
receive contrast media (5.5 vs. 5.6%) [4]. However, these findings could not
be generalized to patients who undergo diagnostic coronary angiography and/
or PCI. Patients who undergo coronary angiography and PCI have more co-
morbidities, may receive higher volumes of contrast media, and receive contrast
via an arterial route compared to those undergoing CT imaging studies.
The newer generation contrast agents have a lower risk for CI-AKI compared
to the older generation agents that are rarely used today. This improvement is
most likely due to decreased osmolality and the absence of the charge that
characterizes the newer agents [22]. Among newer agents, iodixanol might have
a modestly lower risk of CI-AKI compare to other low-osmolal agents, particu-
larly iohexol, among high-risk patients [23]. Overall, the use of lowest dose of
low- or iso-osmolar contrast media is the most reasonable preventive strategy
among high-risk patients.

Access site
Several studies have compared arterial access sites for cardiac catheterization
and reported that radial artery access compared to femoral artery access could
reduce the risk of CI-AKI [24–26]. The Minimizing Adverse Haemorrhagic
Events by Transradial Access Site and Systemic Implementation of AngioX
(MATRIX) trial demonstrated that patients undergoing coronary angiography
with radial access had reduced incident rates of CI-AKI compared with those
with femoral access. This may be related to the higher rates of access site
bleeding as well as risk of direct embolization into the renal circulation from
direct passage of catheters in proximity to renal arteries when femoral access is
utilized [27].

Intravenous volume expansion


Iodinated contrast media is water-soluble, and therefore, intravascular volume
expansion should enhance urinary elimination of contrast, by increasing renal
filtration and tubular flow. In the absence of contraindications, administration
of intravenous fluids before contrast exposure is a common pre-procedural
practice for patients at increased risk of CI-AKI. Several randomized studies
have demonstrated the effectiveness of this intervention [28–31].
In the Prevention of Contrast Renal Injury with Different Hydration Strate-
gies (POSEIDON) randomized controlled trial, fluid replacement protocol
guided by left ventricular end-diastolic pressure (LVEDP) was compared with
standard intravenous fluid administration among patients with eGFR G 60 mL/
min/1.73 m2. Both groups received standard-of-care of normal saline 3 mL/kg
for 1 h before cardiac catheterization. In the LVEDP-guided group (n = 178),
Curr Treat Options Cardio Med (2018) 20: 32 Page 5 of 13 32

patients received 5 mL/kg/h if LVEDP was lower than 13 mmHg, 3 mL/kg/h if


LVEDP was between 13 and 18 mmHg, and 1.5 mL/kg/h if LVEDP was greater
than 18 mmHg. The control group (n = 172) received 1.5 mL/kg/h. Both groups
received intravenous fluids throughout the procedure and 4 h afterwards. The
LVEDP-guided group received more intravenous fluid and had a lower risk of
CI-AKI compared with control group (6.7 vs. 16.3%). Intravenous fluid admin-
istration was terminated prematurely because of concerns regarding volume
overload in three patients in each group [32•].
A Maastricht Contrast-Induced Nephropathy Guideline (AMACING) ran-
domized controlled trial, however, recently found no benefit in aggressive,
guideline-directed intravenous hydration with saline compared to no hydration
in preventing CI-AKI among 603 patients with eGFR between 30 and 59 mL/
min/1.73 m2 [33]. The overall incidence of CI-AKI was only 2.7% in patients
exposed to contrast media. The findings were explained in part by selective
recruitment of low-risk patients undergoing low-risk procedures. Contrast ad-
ministration was mostly in the context of radiology imaging with only 48% of
cases receiving contrast through intra-arterial route. An additional limitation of
AMACING includes recalculation and reduction of sample size, while the study
was ongoing and selection of a large non-inferiority margin chosen by the
investigators [21].

Intravenous sodium bicarbonate


Theoretically, sodium bicarbonate could prevent CI-AKI by alkalizing the tubu-
lar fluid and reducing the production of free oxygen radicals. However, the
results of trials and meta-analyses of their pooled outcomes comparing sodium
bicarbonate with isotonic saline have yielded conflicting but mostly negative
results [34–37]. The most recent large randomized trial, comparing isotonic
sodium bicarbonate with isotonic saline in patients with the eGFR G 45 mL/min
per 1.73 m2 undergoing elective coronary or peripheral angiography, failed to
demonstrate any significant reduction in the risk of CI-AKI [38]. Similarly,
another recent systematic review and meta-analysis, which included 19 ran-
domized clinical trials, did not show a statically significant benefit from sodium
bicarbonate when compared with normal saline [39].
The recent PRESERVE trial randomly assigned 5177 patients at high risk for
renal complications who were scheduled for angiography to receive intravenous
1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of
oral acetylcysteine or oral placebo using a 2 × 2 factorial design [40••]. The
authors found that there was no significant difference with respect to the
primary endpoint (a composite of death, the need for dialysis, or a persistent
increase of at least 50% from baseline in the serum creatinine level at 90 days)
in the sodium bicarbonate group compared with the sodium chloride group
(odds ratio 0.93; 95% confidence interval [CI] 0.72 to 1.22; P = 0.62) and with
the acetylcysteine group compared to the placebo group (odds ratio 1.02; 95%
CI 0.78 to 1.33; P = 0.88). There were also no significant between-group differ-
ences in the rates of CI-AKI. The authors concluded that there was no benefit of
intravenous sodium bicarbonate over intravenous sodium chloride or of oral
acetylcysteine over placebo for the prevention of death, need for dialysis, or
persistent decline in kidney function at 90 days or for the prevention of
contrast-associated acute kidney injury [40••].
32 Page 6 of 13 Curr Treat Options Cardio Med (2018) 20: 32

Oral N-acetylcysteine
N-Acetylcysteine (NAC) is a modified form of cysteine, a semi-essential amino
acid. NAC is a scavenger of reactive oxygen species and a nitric oxide-associated
vasodilator. Owing to these features, NAC was thought to have the potential to
prevent CI-AKI [41]. Intravenous NAC is not commonly used due to the risk of
anaphylactoid reactions [42], but the oral form of NAC is well-tolerated and
inexpensive. The possible role of NAC in preventing CI-AKI was first shown in a
small study published in 2000 [43]. However, most subsequent studies failed to
reproduce the results of the original study [44], and the results of numerous
trials and meta-analyses conducted on the role of NAC in CI-AKI prevention
have been inconsistent and contradictory [39, 45–47]. For example, the
Acetylcysteine for Contrast Nephropathy (ACT) trial randomized patients un-
dergoing angiographic procedures with at least one risk factor for CI-AKI (age 9
70 years, CKD, diabetes, heart failure, or hypotension) to receive 1200 mg of
NAC orally twice daily for 2 days or placebo. The study enrolled 2308 patients
and demonstrated similar rates of CI-AKI in the NAC and placebo groups (12.7
vs. 12.7%) [48]. Despite the absence of conclusive data, some clinicians have
elected to use NAC due to its low-risk profile and low cost. The effectiveness of
NAC in the prevention of CI-AKI will be tested again in the ongoing PRESERV
trial.

Statins
Aside from their cholesterol-reducing effects, statins can increase nitrous oxide
production, stabilize endothelium, and act as free-radical scavengers [49].
Several studies have investigated the role of statins in CI-AKI prevention. A
systematic review and meta-analysis of eight studies comparing a statin plus
intravenous saline with intravenous saline alone did not show any benefit of
statins. However, a second meta-analysis including five different studies pub-
lished in the same systematic review revealed that statins when co-administered
with NAC and intravenous saline reduced the risk of CI-AKI compared with
NAC and intravenous saline alone [39]. Two more recent meta-analyses includ-
ing 21 and 15 randomized clinical trials demonstrated promising results,
suggesting preventive role of short-term statins in CI-AKI. However, most of
the included trials in both analyses were small and often had low event rate
differences between the two comparison groups [50, 51]. In a large systematic
review and Bayesian network meta-analysis of multiple pharmacologic strate-
gies of 150 trials, and over 31,000 participants, high-dose statin plus hydration
with or without NAC was ranked the best strategy in preventing CI-AKI in
patients undergoing diagnostic or interventional procedures requiring contrast
media [52].

Forced diuresis
It has been suggested that volume administration coupled with monitored forced
diuresis might provide benefit in preventing CI-AKI. This concept is utilized in a
proprietary fluid management system (The RenalGuard™) that matches fluid
replacement to urine output. An independent systematic review and meta-
analysis of four randomized controlled trials, four prospective studies, and two
retrospective observational studies suggested that the use of the RenalGuard
Curr Treat Options Cardio Med (2018) 20: 32 Page 7 of 13 32

system in coronary and TAVR procedures significantly reduced the risk for
development of CI-AKI compared with weight-based hydration strategies [53].

Other agents
Several other pharmacological agents might have protective effects against CI-AKI.
Among these, Trimetazidine (as a cellular anti-ischemic agent) [54, 55] and Iloprost
(a synthetic analogue of a vasodilatory prostaglandin) [56, 57] have shown prom-
ising results in small clinical trials. Ascorbic acid is an antioxidant with the ability to
act as a scavenger of reactive oxygen species, reducing oxidative stress and possibly
preventing CIN. However, high-quality evidence is lacking to determine the effec-
tiveness of ascorbic acid for prevention of CI-AKI [39, 58, 59]. Future larger ran-
domized trials will help elucidate their effectiveness in CI-AKI prevention.

Radiation injury
Exposure to ionizing radiation is associated with short and long-term health
effects. The risk related to radiation exposure in cardiac catheterization labs does
not only affect the patients but can also be harmful to operators who are
repeatedly exposed to smaller amounts of radiation during each procedure,
resulting in potentially high lifetime risk. It has been shown that even low
cumulative doses of radiation exposure are associated with increased prevalence
of lenticular changes and risk of cataracts in interventional cardiology staff [60].
The risk of subclinical atherosclerosis and somatic DNA damage has been
shown to be increased with radiation exposure in interventional cardiologists
[61, 62]. Ionizing radiation can damage cell structure and DNA through differ-
ent and complex mechanisms (Fig. 1). The most concerning risk for patient and
operators is the long-term risk of cancer with radiation exposure. However,
compared with a natural background cancer incidence of about 30%, the

Fig. 1. Mechanisms of injury with ionizing radiation.


32 Page 8 of 13 Curr Treat Options Cardio Med (2018) 20: 32

potential cancer risk with cardiac procedures is expected to be very low.


Unlike CI-AKI, there is no readily available biomarker such as serum
creatinine that can be used to assess tissue level radiation effects, and
we have to rely on peripheral measurements (Table 1). Reported radia-
tion doses to patients and operators vary widely among studies. This
variability can be explained by the difference in the complexity of the
procedures, operator experience, and type and performance of X-ray
equipment. The mean reported effective dose to the patient for diagnostic
angiography and PCI are respectively 11.7 and 20 mSv (before the year
2000) and 8.4 and 13.6 mSv (after the year 2000) [63, 64].

Prevention against radiation injury


Advances in equipment and implementation of radiation safety protocols have
significantly reduced patient and operator radiation exposure. Here, we sum-
marize some of the traditional and newer interventions that have demonstrated
efficacy in reducing the exposure to radiation in the cardiac catheterization
laboratory.

Shielding
Shielding equipment such as a modified arm board, protective side lead glass
screens, radioprotective caps, and lead-free disposable radioprotective drapes
can reduce the radiation exposure to the operator [65–68]. Providing non-
physician staff members with accessory lead shields was associated with a nearly
two-thirds reduction in radiation exposure among both nurses and technolo-
gists [69].
However, shields should not be placed within the imaging field as they can
automatically trigger an increase in the radiation output of the camera. This was
demonstrated in a randomized study where use of pelvic lead shield during
radial angiography reduced operator exposure but doubled the patient dose
[70]. Additionally, these extra protections might induce a sense of security,
which in turn may lead to increased exposure time [71].

Table 1. Dose quantities

Radiation measure
Absorbed dose, It is the concentration of energy absorbed by human tissue as a result of an exposure to ionizing
milligray (mGy) radiation. The unit of measurement for absorbed does is the milligray (mGy). For example, if a
patient undergoes cardiac catheterization, the absorbed dose to the lungs is much higher than
the absorbed dose to the liver
Equivalent dose, Equivalent dose takes the damaging properties of different types of radiation into account.
millisievert (mSv) Because most type of the radiation used in medicine has the same low-harm potential, the
absorbed dose and the equivalent dose are numerically the same, but with different units
Effective dose, This calculated value takes the absorbed dose to all organs, the relative harm level of the
millisievert (mSv) radiation, and the sensitivities of each organ in to the account. It relates to the overall
long-term risk to a person from a certain procedures. It is not intended to apply to a specific
patient dose
Curr Treat Options Cardio Med (2018) 20: 32 Page 9 of 13 32

Equipment modifications
Reducing fluoroscopy and cine-angiography time and low-dose acquisition are
simple and effective methods for reducing operator and patient radiation dose.
Decreasing the fluoroscopy frame rate from 15 to 7.5 frames per second
significantly reduced the operator dose and patient irradiation by 30 and
19%, respectively [72]. Introduction of robotic systems to perform PCI can also
result in a drastic reduction in operator’s radiation exposure. The Percutaneous
Robotically-Enhanced Coronary Intervention (PRECISE) study found that ap-
plication of robotic systems resulted in 95.2% lower radiation to operators
compared to the patients [73].

Conclusion
CI-AKI and radiation injury are two major complications post-coronary
angiography and PCI. Today, despite performance of high volumes of
coronary angiography and PCI on an aging patient population with multi-
ple comorbidities, the overall reported incidence of CI-AKI seems to be
slowly declining. This trend is observed potentially due to adaptation of a
standardized definition for CI-AKI as well as implementation of pre-
procedural protocols to prevent or decrease the risk of CI-AKI. Furthermore,
among hospitalized patients, the risk of AKI in patients receiving and not
receiving contrast was similar, suggesting that the risk of acute kidney injury
attributed to contrast media exposure is lower than what was previously
assumed. Even in the subgroup of patients with acute coronary syndrome
(ACS), the incidence of acute kidney injury was higher among those who
did not receive contrast media [74]. In particular, this is an important
consideration for patients with ACS and CKD that frequently do not under-
go cardiac catheterization due to a perception of higher risk CI-AKI, despite
the fact that they would benefit the most from revascularization [75].
Despite numerous trials, the jury for the best pharmacological agent or
combination regimen is still out there.
Another possible future direction in reducing CI-AKI is to implement
system-based quality improvement strategies with the use of electronic
medical records. In a study using simple quality improvement measures
including withholding nephrotoxic medications, standardizing fluid orders,
and loosening nil per mouth restrictions, mandatory procedure delays to
ensure adequate volume status reduced the rate of contrast-induced ne-
phropathy by 20% [76]. Since the introduction of cardiac catheterization
for diagnosis and treatment of coronary disease, the advancement of equip-
ment has substantially decreased the amount of radiation exposure to both
patients and operators. However, as the aging patient population might
undergo cardiac catheterization multiple times and receive more during
prolong complex PCIs, the need for the practice of preventive measures
remains pertinent. As radial access for coronary cardiac catheterization is
becoming the standard of care, the amount of radiation received by oper-
ators will increase. For prevention of radiation injury for both patients and
operators, the implementation of effective measures, increasing awareness,
and establishing radiation protection culture have shown to be effective
measures in reducing radiation exposure [77, 78].
32 Page 10 of 13 Curr Treat Options Cardio Med (2018) 20: 32

Compliance with Ethical Standards

Conflict of Interest
Arash Ehteshami Afshar and Puja B. Parikh each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent


This article does not contain any studies with human or animal subjects performed by any of the authors.

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